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

AbstractBackground and ObjectiveHypertension 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.MethodsA 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.ResultsPBPK/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/AUCNifedipineof nifedipine were within 0.70- to 1.83-fold. Model simulations showed that the inhibitory effect of ritonavir on CYP3A4 increased the Cmaxof nifedipine by 9.82-34.35 times and the AUC24hby 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.ConclusionsRitonavir 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.