Tianshu Li

Jelena Jenter

Dr Peter W Roesky
email: roesky@kit.edu

New Development in Rare Earth Metal Complexes Containing Anionic Bis(imino)pyrrolyl and Bis(phosphanyl)amide Ligands

Keywords: Rare Earth Elements, N-ligand, Coordination Compounds, Catalysis, Chelates Rare Earth Elements, N-ligand, Coordination Compounds, Catalysis, Chelates

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Bis(imino)pyrrolyl Ligands

1.1 Introduction 2,5-Bis(N-aryliminomethyl)pyrrolyl ligands are monoanionic ligands, which can be easily accessed by deprotonation of the corresponding bis(imino)pyrroles [3]. Bis(imino)pyrroles are prepared by condensation of 2,5-diformylpyrrole with the analogous anilines [4]. 2,5-Bis(N-aryliminomethyl)pyrrolyl ligands contain a pyrrolyl unit and two imino groups, which create three possible coordination sites. As shown in Scheme 1, bis(imino)pyrrolyl derivatives can act as bi-or tridentate chelating ligands to form either A or B coordination mode with a metal center [5].

Scheme 1

The coordination mode of the resulting complexes depends on the nature of the arylsubstituents of the ligand, the number of ligands coordinated, the ionic radius of the metal center and the bulkiness of additional ligands coordinated to the metal atom. 2,5-Bis(N-Page 3 of 27 Wiley-VCH ZAAC aryliminomethyl)pyrrolyl ligands have been introduced into main group and transition metals, such as aluminum [6], group 4 metals [7], chromium [8], iron [9], cobalt [9], and nickel [9]. Many of them have been used as catalysts for the polymerization of ethylene [6][7][8][9] and the oligomerization of ethylene and propylene to linear and branched products [9]. In 2001, Mashima and coworkers prepared the first rare earth metal 2,5-bis(Naryliminomethyl)pyrrolyl complexes with various aryl substituted ligands [4]. The complexes were synthesized via amine elimination reactions of [Y{N(SiMe 3 ) 2 } 3 ] with the corresponding pyrroles (Scheme 2). The reaction of the 2,6-dimethylphenyl substituted ligand with [Y{N(SiMe 3 ) 2 } 3 ] led to the mono-substituted complex 1 in which the ligand is coordinated by all three nitrogen atoms to the metal center. By using the bulkier 2,6-diisopropylphenyl substituted ligand, the bis(pyrrolyl) complex 2 was formed, in which both pyrrolyl ligands coordinate to the metal center in a bidentate fashion. The reaction of [Y{N(SiMe 3 ) 2 } 3 ] with the 2methylphenyl substituted ligand gave a 4:1 mixture of mono(pyrrolyl) complex 3a and bis(pyrrolyl) complex 3b. The reaction of 4-methoxyphenyl or 4-methylphenyl substituted ligand with [Y{N(SiMe 3 ) 2 } 3 ] afforded the homoleptic tris(pyrrolyl) complexes 4a and 4b in which the pyrrolyl ligands are bound in a tridentate fashion to the metal center. The catalytic activities of yttrium complexes 1, 2, 4a and 4b were investigated for the polymerization of ε-caprolactone (CL) [4]. The homoleptic pyrrolyl complexes 4a and 4b showed no activity, while complexes 1 and 2 were active catalysts for the polymerization of CL. The polymers obtained with 2 exhibited narrower polydispersities compared with the polymers produced by 1. The early investigation showed that 2 containing the steric demanding 2,6-diisopropylphenyl substituted ligand afforded the best catalytic activity. Our new development of the rare earth metal bis(imino)pyrrole complexes has been focused on this ligand system [5].

Alkali Metal Compounds

The rare earth metal complexes are generally synthesized by two methods: salt

) (Scheme 4) [10].

Scheme 4

The solid state structures of complexes 6 and 7 were established by single crystal Xray diffraction and showed a dimeric structure, in which two (DIP 2 pyr) -ligands are bridged by two metal atoms, forming a diamond-shaped M 2 N 2 core [11]. This structural motif is very rare in lithium chemistry and unknown for sodium compounds [5,[12][13][14].

Rare Earth Metal Complexes

Whereas the transmetallation of the lithium salt 6 with anhydrous yttrium trichloride afforded the "ate"-complex 9, the salt metathesis reaction of the potassium salt 8 with anhydrous LnCl 3 led to the neutral complexes [(DIP 2 pyr)LnCl 2 (THF) 2 ] (Ln = Y (10a), Lu (10b)) [10] and [(DIP 2 pyr)NdCl 2 (THF)] 2 (12) [15] instead (Scheme 5). The solid state structure of neodymium complex 12 is dimeric, while the chloride complexes of the smaller rare earth metal ions yttrium and lutetium are monomeric. The same product [(DIP 2 pyr)Y(C 5 H 5 ) 2 ] (11) was produced by the reaction of 2 equiv Na(C 5 H 5 ) with either yttrium complex 9 or 10a in THF at room temperature. This seems to indicate that yttrium complexes 9 and 10a have a similar reactivity, regardless of their structural difference. The crystal structures of the complexes 9, 10a, 11 and 12 showed that the (DIP 2 pyr) -ligand coordinates to the yttrium center in a tridentate fashion [5].

Page 7 of 27

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ZAAC

Scheme 5

Many rare earth metal borohydrides and their derivatives were reported as efficient catalysts for the polymerization and copolymerization of styrene [16][17][18],

isoprene [16,[19][20][21][22] and ethylene [21,23]. [Ln(BH 4 ) 3 (THF) n ] is a valuable precursor for preparing rare earth metal borohydride derivatives via salt metathesis reactions with the alkali salt of the corresponding ligand [5]. After the first rare earth metal borohydride complexes of the (DIP 2 pyr) -ligand were prepared in our group in 2009 [24], we have widely developed this catalogue of complexes [15,25]. The borohydride complexes 13- To the best of our knowledge, this coordination mode and a comparable reactivity of the BH 4 -group have not been observed before. We believe that the steric strain resulted from smaller metal center such as scandium and lutetium may cause this unusual redox reactivity [5,24].

Scheme 6

Mixed borohydride-chloride complexes are unusual in rare earth metal chemistry and were only observed in clusters [START_REF] Taube | Applied Homogeneous Catalysis with Organometallic Compounds[END_REF]. Recently, we have prepared two mixed borohydride- complexes exhibited very high activity and good cis-selectivity. By using MMAO-3A as cocatalyst, the chloro compound 12 showed a five times higher activity than those of the borohydride complex 14. The highest turnover frequency of approximately 19000 (mol of Nd) -1 h -1 was observed for compound 12 by using AlEt 3 / B(C 6 F 5 ) 3 (7.2 mmol: 100.98 µmol) as cocatalyst mixture [25].

Bis(phosphanyl)amide Ligand

Introduction

An alternative approach for stabilizing highly reactive metal centers is the use of phosphines with P-N bonds [30]. The monoanionic ligands that contain P-N units such as mono(phosphanyl)amide (PPh 2 NPh) -, bis(phosphanyl)amide (PPh 2 ) 2 N - and bis(phosphinimino)methanides have become more and more popular in rare earth metal the first homoleptic rare earth metal complexes containing only three-member ring system [36]. (PPh 2 ) 2 N -has a greater steric demanding than (PPh 2 NPh) -, thus leads to neutral homoleptic complexes. Additionally, the two PPh 2 units may allow (PPh 2 ) 2 N -to act as a dangling ligand in a catalytic transformation [37]. In this report, we only include the results related to (PPh 2 ) 2 N -ligand.

N P P N R R P N P N P Scheme 8

Rare Earth Metal Complexes

It is well known that the neutral diphosphine amine NH(PPh 2 ) 2 [38] can be used as a bridging ligand to assemble bi-or polynuclear late transition metal complexes [39][40][41][42][43].

Since we reported the first rare earth metal complexes of (PPh 2 ) 2 N -in 2002 [30,37], we have prepared various complexes containing (PPh 2 ) 2 N -.

As shown in Scheme 9, a series of homoleptic complexes [(PPh 2 ) 2 N) 3 Ln] (Ln = Y (19), La (20), Nd (21), Er (22), Sm (23), Gd (24), Dy (25)) were obtained via salt or amine elimination followed by crystallization from toluene [37,44] Within the ligand the P-N bond distance varies significantly. The 31 P NMR data shows a dynamic behavior of the ligand in solution. This is caused by rapid exchange of the two different phosphorus atoms [37,44]. The lutetium complex 26 was prepared by the salt elimination in THF followed by crystallization in THF/pentane (Scheme 9). The solid state structure of 26 reveals a seven coordination sites around the lutetium center. Other than six coordination sites are occupied by three ligands, the seventh is by a THF molecule. This result suggests the (PPh 2 ) 2 N -ligand is flexible in its coordination behavior [37]. The solid state structure of the rare earth metal complexes containing the (PPh 2 ) 2 N - group shows that the bidentate P-N ligand always coordinates to the metal center in a η 2 fashion.

Conclusion

Three types of (DIP 2 pyr) -ligand rare earth metal complexes including chlorides, borohydrides, and mixed borohydride chloride were successfully prepared and fully with a new coordination mode was isolated. In addition, the two neodymium complexes 12 and 14 were investigated as Ziegler-Natta catalysts for the polymerization of 1,3butadiene to form poly-cis-1,4-butadiene with various cocatalysts. High activity and good selectivity were achieved by using the chloride complex 12.

