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

Abstract

Purpose: 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.

Methods: 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.

Results: 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%.

Conclusion: 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.

Fig. 1

pcVPC of amlodipine final model with amlodipine prediction-corrected concentrations (open circles), median of the observed concentrations (solid line) with 90% prediction interval (dashed lines). Grey fields represent the model-based 90% confidence interval of the simulated median and PI_90%

Fig. 2

Simulated amlodipine plasma concentrations for dosage regimens of 2.5 mg qd with CYP3A4 inhibitors (i.e. ritonavir-boosted darunavir, cobicistat-boosted darunavir, ritonavir-boosted atazanavir, cobicistat-boosted elvitegravir) (left) or 10 mg qd with efavirenz (right), compared with standard dosage of 5 mg qd. Continuous line represent the population median prediction for standard (grey) and alternative regimens (orange), while shaded areas and dashed lines represent the 90% prediction interval based on 1000 simulated PLWH