Investigation on the interaction between nifedipine and ritonavir containing antivirus regimens: a physiologically-based pharmacokinetic/pharmacodynamic analysis

Abstract

Background and Objective Hypertension is a common comorbidity of patients with COVID-19, SARS or HIV infection. Those patients are often treated with commonly used antiviral and antihypertensive agents concomitantly, such as ritonavir-containing regimens and nifedipine. Since ritonavir is a strong inhibitor of CYP3A, when nifedipine is combined with ritonavir-containing antiviral drugs, there is a potential risk of drug-drug interaction. This study aimed to provide guidance on nifedipine treatment during and after co-administration with ritonavir-containing regimens using a physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) analysis. Methods A PBPK/PD model was developed for nifedipine by the software of Simcyp, and the model was verified using published data. The effects of ritonavir on nifedipine exposures and systolic blood pressure were assessed for instant-release, sustained-release and controlled-release formulations. Moreover, various nifedipine regimens were investigated when co-administrated with and withdrawing ritonavir. Results PBPK/PD models for three formulations of nifedipine were successfully established. The model predicted pharmacokinetic profiles of nifedipine were comparable to the published data. Ratios of predicted versus observed AUCDDI/AUCNifedipine of nifedipine were within 0.70- to 1.83-fold. Model simulations showed that the inhibitory effect of ritonavir on CYP3A4 increased the Cmax of nifedipine by 9.82-34.35 times and the AUC by 44.94-50.77 times at steady state. Moreover, nifedipine dose reduced to 1/16 of the regular dose during ritonavir co-administration could lead to severe hypotension. Conclusions Ritonavir had a pronounced influence on the pharmacokinetics and antihypertensive effect of nifedipine. It is not recommended for patients to take nifedipine and ritonavir-containing regimens simultaneously.