Mono-, bis-and tris-(PPh 2 ) 2 N -ligand rare earth metal complexes were successfully prepared and characterized. The bidentate P-N ligand coordinates to the metal center in a The Contributor hereby grants to Wiley-VCH for the duration of the statutory term of copyright protection, the full and exclusive rights comprised in the Contribution including but not limited to the right to publish, republish, transmit, sell, distribute, store and process in electronic media of any kind, include in document delivery services and otherwise use the Contribution in whole or in part in electronic and print editions of the Journal and in derivative works throughout the world, in all languages and in all media of expression now known or later developed, and to license or permit others to do so. b. The right to transmit, print and share copies with colleagues. a. Copies for colleagues. The personal right of the Contributor only to send or transmit individual copies of the final published version to colleagues upon thei r specific request provided no fee is charged, and further-provided that there is no systematic distribution of the Contribution, e.g. posting on a listserve, website or automäted delivery For those Contributors who wish to send high-quality e-prints, purchase reprints, or who wish to distribute copies more broadly than allowed hereunder (e.9. to groups of coileagues or mailing lists), please contact the publishing office. 2. In addition to the rights specified as retatned in paragraph B above and the rights granted back to the Contributor pursuant to paragraph C above, Wiley-VCH hereby grants back, without charge, to such company/employer, its subsidiaries and divisions, the right to make copies of and distribute the final published Contribution internally in print format or electronically on the Company's internal network. Copies so used may not be resold or distributed externally. However the company/employer may include information and text from the Contribution as part of an information package included with software or other products offered for sale or license or included in patent applications.

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  Scheme 2

3 Treatment of 5

 35 Scheme 3

  amido and the pyrrolyl unit to the metal center. The N-BH 3 unit coordinates in a η 2fasion via two hydrogen atoms to the metal center. The resulting products [{(DIP)(DIP-BH 3 )pyr}Ln(BH 4 )(THF) 2 ] (Ln = Sc (15), Lu (16)) are shown in Scheme 6. During the ligand reduction process, the symmetry of the ligand in 15 and 16 was broken. The η 2coordination mode of the =N-BH 3 moiety and the η 3 -coordination mode of the BH 4 ligand in complexes 15 and 16 were confirmed in the solid state by single crystal X-ray diffraction as well.

  Scheme 7

  8)[31][32][33][34][35]. In 1999, we prepared the first rare earth metal ate complexes of mono(phosphanyl)amide [(PPh 2 NPh) 4 Ln] -(Ln = Y, Yb, Lu). The anionic bidentate P-N ligands are coordinated to the metal center in a η 2 fashion. They are also

2 (

 2 . The precursor [K(THF) n ][N(PPh 2 ) 2 ] (n = 1.25, 1.5) was prepared by treating NH(PPh 2 ) 2 with KH in THF. The salt elimination reaction of anhydrous LnCl 3 and [K(THF) n ][N(PPh 2 ) 2 ] in 3:1 Page 12 of 27 Wiley-VCH ZAAC molar ratio in THF led to the complexes 19, 22-25. The amine elimination reaction of [Ln{N(SiMe 3 ) 2 } 3 ] and 3 equiv of NH(PPh 2 ) 2 afforded the complexes 19-21, 23. The single X-ray structure showed that the complexes 19-25 are iso-structural. Three η PPh 2 ) 2 N -ligands are coordinated to a metal center in a trigonal prismatic geometry.

  Scheme 9

  characterized. The borohydride complexes are the first examples of rare earth metals borohydride complexes containing the (DIP 2 pyr) -ligand. An unusual redox reaction of a BH 4 -anion with the Schiff-base function of the ligand was observed for the smaller rare earth metal complexes. As product [{(DIP)(DIP-BH 3 )pyr}Ln(BH 4 )(THF) 2 ] (Ln = Sc, Lu)

η 2

 2 fashion in all the cases. The homoleptic tris-(PPh 2 ) 2 N -ligand complexes 19-22 are highly active catalysts for the polymerization of CL. The neodymium complex 21 showed remarkable narrow polydispersity. Rare earth element complexes having the very bulky 2,5-bis{N-(2,6diisopropylphenyl)iminomethyl}pyrrolyl, and the sterically less demanding bis(phosphanyl)amide ligand, (PPh 2 ) 2 N -, in the coordination sphere are reviewed.

2 . 3 .

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Page 8 of 27 Wiley-VCH ZAAC 16 were

		synthesized by reacting 8 with [Ln(BH 4 ) 3 (THF) n ] (Ln = Sc, n = 2; Ln = La, Nd,
	Lu, n = 3) in THF at 60 °C. The reaction of 8 with the larger rare earth metal
	trisborohydrides [Ln(BH 4 ) 3 (THF) 3 ] (Ln = La, Nd) led to [(DIP 2 pyr)Ln(BH 4 ) 2 (THF) 2 ] (Ln
	= La (13), Nd (14)). One borohydride ligand was eliminated to form KBH 4 as a
	byproduct (Scheme 6). The single crystal X-ray crystallography of 13 also confirmed that
	the BH 4	-groups are η 3 -coordinated. On the contrary, the smaller rare earth metal
	trisborohydrides [Ln(BH 4 ) 3 (THF) n ] (Ln = Sc (n = 2), Lu (n = 3)) underwent a redox
	reaction between one BH 4 -group and one of the Schiff-base functions of the ligand. As a
	result, a dianionic ligand containing a N-BH 3 unit was formed and coordinates via the

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Acknowledgement

This work was supported by the Deutsche Forschungsgemeinschaft (DFG Schwerpunktprogramm (SPP 1166): Lanthanoidspezifische Funktionalitäten in Molekül und Material.

Scheme 15

In 2004, we reported several bis (PPh 2 ) that the steric demand of (PPh 2 ) 2 N -ligand is similar to Cp ring [48].

Biographical


Sjoerd Harder
email: s.harder@rug.nl

Benzyllanthanide Chemistry: Revival of Manzer's ortho-Me 2 N-Benzyl Ligand

Keywords: lanthanide, benzyl lanthanide, benzyl, synthesis

The Manzer benzyl ligand, ortho-Me 2 N-benzyl (DMA), has been introduced in lanthanide (Ln) chemistry more than three decades ago with the syntheses of Sc(DMA) 3 and Er(DMA) 3 but no reaction chemistry or structures have been described. Only recently it was shown that a Ln(DMA) 3 complex can also be obtained for the largest Ln metal La and first crystal structures appeared. At present crystal structures of many Ln(DMA) 3 complexes throughout the series have been determined and were found to be isomorphous. This reports describes the improvement of synthetic methods for Ln(DMA) 3 complexes, a discussion on structures and trends and more important, the wide scope of Ln(DMA) 3 reagents as versatile building-blocks in lanthanide chemistry: the fast-growing number of complexes and catalysts that have been made starting from a Ln(DMA) 3 reagent are summarized. Despite the intramolecular chelating Me 2 N-arm, half-sandwich catalysts containing the DMA fragment are still active in alkene polymerizations or other catalytic conversions. The main advantages of Ln(DMA) 3 complexes are: i) easy syntheses from commercially available starting materials, ii) convenient crystallization which warrants high purity, iii) high stability on account of intramolecular coordination while sufficient reactivity for further conversions is maintained and iv) availability of these reagents over the full Ln range which is advantageous for catalyst screening.

Introduction

The benzyl ligand plays an important role throughout organometallic chemistry. It is popular in early main group chemistry as a resonance-stabilized carbanion. Charge delocalization reduces extreme reactivity and facilitates handling to a level that is sufficient for most applications. The benzyl ligand is similarly popular in transition metal chemistry. As it does not possess any β-hydrogen atoms, it prevents decomposition by β-hydrogen elimination. Manzer et al. introduced the benzyl ligand in organolanthanide chemistry (for convenience we abbreviate "lanthanide" with Ln and define this group as the elements Ce-Lu and include the group 3 metals Sc, Y and La) [1][2][3][4]. They used a ligand with a "built-in" chelating Me 2 N group that insures additional stabilization (1). Thus the complexes Sc(DMA) 3 and Er(DMA) 3 have been prepared already at an early stage in the development of organolanthanide chemistry (DMA = o-Me 2 N-benzyl).

Considering their ease of preparation from commercially available precursors, it is surprising that this chemistry never achieved much further attention. In this respect, it should be noted that the most common, highly reactive, organolanthanide precursors were based on the (Me 3 Si) 2 CH and (Me 3 Si)CH 2 ligands. Homoleptic complexes with these ligands are not always available for the larger lanthanide metals and generally show high air and thermal sensitivity [5][6][7][8]. In 2003 the synthesis of Nd(DMA) 3 appeared in a patent [9], but up to then no crystal structure data of any Ln(DMA) 3 complex was available. In 2005 we showed that the early work of Manzer could be applied to the largest of all lanthanide metals and reported the synthesis and crystal structure of La(DMA) 3 [10]. The same paper describes also synthesis and structure of Y(DMA) 3 , a complex with one of the smallest lanthanide metals. As both crystallize isomorphous, it was anticipated that these complexes would be easily available over the whole lanthanide range.

It was questioned whether the Ln metals in these Ln(DMA) 3 complexes, which are stabilized by intramolecular coordination, would still be accessible for further reactivity. In addition, functionalization by ligand deprotonation would form an amine by-product (DMA-H) which possibly could coordinate or disturb further reactivity. However, it could be shown that the least reactive Y(DMA) 3 complex can be easily converted to a constrained geometry catalyst which under hydrogen pressure reacted further to a dimeric hydride complex that does not contain the original DMA ligand or any of the amine side-product DMA-H (Scheme 1).

Scheme 1.

