Wanjie Niu1,2, Size Li3, Shasha Jin3, Xiying Lin3, Mengwan Zhang1, Weimin Cai3, Zheng Jiao1, Xiaoqiang Xiang3. 1. Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University, No. 241 West Huaihai Road, Shanghai, 200030, China. 2. Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, 200040, China. 3. Department of Clinical Pharmacy and Drug Administration, School of Pharmacy, Fudan University, Shanghai, 201203, China.
Abstract
AIMS: 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 coadministration with ritonavir-containing regimens, using a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) analysis. METHODS: The PBPK/PD models for 3 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 coadministered with or without ritonavir. RESULTS: PBPK/PD models for 3 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 >40 mmHg. Thus, the combination of nifedipine and ritonavir could lead to severe hypotension. CONCLUSION: Ritonavir significantly affects the pharmacokinetics and antihypertensive effect of nifedipine. It is not recommended for patients to take nifedipine- and ritonavir-containing regimens simultaneously.
AIMS: 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 coadministration with ritonavir-containing regimens, using a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) analysis. METHODS: The PBPK/PD models for 3 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 coadministered with or without ritonavir. RESULTS: PBPK/PD models for 3 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 >40 mmHg. Thus, the combination of nifedipine and ritonavir could lead to severe hypotension. CONCLUSION:Ritonavir significantly affects the pharmacokinetics and antihypertensive effect of nifedipine. It is not recommended for patients to take nifedipine- and ritonavir-containing regimens simultaneously.
Authors: Gerd Mikus; Kathrin I Foerster; Theresa Terstegen; Cathrin Vogt; André Said; Martin Schulz; Walter E Haefeli Journal: Dtsch Arztebl Int Date: 2022-04-15 Impact factor: 8.251
Authors: Panagiotis Zagaliotis; Anthi Petrou; George A Mystridis; Athina Geronikaki; Ioannis S Vizirianakis; Thomas J Walsh Journal: Int J Mol Sci Date: 2022-07-20 Impact factor: 6.208