BACKGROUND AND OBJECTIVE: Hypertension is a common comorbidity of patients with COVID-19, SARS or HIV infection. Such patients are often concomitantly treated with antiviral and antihypertensive agents, including ritonavir and nifedipine. Since ritonavir is a strong inhibitor of CYP3A and nifedipine is mainly metabolized via CYP3A, the combination of ritonavir and nifedipine can potentially cause drug-drug interactions. This study provides guidance on nifedipine treatment during and after co-administration with ritonavir-containing regimens, using a physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) analysis. METHODS: The PBPK/PD models for three formations of nifedipine were developed based on the Simcyp® nifedipine model and the models were verified using published data. The effects of ritonavir on nifedipine exposure and systolic blood pressure (SBP) were assessed for instant-release, sustained-release, and controlled-release formulations in patients. Various nifedipine regimens were investigated when co-administered with or without ritonavir. RESULTS: PBPK/PD models for three formulations of nifedipine were successfully established. The predicted maximum concentration (Cmax ), area under plasma concentration-time curve (AUC), maximum reduction in SBP, and area under effect-time curve were all within 0.5-2.0-fold of the observed data. Model simulations showed that the inhibitory effect of ritonavir on CYP3A4 increased the Cmax of nifedipine 17.92-48.85-fold and the AUC 63.30-84.01-fold at steady state and decreased the SBP by more than 40 mmHg. Thus, the combination of nifedipine and ritonavir could lead to severe hypotension. CONCLUSIONS: Ritonavir significantly affects the pharmacokinetics and antihypertensive effect of nifedipine. It is not recommended for patients to take nifedipine- and ritonavir-containing regimens simultaneously.
Investigating the interaction between nifedipine- and ritonavir-containing antiviral regimens: a physiologically-based pharmacokinetic/pharmacodynamic analysis