Despite the unproblematic functionalization of Ln(DMA) 3 complexes, benzyllanthanide complexes that do not contain intramolecularly chelating side-arms (2) have been introduced and were prepared according to the same synthetic route, i.e. reaction of benzylpotassium precursor with a lanthanide(III) halide salt. Hessen et al. and our group reported syntheses and crystal structures of the following compounds: La(benzyl) 3 [11], La(para-Mebenzyl) 3 [11], La(para-tBu-benzyl) 3 [12] and Y(benzyl) 3 [12]. All crystallize as THF-adducts of general formula Ln(Bn) 3 •(THF) 3 with distorted octahedral metal coordination environments. The three benzyl ligands, as well as the three THF ligands, are in a facial arrangement. It is not clear why the negatively charged benzyl ligands are in close proximity.

Five years after the report on the syntheses and structures of La(DMA) 3 and Y(DMA) 3 [10], many intermediate members in the Ln(DMA) 3 family have been prepared and were shown to form isomorphous crystals [12][13][14]. Although this series of complexes is not as reactive as the unstabilized Ln(Bn) 3 complexes, they are reactive enough for further functionalization (vide infra). There seems to be a good compromise between stability (ease of handling) and reactivity (functionalization/catalysis). This manuscript gives a short overview on the syntheses, structures, trends, reactivity and use of Ln(DMA) 3 complexes.

Results and Discussion

Syntheses

Complexes Ln(DMA) 3 can be obtained by simple metathesis between LnCl 3 and three equivalents of the alkali metal salt of the DMA anion. Manzer's original synthetic procedures for Sc(DMA) 3 and Er(DMA) 3 made use of Li(DMA) and complexes could be obtained in yields of 81 % and 44 %, respectively [2,4]. Likewise, Nd(DMA) 3 was obtained by metathesis with Li(DMA) in 40 % yield [9]. ]. This is especially a problem for large Ln metals that possess considerably sized coordination spheres. For this reason we chose to use the potassium reagent K(DMA) which would produce the much less soluble KCl and avoid contamination of the product with alkali metal salts. Reaction of the appropriate LnCl 3 with three equivalents of K(DMA) gave Y(DMA) 3 and La(DMA) 3 in crystallized yields of 59 % and 41%, respectively (the yields of the raw products were 92 % and 85 %, respectively) [10]. Complexes with other Ln metals like Yb, Tm, Sm, Nd, Dy, Ho were made by the same procedure and have been isolated in crystalline purity in yields between 21 % and 40 % (these yields are based on unoptimized small scale synthetic procedures, < 1 mmol) [12,19].

Hou et al published a modified procedure for the synthesis of La(DMA) 3 in which LaBr 3 is used instead of LaCl 3 . This increased the crystalline yield from 41 % up to 87 % and gave good yields for other metals like Pr and Nd (92 % and 83 %, respectively) [14]. It was further found that reaction of LnCl 3 precursors with Li(DMA) also gave satisfactory crystalline yields for the metals Y (75 %), Sm (92 %), Gd (85 %) and Lu (77 %) [14]. Also Xie et al report that Y(DMA) 3 and Er(DMA) 3 have been prepared from LnCl 3 and Li(DMA) in yields of 81 % and 55 %, respectively [20]. It is therefore not a necessity to use K(DMA); Li(DMA) conveniently can be used instead. Apparently formation of "ate" complexes is not an issue for Ln(DMA) 3 complexes. This is likely due to the three chelating Me 2 N-substituents which block the metal for further interactions with halide ions. This is supported by crystal structures of these complexes (vide infra). The ease of crystallization of Ln(DMA) 3 facilitates the isolation of these complexes in high purity and is an added advantage to the use of this precursor. Despite these factors, in cases where it is crucial to obtain absolute halide free Ln(DMA) 3 , the use of K(DMA) is highly recommended.

Attempted synthesis of Eu(DMA) 3 by the same established salt metathesis route, i.e. reaction of EuCl 3 with K(DMA), led to the formation of an orange-brown powder that is insoluble in common polar solvents [19]. As the mother liquor contained considerable quantities of the C-C coupled DMA-DMA, (ortho-Me 2 N-C 6 H 4 CH 2 ) 2 , it is presumed that oxidation of the DMA anion is accompanied by spontaneous Eu(III) Eu(II) reduction. Considering the low reduction potential of -0.35 V (E 1/2 Eu 3+ /Eu 2+ [22]), this is a likely process. The product of this reduction process, Eu(DMA) 2 , could be a coordination polymer on account of the much larger ionic radius for Eu 2+ (1.20 Å, cf. Eu 3+ 0.95 Å; both for 6-coordinate metal ions) [22].

Hitherto, Ln(DMA) 3 complexes of nearly all 17 lanthanide metals have been prepared by a very similar salt metathesis route. So far, only Ce, radioactive Pm, Tb and Eu are missing. All complexes show excellent solubility in aromatic solvents and are remarkably stable. Toluene solutions of Y(DMA) 3 that are kept at 20 °C show after one year only minor decomposition (< 5 %). Keeping a solution overnight at reflux temperature, also hardly gives any decomposition. This contrasts with the stability of the unchelated benzyllanthanide complexes: THF solutions of Ln(Bn) 3 •(THF) 3 darken within hours at room temperature.

The exact nature of this decomposition reaction has not been established but it has been proposed that carbene-like intermediates (Bn)Ln=CHPh are formed by α-elimination [23].

Structures and Trends

The hitherto structurally known Ln(DMA) 3 complexes crystallize isomorphic in the monoclinic space group P2 1 /c. The molecular structures show a paddlewheel geometry in which the metal has a distorted trigonal prismatic coordination geometry (Figure 1). The three Me 2 N substituents are not arranged in a facial geometry but surround the metal in a planar trigonal conformation. The potential three-fold symmetry of the molecule is broken by "up-side-down" coordination of one of the chelating DMA ligands. This asymmetry is likely caused by repulsion between the more sterically demanding Me 2 N-substituents. The crystal structures also show that part of the aryl ring is coordinated to the Ln metal (C ipso and C ortho ). This side-on benzyl-Ln interaction is especially important for the larger metals like La. The Ln-C and Ln-N bond distances naturally increase with metal size, however, the increment in Ln-C bond distances is much steeper than that for the Ln-N bond distances (Figure 2). The 0.150(3) Å difference between the longest (La) and shortest (Yb) Ln-N bonds agrees well with the difference of 0.164 Å in their ionic radii. The difference between their respective Ln-C α bonds, 0.226(3) Å, is significantly larger. Additional lengthening of the Ln-C bonds with metal size, is explained by the increasing importance of benzyl side-on coordination. The graph in Figure 2 shows that the average Ln•••ring contact (C ipso , C ortho ) hardly increases with metal size (0.061(3) Å), i.e. this contact becomes more important for the larger metals.

Typical for benzyl ligands in polar organometallic compounds is delocalization of the negative charge on the benzylic carbon into the aryl ring. The extent of delocalization is highly dependent on the nature of the metal. The importance of charge delocalization decreases with increasing metal Lewis-acidity. Small, highly charged, cations polarize the negative charge on the benzylic carbon atom. Much weaker Lewis-acids, like the larger alkali metal ions, lead to extensive charge delocalization of which the extent can be qualitatively estimated by several structural or spectroscopic features. It is well-known that the C α -C ipso bond distance decreases with increasing importance of delocalization [24]. This goes hand in hand with aryl ring distortions: the endocyclic angle at C ipso is squeezed considerably. Although these features are also present in the structures of Ln(DMA) 3 complexes, the change in Lewisacidity from La 3+ to Yb 3+ is too small for a clear correlation between aryl ring distortion and metal size. In line with increased Lewis-acidity (and decreased charge delocalization) the endocyclic C-C-C angle increases from 115.0(2)° (La) to 115.5(3)° (Yb) and the C α -C ipso bond distance increases from 1.432( 4) Å (La) to 1.454( 5) Å (Yb). However, with the relatively large standard deviations, differences are too small to be significant. The extent of charge delocalization is also connected to the hybridization state of the benzylic carbon which can be evaluated by the sum of the valence angles at this atom and should be dependent on metal size (Scheme 2). As the hydrogen atom positions in the crystal structures of Ln(DMA) 3 could not always be reliably established, this parameter does not provide precise information on the hybridization of C α . However, the 1 J CH coupling constants at C α correlate with its hybridization and some information could be obtained from these. In La(DMA) 3 and Y(DMA) 3 , these coupling constants measure 142.8 Hz and 133.2 Hz, respectively [10]. Thus, the benzylic carbon in La(DMA) 3 is somewhat less pyramidalized than that in Y(DMA) 3 . This is in agreement with more ionic bonding and more extensive charge delocalization in the La complex.

Another probe for charge delocalization is the 1 H NMR chemical shift for the ring proton in para-position of the benzylic carbon. The shift for this hydrogen atom is highly sensitive to the nature of the metal cation. Large, soft electropositive metal cations result in extensive charge delocalization and cause a significant high-field shift of this signal. For ortho-Me 2 N-a-Me 3 Si-benzylmetal compounds the following shifts have been measured (ppm): 5.77 (K + ) [25], 6.29 (Li + ) [19], 6.33 (Ca 2+ ) [25], 6.36 (Yb 2+ ) [26]. Whereas the K complex shows an unusually low chemical shift for an aryl proton, the smaller Li + localizes the negative charge much more on the benzylic carbon. For the compound with the larger Ca 2+ , the increased 2+ charge counterbalances the size effect and a similar chemical shift is found as for the Li compound. It is interesting to note that the Yb 2+ and Ca 2+ complexes show very similar chemical shifts. This is in line with their similar ion sizes (1.02 Å vs 1.00 Å) [22]. Therefore, Yb(II) complexes show very similar structures and properties as their analogous Ca compounds [26]. In the series of Ln(DMA) 3 complexes, we compared the chemical shifts of this para-H atom for the metals Y 3+ and La 3+ . The values of 6.66 (Y 3+ ) and 6.43 (La 3+ ) indicate that the latter is significantly more ionic (and reactive). Thus, the chemical shift for the para-H atom, as well as the 1 J CH coupling constant, are much more sensitive probes for ionicity (charge delocalization) as structural distortions in the aryl ring.

