Population pharmacokinetic modelling to quantify the magnitude of drug-drug interactions between amlodipine and antiretroviral drugs.

Details

Serval ID
serval:BIB_DCBBE5FFBE88
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Population pharmacokinetic modelling to quantify the magnitude of drug-drug interactions between amlodipine and antiretroviral drugs.
Journal
European journal of clinical pharmacology
Author(s)
Courlet P., Guidi M., Alves Saldanha S., Cavassini M., Stoeckle M., Buclin T., Marzolini C., Decosterd L.A., Csajka C.
ISSN
1432-1041 (Electronic)
ISSN-L
0031-6970
Publication state
Published
Issued date
07/2021
Peer-reviewed
Oui
Volume
77
Number
7
Pages
979-987
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Drug-drug interactions (DDIs) with antiretroviral drugs (ARVs) represent an important issue in elderly people living with HIV (PLWH). Amlodipine is a commonly prescribed antihypertensive drug metabolized by CYP3A4, thus predisposed to a risk of DDIs. Guidance on the management of DDIs is mostly based on theoretical considerations derived from coadministration with other CYP3A4 inhibitors. This study aimed at characterizing the magnitude of DDIs between amlodipine and ARV drugs in order to establish dosing recommendations.
A population pharmacokinetic analysis was developed using non-linear mixed effect modelling (NONMEM) and included 163 amlodipine concentrations from 55 PLWH. Various structural and error models were compared to characterize optimally the concentration-time profile of amlodipine. Demographic and clinical characteristics as well as comedications were tested as potential influential covariates. Model-based simulations were performed to compare amlodipine exposure (i.e. area under the curve, AUC) between coadministered ARV drugs.
Amlodipine concentration-time profile was best described using a one-compartment model with first-order absorption and a lag-time. Amlodipine apparent clearance was influenced by both CYP3A4 inhibitors and efavirenz (CYP3A4 inducer). Model-based simulations revealed that amlodipine AUC increased by 96% when coadministered with CYP3A4 inhibitors, while efavirenz decreased drug exposure by 59%.
Coadministered ARV drugs significantly impact amlodipine disposition in PLWH. Clinicians should adjust amlodipine dosage accordingly, by halving the dosage in PLWH receiving ARV with inhibitory properties (mainly ritonavir-boosted darunavir), whereas they should double amlodipine doses when coadministering it with efavirenz, under appropriate monitoring of clinical response and tolerance.
Keywords
Amlodipine, Drug-drug interactions, HIV, NONMEM, Pharmacokinetics
Pubmed
Web of science
Open Access
Yes
Create date
26/01/2021 15:12
Last modification date
27/06/2021 6:37
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