Model-based approach to dose optimization of lopinavir/ritonavir when co-administered with rifampicin

Abstract

Aims: Rifampicin, a key component of antitubercular treatment, profoundly reduces lopinavir concentrations. The aim of this study was to develop an integrated population pharmacokinetic model accounting for the drug-drug interactions between lopinavir, ritonavir and rifampicin, and to evaluate optimal doses of lopinavir/ritonavir when co-administered with rifampicin.

Methods: Steady-state pharmacokinetics of lopinavir and ritonavir were sequentially evaluated after the introduction of rifampicin and gradually escalating the dose in a cohort of 21 HIV-infected adults. Intensive pharmacokinetic sampling was performed after each dose adjustment following a morning dose administered after fasting overnight. A population pharmacokinetic analysis was conducted using NONMEM 7.

Results: A simultaneous integrated model was built. Rifampicin reduced the oral bioavailability of lopinavir and ritonavir by 20% and 45% respectively, and it increased their clearance by 71% and 36% respectively. With increasing concentrations of ritonavir, clearance of lopinavir decreased in an E(max) relationship. Bioavailability was 42% and 45% higher for evening doses compared with morning doses for lopinavir and ritonavir, respectively, while oral clearance of both drugs was 33% lower overnight. Simulations predicted that 99.5% of our patients receiving doubled doses of lopinavir/ritonavir achieve morning trough concentrations of lopinavir > 1 mg l(-1) during rifampicin co-administration, and 95% of those weighing less than 50 kg achieve this target already with 600/150 mg doses of lopinavir/ritonavir.

Conclusions: The model describes the drug-drug interactions between lopinavir, ritonavir and rifampicin in adults. The higher trough concentrations observed in the morning were explained by both higher bioavailability with the evening meal and lower clearance overnight.

© 2011 University of Cape Town. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Figures

Figure 1

Observed morning and evening trough concentrations of lopinavir (A) and ritonavir (B). predose concentration C0 (); trough concentration C12 (□)

Figure 2

Structure of the final integrated lopinavir-ritonavir pharmacokinetic model. (LPV: lopinavir; RTV: ritonavir; MTT: mean transit time; CL/F apparent oral clearance, V/F apparent volume of distribution, ka absorption rate constant, kTR transit absorption rate constant, Emax the maximum inhibition effect on lopinavir oral clearance by ritonavir, EC50 the ritonavir concentration needed to reach half of Emax, C concentration)

Figure 3

The influence of ritonavir concentrations (indicated in black) on the oral clearance of lopinavir (grey) in a typical patient. (LPV/r: lopinavir/ritonavir; rif: rifampicin). 400/100 mg LPV/r no rifampicin (); 400/100 mg LPV/r with rifampicin (); 600/150 mg LPV/r with rifampicin (); 800/200 mg LPV/r with rifampicin ()

Figure 4

Visual predictive check (VPC) of the final combined model for lopinavir (A) and ritonavir (B) stratified by occasion (PK1–PK4) from 1000 simulations. The solid line is the median of the observed data and the dotted lines are the 5th and 95th percentiles of the observed data. The grey shaded areas are the 95% CIs for the median, 5th percentile and the 95th percentiles of the simulated data. Observed concentrations are displayed as circles. PK1: 400/100 mg LPV/r no rifampicin; PK2: 400/100 mg LPV/r with rifampicin; PK3: 600/150 mg LPV/r with rifampicin; PK4: 800/200 mg LPV/r with rifampicin