Scheme 2

Conversions and Applications

From the early work of Manzer on Sc(DMA) 3 and Er(DMA) 3 [1][2][3][4], it was not clear what the synthetic potential of these complexes is. The 2003 patent on the use of Nd(DMA) 3 in butadiene polymerization also does not describe further reaction chemistry [9]. The Nd(DMA) 3 itself is activated with non-hydrolytic methyl alumoxane (i.e. Me 3 Al-poor PMAO-IP) and produces polybutadiene with a high cis-1,4-content [9]. Our earlier study described the reactivity of Y(DMA) 3 with a combined fluorene-amine ligand and its subsequent conversion with hydrogen (Scheme 1). This demonstrates that the Ln-DMA functionality is highly reactive. Protection of the metal center by intramolecular Me 2 N-Ln coordination apparently does not diminish its synthetic potential and even H 2 , with a pK a value of circa 35 [27,28], could be efficiently deprotonated. As Y is one of the smaller Ln metals, the Hou et al. showed that Sc(DMA) 3 also efficiently reacts with a combined cyclopentadiene-amine ligand and a constrained geometry catalyst of type 5 (Scheme 3) could be isolated [14]. Access to Ln(DMA) 3 complexes over the full Scheme 3 range of the Ln series enabled the syntheses of 5 with various metals (La, Pr, Nd, Sm, Gd, Lu, Y and Sc). This series of catalysts was tested in the addition of the phosphine P-H bond to carbodiimides and allowed screening of the metal size: an increase in the size of the metal results in increased activity. The same type of catalysts has shown good activity in the cross-coupling of various alkynes with isocyanide and shows an unprecedented Z-selectivity [29]. Catalysts of type 5, which contain the DMA ligand as the active part, showed the same activity as similar catalysts with CH 2 SiMe 3 as the active group. This demonstrates that the activity of DMA-containing catalysts is not significantly affected by the initially chelating benzyl fragment.

The compound Sc(DMA) 3 was also shown to react with differently substituted Cp'H compounds and is a convenient precursor for half-sandwich complexes of the type Cp'Sc(DMA) 2 (6, Scheme 3) [30]. Although these complexes have been prepared in THF, the products are THF-free on account of the chelating side-arms. These halfsandwich complexes have been further activated by reaction with Ph 3 C + /(C 6 F 5 ) 4 B and one of the products, [(Me 3 Si)Me 4 Cp]Sc(DMA) + /(C 6 F 5 ) 4 B (type 7), could be characterized by X-ray diffraction [30]. It represents the first example of a cationic rare-earth metal species that is free of external Lewis-bases. It was questioned whether intramolecular Me 2 N-coordination would inhibit its activity for olefine polymerization, however, 7 could initiate the polymerization of a variety of olefins such as ethylene, 1hexene, styrene, norbornene (NB) and dicyclopentadiene (DCPD). More remarkably, it could copolymerize 1-hexene with NB or DCPD to give random copolymers. This demonstrates that the DMA ligand is an excellent scaffold for the stabilization of external-Lewis-base-free cationic Ln species. The coordinating side-arm does not hinder olefine coordination and polymerization and apparently walks away from the metal during the progress of the polymerization reaction. External THF ligands would continuously coordinate to the metal site and seriously hinder the polymerization reaction. Similar Cp'Sc(DMA) 2 (6) complexes have been used as catalysts for the carboalumination of alkoxy substituted alkynes or alkenes and display unique regio-and stereoselectivity [31].

Half-sandwich complexes could also be obtained by the in situ reaction of Sc(DMA) 3 with a sterically hindered phosphole (8) [32]. The resulting compound, which could not be obtained by the alternative salt metathesis route, was activated with Ph 3 C + /(C 6 F 5 ) 4 B and found to be an excellent catalyst for syndiospecific styrene polymerization. Reaction of various Ln(DMA) 3 complexes with a similar sterically hindered pyrrole gave the analogous complex (9) which is also active in syndiospecific styrene polymerization [33]. The availability of a set of catalysts (Ln = Sc, Y, La) allowed for screening of the effect of metal size: activities increase with decreasing metal size along the row La < Y < Sc. Use of a less sterically hindered phosphole gave the η 1 edge-on coordinated complex 10 which is inactive in styrene polymerization [33]. This demonstrates the importance of η 5 face-on coordination of the ligand for catalyst activity.

Reaction of Y(DMA) 3 with a sterically hindered amidine gave access to the amidinate complex 11 (Ln = Y) [34]. Once activated with Ph 3 C + /(C 6 F 5 ) 4 B, it polymerizes isoprene with high 3,4-regioselectivity and some isotacticity (mm ≈ 50%). Reaction of 11 with excess Me 3 Al led to exchange of the DMA ions for Me 4 Al ions. Interestingly, subsequent activation with Ph 3 C + /(C 6 F 5 ) 4 B gave a switch in selectivity and largely 1,4-cis-polyisoprene was isolated (up to 98% selective) [34,35]. The analogous Sc complex of 11 has been used for the synthesis of a cyclized polyisoprene [36]. Other conversions of Ln(DMA) 3 complexes include the reactions with an indene ligand that contains a chelating arm with the bulky anion cage 1,2-closo-B 10 C 2 H 10 (12, Ln = Sc or Er) [21], with a partially hydrogenated fluorene ligand (13, Ln = Sc) [37] or with a cyclopentadiene ligand containing a pendant arm (14, Ln = Sc or Y) [37]. Activation of the Sc complex 14 with MAO gives a catalyst that is active for ethylene/1-hexene copolymerization or for the polymerization of lactones. Activation of 14 with Al(iBu) 3 and Ph 3 C + /(C 6 F 5 ) 4 B gives a catalyst for ethylene/styrene copolymerization (the ratio PE/PS can be effectively tuned by ethylene pressure). The latter catalyst also allows for the synthesis of PE/PS block-copolymers in which PS blocks have significant syndiotacticity [37].

Reaction of Ln(DMA) 3 with sulphur bridged biphenol compounds gave complexes of type 15 (Ln = Sc, Y) [38]. Activation with MAO resulted in catalysts for the polymerization of ethylene or for copolymerization of ethylene and 1-hexene.

Reaction of Ln(DMA) 3 complexes with superbulky cyclopentadiene (Ar 5 CpH, Ar = 4-nBu-C 6 H 4 ; abbreviated in here as Cp BIG H) has been investigated [39]. For Ln = Y the half-sandwich complex of type 6 was obtained: Cp BIG Y(DMA) 2 . This demonstrates that the less reactive Y(DMA) 3 efficiently deprotonates the superbulky Cp BIG H ligand. For Ln = Yb and Sm, however, spontaneous reduction to the metallocene (Cp BIG ) 2 Ln has been observed [39]. As the reduction potential for Sm is highly negative (E 1/2 Sm 3+ /Sm 2+ = -1.55 V) [22], this spontaneous metal reduction should be considered remarkable (especially when one considers that Cp* 2 Sm is oxidized by N 2 [40]). The detection of large amounts of the C-C coupled DMA-DMA, (ortho-Me 2 N-C 6 H 4 CH 2 ) 2 , indicates that the mechanism of formation could be sterically induced (SIR) [START_REF] Evans | chemistry at the university of Groningen. His current research interests include: catalysis with early main group organometallics, hydrogen elimination[END_REF].

Conclusions

The early work of Manzer has produced Ln(DMA) 3 complexes of the metals Sc and Er. This chemistry has been revived three decades later with the syntheses of the Ln(DMA) 3 complexes containing either one of the smallest Ln metals, Y, or the largest Ln metal La. The crystal structures of these two complexes are isomorphous and suggested that the whole series would crystallize similar. With few exceptions, Ln(DMA) 3 complexes over the whole metal size range have been obtained: Sc, Y, La, Pr, Nd, Sm, Gd, Dy, Ho, Er, Tm, Yb and Lu. These complexes indeed all crystallize isomorphous. The DMA ligand represents the first (resonance-stabilized) alkyl system that allows access to highly reactive lanthanide precursors for the complete Ln series. Optimization of synthetic procedures has led to convenient methods for their syntheses from cheap commercially available starting materials. As all Ln(DMA) 3 complexes crystallize nicely in the form of large blocks, the purity of the final products is warranted.

The availability of Ln(DMA) 3 complexes over the whole series does not only allow for a discussion of trends in their molecular structures but also for screening of metal size effects in catalysis. All Ln(DMA) 3 complexes can be easily converted by reaction with mono-protic (LH) or diprotic (LH 2 ) ligands and various products LLn(DMA) 2 or LLn(DMA) have been routinely obtained. Bulky ligands do not pose a problem and H 2 can be deprotonated to give a Ln-H functionality.

The catalytic behaviour of the resulting complexes is not negatively influenced by the presence of the intramolecular chelating Me 2 N-arm. In contrast, this chelating substituent allows for isolation of compounds that are free of external Lewis-bases like THF. In the time frame 2007-2010, DMAcontaining complexes have emerged as efficient catalysts for the polymerization of a wide variety of monomers. The system is also increasingly popular for other catalytic conversions like the hydrophosphination of carbodiimides, carboalumination of alkoxy substituted alkynes (or alkenes) and cross-coupling of various alkynes with isocyanides. The fast-growing number of patents which make use of Ln(DMA) 3 precursors, shows that interest is not only academic. In conclusion, the Manzer ligand system has been shown to be very versatile in Ln chemistry and its rapid progress during the last few years promises an even brighter future.

