Rifamycins (rifampin, rifabutin, and rifapentine) play an essential role in the treatment of mycobacterial and some non-mycobacterial infections. They also induce the activity of various drug transporting and metabolizing enzymes, which can impact the concentrations and efficacy of substrates. Many anticoagulant and antiplatelet (AC/AP) agents are substrates of these enzymes and have narrow therapeutic indices, leading to risks of thrombosis or bleeding when co-administered with rifamycins. The objective of this systematic review was to evaluate the effects on AC/AP pharmacokinetics, laboratory markers, and clinical safety and efficacy of combined use with rifamycins. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidance was performed. The PubMed, Embase, and Web of Science databases were queried for English-language reports on combination use of rifamycins and AC/AP agents from database inception through August 2021. The twenty-nine studies identified examined warfarin (n=17), direct oral anticoagulants (DOACs) (n=8), and antiplatelet agents (n=4) combined with rifampin (n=28) or rifabutin (n=1). Eleven studies were case reports or small case series; 14 reported on pharmacokinetic or laboratory markers in healthy volunteers. Rifampin-warfarin combinations led to reductions in warfarin area under the curve (AUC) of 15-74%, with variability by warfarin isomer and study. Warfarin dose increases of up to 3-5 times pre-rifampin doses were required to maintain coagulation parameters in the therapeutic range. DOAC AUCs were decreased by 20-67%, with variability by individual agent and with rifampin versus rifabutin. The active metabolite of clopidogrel increased substantially with rifampin co-administration, whereas prasugrel was largely unaffected and ticagrelor saw decreases. Our review suggests most combinations of AC/AP agents and rifampin are problematic. Further studies are required to determine whether rifabutin or rifapentine could be safe alternatives for coadministration with AC/AP drugs.
Systematic Review of Drug-drug Interactions between Rifamycins and Anticoagulant and Antiplatelet Agents and Considerations for Management.