Investigating the interaction between nifedipine‐ and ritonavir‐containing antiviral regimens: A physiologically based pharmacokinetic/pharmacodynamic analysis
Autor: | Xiaoqiang Xiang, Meng-wan Zhang, Wan-jie Niu, Weimin Cai, Size Li, Shasha Jin, Xi-ying Lin, Zheng Jiao |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
Physiologically based pharmacokinetic modelling
Nifedipine Cmax HIV Infections Pharmacology 030226 pharmacology & pharmacy Antiviral Agents Models Biological 03 medical and health sciences 0302 clinical medicine Pharmacokinetics medicine Humans Drug Interactions Pharmacology (medical) 030212 general & internal medicine Ritonavir CYP3A4 business.industry SARS-CoV-2 virus diseases COVID-19 Drug Treatment Blood pressure Pharmacodynamics Area Under Curve business medicine.drug |
Zdroj: | British Journal of Clinical Pharmacology |
ISSN: | 1365-2125 0306-5251 |
DOI: | 10.1111/bcp.14684 |
Popis: | 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. |
Databáze: | OpenAIRE |
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