Figure 1 .

 1 Figure 1. Crystal structure of La(DMA) 3 . All other Ln(DMA) 3 structures are isomorphous and show slightly different Ln-C α and Ln-N bonds as well as a less pronounced side-on coordination of the aryl ring (Ln-C ipso and Ln-C ortho ).

Figure 2 .

 2 Figure 2. Trends for the Ln-C, Ln-N and Ln•••ring contacts in the series of Ln(DMA) 3 complexes.

  DMA) 3 complexes are expected to be even more reactive. Only Sc(DMA) 3 might show lower reactivity.

  The use of Li reagents generates LiCl which could complicate isolation of the product. First of all, LiCl dissolves well in organic solvents, especially in the presence of polar ethereal cosolvents like Et 2 O and THF. As is often

	seen in lanthanide chemistry [15-18], reaction of a LnCl 3	tBuNH
	with an organolithium reagent RLi can result in formation of "ate" complexes like [LnR 3 Cl x x-][Li + ] x or [LnR 4 -][Li +	Me 2 Si	H	Me 2 N H Y tBuN	THF H
									Me 2 Si
								Y(DMA) 3	THF, -2 DMA-H
									3
									SiMe 2
									THF THF	Y	NtBu
								0.5	tBuN H	Y	H	THF THF	+ H 2 (10 bar), THF -DMA-H
									Me 2 Si
									4
					R
		Me
		N	Me			THF
	H 2 C		CH 2	H 2 C		CH 2
	CH 2	N Ln	N Me	Me	THF	CH 2 Ln	THF	R
		Me Me				R = H, Me, tBu
				R
	1, Ln(DMA) 3	2, Ln(Bn) 3 •(THF) 3

Acknowledgement

S. Harder acknowledges the Deutsche Forschungsgemeinschaft for generous support within the framework of the high priority program SPP1166 "lanthanide-specific functionalities in molecule and material". ____________


Liliana Montella
email: lilianamontella@libero.it

Raffaele Addeo

Giovannella Palmieri

Michele Caraglia

Gregorio Cennamo

Bruno Vincenzi

Rosario Guarrasi

Rosanna Mamone

Vincenzo Faiola

Nicola Frega

Del Prete

Addeo Raffaele

Zoledronic acid in the treatment of bone metastases by hepatocellular carcinoma: a case series

Keywords: Zoledronic acid, bone metastases, liver, hepatocellular carcinoma, bisphosphonate

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide in terms of incidence 1 . Only 30% of HCC are diagnosed in early stage and can be treated with potentially curative treatments, while the majority of tumors are diagnosed when advanced, has limited chances of care and a dismal prognosis, less than one year of mean survival if left untreated. Treatment options and outcome of HCC patients ultimately depend on tumor extension and the severity of underlying liver cirrhosis.

Multimodality treatment of liver lesions prolonged survival 2 and recent introduction of biologic treatments gave a real chance of prolonged disease control 3 . Moreover, the available diagnostic tools increased both the rate of small HCC detected and extrahepatic metastatic sites. In this new scenario, metastatic disease is increasingly disclosed. The most common sites are the lung, abdominal lymph nodes and bones 4 .

Autopsy series have shown that bone metastases followed lung and adrenal secondary lesions 5 . Bone metastases are reported less frequently than lung and lymph node metastases, i.e. 2-20% as compared to 37-70% and 23-45%, respectively 6 . The most frequent sites of bone metastases are spine, pelvis, ribs and skull in that order 7 .

Approximately half of patients with solid tumors metastasizing to bone experience one or more skeletal events (including pathologic fractures, spinal cord compression, radiotherapy or surgery to bone, and hypercalcemia) during the course of their disease 8 . In a study evaluating the prognosis of HCC patients with metastatic disease, bone metastases were not significantly influent in the outcome of patients. In fact 90% of patients with bone metastases only as extrahepatic disease died from hepatic causes and none patients died from extrahepatic disease 9 . Single bone lesion was associated with a favorable outcome, while multiple bone lesions may be associated with severe pain and increasing rate of leukopenia, anemia and thrombocytopenia, making sometimes difficult radiotherapy administration. In fact, bone involvement by tumor may contribute to multifactorial pathogenesis of pancytopenia in HCC patients. When spine is involved, clinical presentation may be critical and require prompt intervention 6 .

Moreover, bone metastases may cause pain, discomfort and functional inability.

Representing both a manifestation of systemic disease as well as causing localized symptoms, bone metastases require a multidisciplinary therapeutic approach.

Treatment of bone metastases is based on radiotherapy on bone lesions especially if painful and/or critical for impending fractures. Radiation therapy provides both localized and systemic treatment options in addition to chemohormonal therapies and surgery 10 . Bisphosphonates delay cancer-related skeletal complications in patients with bone metastases 11 . Radionuclide therapy is shown to be useful and costeffective in relieving bone pain in metastatic disease and may be more effective when combined with chemotherapy, bisphosphonates and radiation therapy 12 .

Zoledronic acid is a highly potent new-generation bisphosphonate proven effective in the treatment of bone metastases secondary to all solid tumor types and bone lesions from multiple myeloma based on the results of three large, randomized, phase III clinical trials enrolling more than 3,000 patients 8 . Differently from breast cancer and myeloma, no guidelines have been developed for patients with bone metastases by solid tumors other than breast cancer. Therefore, treatment with zoledronic acid at the first diagnosis of metastatic bone disease is a reasonable approach 8 . Administration of zoledronic acid is generally safe when the patients are monitored for the risk of renal toxicity and osteonecrosis of the jaw.

Following we describe the pattern of presentation and treatment of bone metastases in 17 advanced HCC patients which were evaluated among more than 50 patients come at our observation. In particular, the use of zoledronic acid in these patients is presented.

METHODS

Between December 2006 and July 2008, we recruited 17 (male:female, 12:5) consecutive HCC patients presenting with bone metastases (table 1). Patients were required to have HCC confirmed by biopsy or diagnosed by clinical criteria (hypervascular liver masses more than 2 cm and alfafetoprotein more than 400 ng/dL) and bone metastases confirmed by bone biopsy or demonstrated by at least two radiographic methods (bone scintigraphy and Computed Tomography (CT) or Magnetic Resonance Imaging (MRI)). Adequate renal function defined as a serum creatinine level <1.5 ULN was required together with a serum calcium level revised by albumin levels >8.0 mg/dL. In particular creatinine clearance (Cr Cl) was calculated for each patient. Moreover, all patients were screened for potential risk factors of osteonecrosis of the jaw. The patients were clinically evaluated and monitored by biochemistry every month. The study protocol was approved by Local Ethical Committee and every patient gave written informed consent prior to study entry. No funding source was provided.

Bone metastases were monitored by CT and/or MRI every six months. Exclusion criteria included previous radiotherapy on bone metastasis until four weeks before starting zoledronic acid, an advanced second primary malignancy, significant medical comorbidities, clinically significant cardiovascular disease including uncontrolled hypertension, myocardial infarction and unstable angina, NYHA grade II or greater congestive heart failure, history of active bleeding. Zoledronic acid was started at the diagnosis of bone metastases and administered monthly according to Cr Cl. The administered dosages were the following: 4 mg if basal Cr Cl was upper than 60 mL/min; 3.5 mg if Cr Cl was 50-60 mL/min; 3.3 mg for Cr Cl of 40-49 mL/min; 3 mg for Cr Cl of 30-39 mL/min. Zoledronic acid was diluted in 100 mL of physiologic solution and administered in 15 minutes. All patients received 500 mg calcium supplemented with 400 IU of vitamin D daily and eventual intravenous calcium gluconate administration if needed.

Pain assessments were conducted at baseline, and after three infusions using a 100-mm visual analog scale (VAS) and analgesic consumption recorded at each examination.

A descriptive analysis was performed using the mean values of each variable and the corresponding inferior and superior standard deviation (SD). Kruskal-Wallis one-way analysis of variance by ranks was used to compare medians among groups of variables with non parametric and independent distribution (such as the narcotic score between groups) [START_REF] Kruskal | Use of ranks in one-criterion variance analysis[END_REF].

The overall survival (OS) time was calculated as the period from the date of starting treatment until death from any cause or until the date of the last follow-up, at which point data were censored. OS was both determined by Kaplan-Meier product-limit method 14 .

RESULTS

Five females and twelve males presenting with bone metastases were treated with zoledronic acid. Median age of the patients was was 68 years (age range: 62-85 years).

ECOG performance status was 0-2. Underlying HCV infection was detected in all patients but four. In one patient no causative agent was identified, one patient had ethanol abuse was considered responsible for chronic live r damage, in two cases double 12.255 months). All treated patients appeared to benefit from zoledronic acid in terms of pain reduction and tapering of analgesic drugs. Before starting treatment, the mean VAS for patients who received at least 3 administration (15/17 patients) of zoledronic acid was 7,1 (±0.24), and after three months 5,3 (±0.20). Radiotherapy was administered before zoledronic acid and, despite an initia l benefit, we were unable to reduce or stop treatment with analgesic drugs in our patients. However zoledronic acid administration produce increasing pain control with reduced need of analgesic drugs. A decrease in narcotic score was also observed, but this change was not statistically significant when using analysis of variance. In particular the patient n.7 with advanced tumor disease gained fast and significant clinical benefit from the only administration of zoledronic acid performed. In fact, he spontaneously stopped to use morphine for breakthrough pain. However, all patients did not completely stop analgesic drugs. The patient n.3 which stopped zoledronic acid for persistent hypocalcemia showed bone progression seven months after the last zoledronic acid administration, while the other patients did not experience bone progression and skeletal complications. All patients recovered as concerns functional abilities previously compromised. Median survival was 10 months (CI: 6,353-13,647).

