Guiding dose adjustment of amlodipine after co-administration with ritonavir containing regimens using a physiologically-based pharmacokinetic/pharmacodynamic model

AbstractAmlodipine, a commonly prescribed anti-hypertensive drug, shows increased systemic exposure with cytochrome P450 (CYP) 3A inhibitors. Ritonavir (RTV) is a potent mechanism-based and reversible CYP3A inhibitor and moderate inducer that is used as a pharmacokinetic enhancer in several antiviral treatment regimens. Drug –drug interaction (DDI) between RTV and amlodipine is due to mixed inhibition and induction of CYP3A4, which is challenging to predict without a mechanistic model that accounts for the complexity of both mechanisms occurring simultaneously. A novel physiologically-based pharmacokinetic (PBPK) mode l was developed for amlodipine, and the model was verified using published clinical PK and DDI data. The verified amlodipine PBPK model was linked to a pharmacodynamics model that describes changes in systolic blood pressure (SBP) during and after co-administration with RTV. The magnitude and time c ourse of RTV effects on amlodipine plasma exposures and SBP were evaluated, to provide guidance on dose adjustment of amlodipine during and after co-administration with RTV-containing regimens. Model simulations suggested that the increase in amlodipine’s plasma exposure by RTV diminishes by appro ximately 80% within 5 days after the last dose of RTV. PBPK simulations suggested that resuming a full dose of amlodipine [5 mg once daily (QD)] immediately after RTV’s last dose would decrease daily average SBP by a maximum of 3.3 mmHg, while continuing with the r...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research