Investigating the interaction between nifedipine- and ritonavir-containing antiviral regimens: a physiologically-based pharmacokinetic/pharmacodynamic analysis.

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.