DISCUSSION

Bone metastases are the most common cause of cancer-related pain and often require palliative radiotherapy. Skeletal complications such as painful and debilitating pathologic fractures and spinal cord compression can seriously compromise life of patients and may require surgical interventions. Moreover bone metastases contribute to the deterioration in quality of life and independence of many cancer patients.

Bone metastases are rarely showed among extrahepatic sites of disease in HCC patients. Bone scintigraphy is not mandatory among staging examination in this tumor if there is not clinical suspicion of bone metastases. However, the increasing survival due to improvement in local therapies and the available targeted therapies are changing the clinical features of this tumor. In presence of incidental bone pain, bone lesions can be detected. They are generally demonstrated by radiography, CT, and nuclear scintigraphy. The plain film appearance of skeletal metastases from HCC was osteolytic in most cases. CT scans demonstrated the destructive nature of these lesions, which were associated with bulky soft-tissue masses 15 . Since 1986, search for bone metastases was advocated in patients with long-standing cirrhosis or known hepatocellular carcinoma that also have skeletal symptoms 16 . Often bone metastases from hepatocellular carcinoma are not detected by bone scintigraphy because of low uptake or a photopenic area in the tumor 17 . Last generation CT scans is significantly powered to detect bone lesions 18 .

Bisphosphonates are taken up by the bone at sites of active bone metabolism and inhibit osteoclast activity and survival 19 . Novel bisphosphonates include pamidronate, ibandronate and zoledronic acid. They are characterized by the presence of nitrogen in their molecule and inhibit the mevalonate pathway in osteoclasts. Bisphosphonates also cause apoptosis in osteoclasts and may have apoptotic effects in tumour cells. The nitrogen containing bisphosphonates are much more potent than first generation compounds. Specifically, they acquire the ability to inhibit the farnesyl pirophosphate synthase enzyme that is essential for the isoprenoid synthesis and for the subsequent activation of signal transduction proteins, such as ras family proteins, that are critically involved in the control of osteoclast and tumour cells proliferation and survival 20 .

Several large clinical trials assessed the clinical activity of bisphosphonates evaluating several primary end points of efficacy such as the time to first skeleta l event, fractures, the need of radiotherapy, spinal cord compression, hypercalcemia related to malignancy. Combined treatment with radiotherapy and zoledronic acid restores normal bone qualities with respect to bone density, microarchitecture, and biomechanical strength 21 .

Bisphosphonates seem to improve clinical results obtained with radiotherapy alone.

Combined therapy as RT + Z achieved a higher objective response rate measured as shrinkage and/or calcification of bone lesions and prolonged SRE-free survival than RT alone in patients with bone metastases from RCC 22 .

Advanced HCC patients presenting with bone metastases are undoubtly different from breast and prostate cancer patients with bone metastases especially as concern liver function impairment, prognosis and available effective treatments. Cirrhosis is an independent prognostic factor for osteoporosis 23 . Bone formation is reduced and bone turnover is low in liver cirrhosis. A reduction in bone mineral density leads to increased bone fragility, with osteopenia and osteoporosis leading to a two-fold and four-to five-fold increased risk for fracture, respectively 24 . Therefore, bone is already fragile in cirrhotic patients independently from metastases. The management of advanced HCC patients becomes even more complicated in presence of bone metastases.

Limited experience has been reported in medical literature with bisphosphonates in bone metastases by HCC. Two patients who developed hypercalcemia associated with bone metastasis after surgery for HCC were treated with alendronate and experienced pain relief, improvement of their quality of life and a marked decrease in alpha-fetoprotein levels with tumor regression 25 . Only one case of bone metastases treated with zoledronic acid was reported until now 5 . The present is the first series describing the attempt to include zoledronic acid in the therapeutic strategy of advanced HCC with bone metastases. The exact value of zoledronic acid alone is difficult to be determined because of limited number of evaluable patients and concomitant use of other treatments. However, patients regularly receiving zoledronic acid showed decreasing need for analgesic drugs and functional recovery if the lesions were located in the spine and limbs together with quality of life improvement.

In the present trial pain scores in patients receiving ZA decreased from baseline at subsequent assessment, suggesting, as we previously demonstrated 26,27,28 , that ZA may help in the management of pain.

This can be particularly important because of impaired liver metabolism of drug and increased risk for encephalopathy in these patients. The referred need to continue analgesic drugs was mostly related not only to bone pain, but also to abdominal pain which is frequent in multinodular HCC. HCC patients are difficult to be evaluated as concern analgesic assumption and eventual reduction over time. In fact, oppioid drug may be preferred to minor analgesic drugs, i.e. nonsteroidal anti-inflammatory drug because of reduced risk of bleeding. An increased use of drugs considered on the upper level of analgesic scale does not translate into worse conditions, thus making the impact of any drug on pain more difficult to be assessed. No patient who continued to receive zoledronic acid showed bone progression, while the only patient who stopped treatment because of persistent hypocalcemia showed new bone lesions. No skeletal complications were registered during zoledronic acid administration.

In this study zoledronic use was used in patients with Cr Cl below 60 mL/min. No significant side effect was registered and in particular renal function did not worsen in this series of patients.

In conclusion, zoledronic acid was safe and effective in the treatment of bone metastases in the present series and may be considered as an important part of novel therapeutic strategies.

  infection by HCV and HBV was detected. Ten patients were Child-Pugh class A, four were Child-Pugh class B, three were Child-Pugh C. All patients had multinodular HCC. Only three patients were naïve from local and systemic therapies. The patients were previously treated with different options: liver surgery (2 pts), percutaneous ethanol injection (PEI) and/or radiofrequency ablation (7 pts), intra-arterial chemotherapy (5 pts), systemic treatments (14 patients). Most of the patients (10 out of 17, 58.8%) had received local and systemic therapies. One patient (pt.7 in table 1) presented recurrence on transplanted liver and concomitant bone metastases. He received radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) on transplanted liver. At presentation of bone metastases, 11 out of 17 patients showed alpha-fetoprotein levels higher than 200 ng/mL. All patients but two (pts 1,8) were treated with sorafenib plus octreotide (Del Prete S, Montella L, Caraglia M, Maiorino L, Montesarchio V, Cennamo G, Leo L, Palmieri G, Bianco M, Addeo R. behalf of SOLAR study group Sorafenib plus long-acting octreotide in advanced hepatocellular carcinoma. Preliminary results of a multicenter ongoing study. American Society of Clinical Oncology 2008 Chicago (USA) Annual Proceedings). One patient (pt 1) received octreotide alone. Most frequent sites of bone metastases in the present series were spine (11/17, 64.7%), pelvis (10/17, 58.8), long bones (6/17, 35%), ribs (8/17, 47%). Two patients had single bone metastases (pts 9,15). Ten patients presented extrahepatic disease other than bone (lungs and/or abdominal lymph node). In fig.1 wedge compression fracture of the first lumbar vertebra together with a liver lesion and right adrenal gland involvement by tumor were shown. In patient n.5 disease progression was announced by the appearance of a tumor corresponding to rib cage (fig.2a) which was confirmed by CT (fig.2b). Two patients (pts 1 and 8) were hospitalized with low backache. All patients referred relentless pain despite various analgesic treatments. Zoledronic acid was administered in all patients (total number of administrations: 93, mean number of administrations: 5.47). Fifteen patients received at least 3 administrations. Four patients received concomitant radiotherapy. One patient (pt1) stopped radiotherapy on bone lesions because of thrombocytopenia. One patient received only one administration of zoledronic acid because of death due to variceal bleeding. Three patients (pts 1, 3, 7) showed serum calcium revised by albumin levels below 8,4 mg/dL despite oral and intravenous calcium administration and stopped therapy after a maximum of three administrations. One of this patient (pt3) showed bone disease progression. Zoledronic acid was well tolerated and only in one case we registered an acute phase reaction (low-grade fever) 24 hours after the first administration. Basal Cr Cl ranged from 40 to 95 mL/min. Four patients had Cr Cl below 49 mL/min. However, this value maintained within the start-up range during the follow-up. In fig.2c bone remodelling after two administrations of zoledronic acid in the same patient shown in fig.2a and b was imaged. Six patients (66.6%) remained stable while 3 patients progressed. During follow-up eleven patients died because of progressing cirrhosis and/or tumor. Mean survival was 10.25 months (CI 95%, 8.245-

Fig. 1

 1 Fig.1 Choronal section of CT scan showing wedge compression fracture of the first

Fig. 2

 2 Fig.2 Clinical (a) and CT (b) images of rib involvement by tumor. In fig.2b CT shows

Table 1

 1 Comprehensive patients' profile Pt patient; S/A: Sex/Age; abd abdominal; ZA zoledronic acid; PEI percutaneous ethanol injection; TACE transarterial chemoembolization; CT chemotherapy; RFA radiofrequency ablation; LT liver transplantation; RT radiotherapy.

	Pt S/A	Etiology	Child	Sites of disease		Treatment		ZA	Basal Alpha-	Outcome
											FP (UI/mL)
	1	F/69	HCV	B	Liver, lumbar vertebrae PEI, RFA, bone	3	7,83	Dead (10 months)
								RT (stopped),
								OCT
	2	M/62	HCV	A	Liver,	Lumbar	CT, bone RT,	7	273	Dead (7 months)
					vertebrae			sorafenib+OCT
	3	M/68	HCV	A	Liver, abd lymph node,	RFA, TACE,	3	4472	Dead (10 months )
					ribs, dorsal and lumbar	bone	RT,
					vertebrae, pelvis		sorafenib+OCT
	4	M/66	HCV	A	Liver, lung, ribs, right	Liver surgery,	11	545	Alive (14 mo.)
					homerus, left femur	CT, bone RT,
								sorafenib+OCT
	5	M/63	NAS	A	Liver, lung, abd lymph	bone	RT,	5	30000	Dead (6 mo.)
					nodes, ribs, pelvis,	sorafenib+OCT
					dorsal vertebrae
	6	M/79	HCV	A	Liver, dorsal vertebra,	RFA, PEI, bone	9	13900	Alive (10 months)
					pelvis			RT,
								sorafenib+OCT
	7	M/69	HCV	A	Liver,	left	femur,	LT, bone RT,	2	1430	Dead (6 months)
					dorsal and lumbar	RFA	and
					vertebrae, ribs, pelvis	TACE,
								sorafenib+OCT
	8	M/64	HCV	B	Rib, pelvis, lumbar	RFA,	PEI,	1	11850	Dead (1 month)
					vertebra			TACE,	liver
								surgery
	9	F/80	HCV	A	Liver, right femur	bone	RT, 7	3,2	Alive (9 months)


Professor Malcolm Ranson
email: malcolm.ranson@manchester.ac.uk

H Shaw

J Wolf

M Hamilton

S Mccarthy

E Dean

A Reid

I Judson

A Phase I Dose-Escalation and Bioavailability Study of Oral and Intravenous Formulations of Erlotinib (Tarceva ® , OSI-774) in Patients with Advanced Solid Tumors of Epithelial Origin

    A phase I dose-escalation and bioavailability study of oral and intravenous formulations of erlotinib (Tarceva, OSI-774) in patients with advanced solid tumors of epithelial origin

INTRODUCTION

Erlotinib (Tarceva ® , OSI Pharmaceuticals, Melville, NY; Roche, Basel, Switzerland; Genentech, South San Francisco, CA) is an orally active, potent selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase [START_REF] Moyer | Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase[END_REF]. It is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least 1 prior chemotherapy regimen, and in combination with gemcitabine for the treatment of patients with local advanced, unresectable, or metastatic pancreatic cancer.

The absolute bioavailability of oral erlotinib was previously determined in a randomized crossover study in healthy subjects [START_REF] Frohna | Evaluation of the absolute oral bioavailability and bioequivalence of erlotinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in a randomized, crossover study in healthy subjects[END_REF]. This study compared the plasma AUC 0-of a single oral 150 mg erlotinib tablet with a single 25 mg erlotinib IV infusion given over 30 minutes. The IV dose of 25 mg was selected as the lowest dose that would provide the quantifiable erlotinib plasma concentrations necessary for this assessment. The results indicated that the terminal phase differed significantly between the two formulations, with a mean terminal half-life of 21.3 hours following the oral dose and 13.1 hours following IV administration, a difference attributed to faster clearance of erlotinib at the IV 25 mg dose compared with the oral 150 mg dose. Calculation of erlotinib bioavailability using noncompartmental methods resulted in a value of 106% (95% CI, 99%-114%). Data analysis using a two-compartment nonlinear model with a nonlinear elimination process provided what is considered a more accurate estimate of bioavailability of 59% (95% CI: 55%, 63%).

Intravenous administration of erlotinib has previously not been characterized in cancer patients. Here we present findings concerning single 30-minute IV infusion of erlotinib in patients with advanced solid tumors of epithelial origin. Characterization of an IV formulation may be of clinical value for patients with gastrointestinal abnormalities, including inability to take oral medication, requirement for IV alimentation, active peptic ulcer, or prior surgical procedures affecting absorption. The objectives of the study were to determine the maximum tolerated dose (MTD) and recommended dose of erlotinib administered as a single 30-minute infusion in patients; to determine the safety, tolerability, dose-limiting toxicities (DLT), and pharmacokinetic profile in this patient population; and to determine the absolute oral bioavailability of erlotinib tablets at matched doses.

PATIENTS AND METHODS

This was a 2-center, open label, Phase I, dose escalation and bioavailability trial of single dose IV and oral erlotinib in patients with advanced solid tumors, conducted at the Christie and Royal Marsden Hospitals in the UK.

Patient Eligibility

The study population comprised adult patients with advanced and/or metastatic solid tumors of epithelial origin either refractory to previous therapy, or not deemed candidates for further cytotoxic chemotherapy. It was considered appropriate to permit enrollment to a broad patient population and not restrict to the approved indication for single agent erlotinib of patients with previously treated NSCLC. Patients must have had a minimum of 21 days from last chemotherapy, and recovered from treatment-related toxicities. Patients had an ECOG PS 2, a predicted life expectancy of at least 12 weeks, and adequate hematopoietic, hepatic, and renal function. An entry criterion of patients refraining from smoking for 25 days (14 days prestudy and 11 days on study) was imposed to reduce the inter-patient variability of erlotinib pharmacokinetics given the known impact of smoking on erlotinib plasma clearance [START_REF] Hughes Andrew | Overcoming CYP1A1/1A2 Mediated Induction of Metabolism by Escalating Erlotinib Dose in Current Smokers[END_REF].

Research ethics committees of the participating centers approved the study before patient accrual, in accordance with regulatory and institutional guidelines. The study was conducted using Good Clinical Practices and all patients provided written informed consent.

Study Design and Treatment

The dose-escalation schema utilized cohorts of at least 3 patients each, in which each patient received a single IV infusion of erlotinib (formulated in 6% [w/v] 6% aqueous Captisol® [CyDex Pharmaceuticals, Lenexa, KS ] at a concentration of 10 mg/mL) over 30 minutes on Day 1 followed by a matched single oral dose of erlotinib (supplied as 25 mg tablets) on Day 8 for calculation of absolute oral bioavailability. Upon completion of each dose level cohort, the investigators and sponsor reviewed observed toxicities and erlotinib plasma levels to determine if dose escalation to the next cohort was appropriate. Dose cohorts were filled sequentially and doses were escalated in 25 mg increments when all patients at a given dose level completed a single IV infusion of erlotinib with acceptable tolerability in the first 7 days following treatment. The starting dose was 25 mg.

The MTD of the IV formulation was defined as the dose at which 2 of 6 patients experienced a DLT by Day 7. The recommended IV dose of erlotinib was defined as one dose level below the MTD. A DLT was a toxicity considered related to study drug, occurring within the first 7 days of treatment and defined as either: a Common Terminology Criteria for Averse Events v3.0 (CTC) grade 3 or 4 toxicity (excluding alopecia or unpremedicated or inadequately treated nausea, vomiting, or diarrhoea); or: a CTC grade 3 AST and/or ALT for 7 days or CTC grade 4 AST and/or ALT. In addition, the occurrence of any CTC grade 3 or 4 toxicity had to also represent at least a 2-grade increase from baseline to be considered a DLT.

In the event an MTD was not established, an escalation cap was imposed of either a dose level of 200 mg or if 2 of 3 patients in a cohort had an observed erlotinib C max of 4 μg/mL, whichever occurred first. The mean C max following a 25 mg IV infusion in healthy adult subjects was 0.545 g/mL. Assuming dose linearity, the mean C max at 200 mg would be 4.36 g/mL, which is below the 5.6 g/mL plasma concentrations observed following a single oral 1000 mg dose in humans and also below the C max observed for the lowest IV dose (7 mg/kg) tested in dogs, approximately 5 g/mL. The no observed adverse effect level (NOAEL) dose by this route was not established in dogs but was < 7 mg/kg. Furthermore, if the pharmacokinetics of erlotinib were similar between the IV and oral 5 of 17 routes when administered at similar doses, 200 mg given intravenously should be equivalent to a 338 mg dose administered orally (based on 59% absolute oral bioavailability).

The recommended IV dose of erlotinib was the dose level below the MTD. When the recommended dose of IV erlotinib was determined, 6 to 10 patients evaluable for PK were to be treated at this dose level to further evaluate the safety profile and pharmacokinetic profile.

At the investigators' discretion, patients could receive standard-dose (150 mg PO QD) oral erlotinib treatment after Day 11.

Pharmacokinetic Analyses

Pharmacokinetic samples were taken on Days 1 -3 and Days 8 -11 and plasma concentrations of erlotinib and its active metabolite, OSI-420, were determined using a previously reported validated LC/MS/MS (liquid chromatography with triple quadrupole tandem MS detection) assay [START_REF] Hamilton | Effects of smoking on the pharmacokinetics of erlotinib[END_REF]. Noncompartmental methods were used to calculate pharmacokinetic parameters: AUC 0-, C max , T max , CL (IV only), V ss (IV only), and oral bioavailability for each patient. Absolute oral bioavailability of erlotinib tablets was calculated as the ratio of erlotinib AUC 0- following a single IV dose on Day 1 with that from the matched single oral dose on Day 8. For AUC 0-values to be reportable there had to be sufficient data obtained in the terminal elimination phase such that less than 20% of the value was extrapolated.

Descriptive statistics (N, median, min, max, and geometric mean where appropriate) were calculated for pharmacokinetic parameters. Deviations from dose linearity of C max and AUC 0-were tested using analyses of variance with trend tests.

RESULTS

Patient Characteristics

Between May and December 2005, 10 male and 6 female patients with advanced and/or metastatic tumors of epithelial origin were enrolled, (Table 1). All 16 patients had received prior chemotherapy; 50% received 2 or more prior regimens. Half of the patients had prior radiotherapy, 15 patients underwent prior disease-related surgery, and 2 patients received prior hormonal therapy, immunotherapy, or cytostatic therapy. Patients with a broad variety of tumor histologies were enrolled, with the most common tumor type being esophageal (n = 4).

Patients received at least 1 erlotinib dose in the following dose cohorts: 25 mg (n = 3), 50 mg (n = 4), 75 mg (n = 3), and 100 mg (n = 6). All 16 patients received the single IV erlotinib dose; however, only 15 patients completed the study, as 1 patient in the 50 mg cohort with a history of DVT discontinued on Day 8 before starting the oral erlotinib dose due to an unrelated adverse event of DVT (see Figure 1).

Toxicity

Table 2 presents an overall summary of safety during the 11-day pharmacokinetic phase of the study, which included the IV (Days 1 -7) and oral (Days 8 -11) dosing stages. Neither the single IV nor oral dose of erlotinib resulted in any notable toxicity, as evidenced by the absence of any grade 3/4 adverse events, treatment-related > grade 1 severity, serious adverse events, dose-limiting toxicities, or notable changes in laboratory values.

During the IV portion of the study, 9 patients experienced adverse events, the most frequent being diarrhea (3 patients, 19%), vomiting, and anemia (2 patients each, 13%). Two patients experienced IV grade 1 erlotinibrelated adverse events (injection site reaction and pruritus). During the oral portion of the study, 8 patients experienced adverse events, with diarrhea and arthralgia (2 patients each, 13%) occurring most frequently. Three patients experienced grade 1 erlotinib-related adverse events during the oral phase, including 1 patient with dermatitis acneform, 1 with dry skin and pruritus, and 1 with diarrhea.

Determination of MTD and Recommended IV Dose

The protocol mandated that IV dose escalation would stop if 2 of 3 patients had an observed erlotinib C max 4 μg/mL even if an MTD had not been reached. This capped C max value was achieved at the 100 mg dose level, which was expanded to 6 patients. Three of the 6 patients had an observed erlotinib C max > 4 μg/mL, therefore the study was closed and an MTD for IV erlotinib was not established.

Because no MTD was established, it was not possible to formally determine a recommended IV single dose of erlotinib. The 100 mg IV dose level, however, was well tolerated with only mild adverse events reported for the 6 patients at that level.

Pharmacokinetics

Pharmacokinetic data were collected and analyzed for 16 patients during the IV and oral portions of the study (Table 3). Of these, oral bioavailability of the erlotinib tablets could not be assessed for 4 patients. In 2 patients (both in the 25 mg cohort), the IV administration was interrupted by problems with the infusion pumps. Another patient did not have bioavailability calculated because there was > 20% extrapolation in the AUC 0-following IV administration, and the final patient had only IV PK data as a result of study discontinuation prior to the administration of the Day 8 oral dose. The median plasma C max and AUC 0-also increased with dose following oral administration and did not significantly deviate from dose linearity, P = 0.9054 and P = 0.5053, respectively. The median oral bioavailability of the erlotinib tablets was 76% (min-max of 47 -131%) and appeared to be independent of dose. OSI-420 plasma vs time profiles (not shown) were consistent with observations in previous studies. OSI-420 plasma concentrations tracked with parent concentrations over time and the median ratio of AUC 0-of OSI-420 to erlotinib across all doses was 6.2 and 7.3% following IV and oral administration, respectively, and appeared independent of dose.

DISCUSSION

A maximum tolerated single IV dose of erlotinib was not determined in this study due to the cessation of dose escalation when patient's erlotinib plasma concentrations reached/exceeded a predetermined cap of 4 μg/mL. This cap was established as a conservative precaution based on observations from a repeat dose erlotinib toxicology study in dogs where a bolus IV administration of erlotinib at 15 mg/kg resulted in ataxia, tremors, salivation, transient decreased activity, and papillary dilation. In this dog study, apparent toxicity was observed following IV administration at exposures that were below those tolerated by dogs given oral erlotinib. This observation remains unexplained, and so to be conservative in humans, this cap was imposed. Human exposure to IV erlotinib prior to this trial was limited to 25 mg in healthy subjects and therefore did not provide a basis to set an exposure limit for this trial. Although a slower infusion did reduce the observed toxicity in dogs, the half-life in dogs is much shorter than in humans (~2 vs 24hrs). So it was feasible to significantly impact the exposure in dogs by changing from IV bolus to 30 min infusion. To achieve similar effects in humans would require continuous infusion at a very slow rate or highly diluted solution for many hours.

The erlotinib maximum plasma concentrations in this preclinical study were in the 5 -7 µg/mL range. When the dose was given as a 30-minute infusion, the effects were reduced. The reasons for these effects are unknown and have not been observed in any other preclinical study, or in humans at plasma concentrations far in excess of these values (following oral erlotinib). Prior to the current Phase 1 study, the only tolerability data for IV erlotinib in humans was from the 25 mg single dose administered to healthy adult subjects [START_REF] Frohna | Evaluation of the absolute oral bioavailability and bioequivalence of erlotinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in a randomized, crossover study in healthy subjects[END_REF]. The highest IV dose administered in the current study (100 mg) was well tolerated with only mild adverse events reported for the 6 patients at that level.

The pharmacokinetics of erlotinib and its active metabolite, OSI-420, showed high interpatient variability (plasma clearance IV CV 54.2%, and apparent oral clearance CV 66.9%) that is consistent with previous PK studies.

Combined with the small numbers of patients exposed, this complicates data interpretation but some observations may still be made. For both routes of administration, erlotinib C max and AUC 0-values did not deviate from dose proportionality. However, there are differences in the erlotinib terminal half-life at escalating doses over the dose range for the both routes of administration. Median half-lives for each dose level following IV administration drawn in the healthy subject bioavailability study that this is a dose effect and not related to route of administration.

While statistically erlotinib C max and AUC 0-values did not significantly deviate from dose proportionality, the erlotinib plasma concentrations observed at the 100 mg dose, both IV and oral, were about 2-fold higher than those observed at the 75 mg dose. These preliminary findings of IV dose proportionality require validation in a larger study given the high interpatient variability and small sample size. An earlier study, Hidalgo et al, reported dose proportional changes in C max and AUC across the dose range 25 -200 mg of oral erlotinib [START_REF] Hidalgo | Phase I and pharmacological study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies[END_REF].

Finally, this study confirmed the high level of oral absorption of erlotinib in cancer patients, median of 76%, consistent with the findings from the study in healthy subjects (59%).

A 100 mg single IV dose of erlotinib, given as a 30-minute infusion, was well tolerated with only minor adverse events in this study of advanced cancer patients with solid tumors. The high bioavailability of oral erlotinib was confirmed when matched IV and oral doses were administered in this patient population.

TABLES

Figure 2

 2 Figure 2 illustrates median erlotinib plasma concentration versus time plots for the different dose cohorts using planned blood collection times. Median erlotinib plasma concentration versus time plots for the 100 mg IV and oral dose are shown in Figure 3. Following the IV administration, median plasma C max and AUC 0-of erlotinib increased with dose and did not significantly deviate from dose linearity, P = 0.9144 and P = 0.1761, respectively.

Figure 1

 1 Figure 1: CONSORT Diagram

Figure 2

 2 Figure 2: Median Erlotinib Plasma Concentrations versus Time

Figure 3

 3 Figure 3: Median (range) Erlotinib Plasma Concentrations versus Time (100mg dose)

Table 1 : Patient Demographics and Disease Characteristics

 1

		All Cohorts
		(N=16)
	Characteristics	n (%)
	Gender
	Female	6 (38%)
	Male	10 (63%)
	Race
	White	15 (94%)
	Other	1 (6%)
	Age (years)
	Median	54
	Min -Max	24 -74
	18-39	2 (13%)
	40-64	10 (63%)
	65	4 (25%)
	Prior chemotherapy
	regimens
	1	8 (50%)
	2	3 (19%)
	3	2 (13%)
	4	3 (19%)

Table 3 : Non compartmental Pharmacokinetics of Erlotinib Following IV and Oral Dosing Parameter IV Oral

 3

			25 mg	50 mg	75 mg	100 mg	25 mg	50 mg	75 mg	100 mg
	C max (μg/mL)	N	1	4	3	6	3	3	3	6
		Median	0.683	1.32	1.56	4.07	0.252	0.473	0.542	1.25
		Min -Max		0.848 -10.7	1.03 -2.11	1.69 -6.67	0.251 -0.376	0.262 -0.834	0.346 -0.936	0.341 -3.46
		Geometric Mean		1.99	1.50	3.75	0.288	0.469	0.560	1.16
	T max (hr)	N	---	---	---	---	3	3	3	6
		Median	---	---	---	---	4.2	4	4	3.07
		Min -Max	---	---	---	---	1.03 -7.00	3.98 -4.00	2.02 -7.05	1.00 -7.08
	AUC 0-inf (μg.hr/mL)	N	1	4	2	6	3	3	3	6
		Median	2.97	8.62	13.2	32.0	3.10	3.20	11.5	29.9
		Min -Max		4.85 -24.4	11.3 -15.0	13.9 -48.0	2.61 -8.71	3.15 -16.0	7.04 -14.8	7.30 -45.4
		Geometric Mean		9.20	13.0	30.4	4.13	5.44	10.6	24.4
	Clearance (L/hr)	N	1	4	3	6	---	---	---	---
		Median	8.41	7.13	6.64	3.12	---	---	---	---
		Min -Max		2.05 -10.3	5.00 -6.64	2.08 -7.21	---	---	---	---
	Terminal half-life (hr)	N	1	4	3	6	3	3	3	6
		Median	5.06	7.07	6.19	12.4	5.47	6.03	7.75	14.4
		Min -Max		2.75 -15.2	5.30 -22.9	9.61 -18.4	3.34 -21.8	2.94 -11.

ACKNOWLEDGMENTS

Authors Shaw, Reid and Judson gratefully acknowledge the support of the National Institute for Health Research, London. UK.

Patients who died due to a treatment-related AE 0 (0) 0 (0)