Population Pharmacokinetic Model and Alternative Dosing Regimens for Dolutegravir Coadministered with Rifampicin

Abstract

Dolutegravir-based regimens are recommended as first-line therapy for HIV in low- and middle-income countries where tuberculosis is the most common opportunistic infection. Concurrent HIV/tuberculosis treatment is challenging because of drug-drug interactions. Our analysis aimed to characterize dolutegravir's population pharmacokinetics when coadministered with rifampicin and assess alternative dolutegravir dosing regimens. We developed a population pharmacokinetic model of dolutegravir in NONMEM with data from two healthy-volunteer studies (RADIO and ClinicalTrials.gov identifier NCT01231542) and validated it with data from the INSPIRING study, which consisted of participants living with HIV. The model was developed with 817 dolutegravir plasma concentrations from 41 participants. A 2-compartment model with first-order elimination and lagged absorption best described dolutegravir's pharmacokinetics. For a typical 70-kg individual, we estimated a clearance, absorption rate constant, central volume, and peripheral volume of 1.03 L/h, 1.61 h-1, 12.7 L, and 3.85 L, respectively. Rifampicin coadministration increased dolutegravir clearance by 144% (95% confidence interval [CI], 126 to 161%). Simulations showed that when 50 or 100 mg once-daily dolutegravir is coadministered with rifampicin in 70-kg individuals, 71.7% and 91.5% attain trough concentrations above 0.064 mg/L, the protein-adjusted 90% inhibitory concentration (PA-IC90), respectively. The model developed from healthy-volunteer data describes patient data reasonably well but underpredicts trough concentrations. Although 50 mg of dolutegravir given twice daily achieves target concentrations in more than 99% of individuals cotreated with rifampicin, 100 mg of dolutegravir, once daily, in the same population is predicted to achieve satisfactory pharmacokinetic target attainment. The efficacy of this regimen should be investigated since it presents an opportunity for treatment simplification.

Keywords: dolutegravir; population pharmacokinetics.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIG 1

Visual predictive check of the final model. Blue circles represent observed plasma concentrations. The solid line in the middle represents the median observed concentration, and the broken lines below and above it represent the 10th and 90th percentiles of the observed concentrations, respectively. The shaded areas around each line represent the 95% confidence boundary of the simulated prediction for the same percentiles. OD, once daily; BD, twice daily; RIF, rifampicin.

FIG 2

Visual predictive check of the final model in healthy volunteers fitted to patient pharmacokinetic data from the INSPIRING study. Blue circles represent observed plasma concentrations. The solid line in the middle represents the median observed concentration, and the broken lines below and above it represent the 10th and 90th percentiles of the observed concentrations, respectively. The shaded areas around each line represent the 95% confidence boundary of the simulated prediction for the same percentiles. RIF, rifampicin; TB, tuberculosis.

FIG 3

Simulated trough concentrations (C24 and C12 for the twice-daily regimen) of dolutegravir (DTG) administered (from left to right) at 50 mg once daily (OD), 50 mg OD with rifampicin (RIF), 50 mg twice daily (BD) with rifampicin, and 100 mg OD with rifampicin under fasted conditions, with the final model described in Table 2 including between-subject and between-occasion variability. For the absorption lag time, we used the value estimated for the NCT01231542 study since this was done under fasted conditions. Simulations are based on 1,000 individuals categorized by weight. The boxes represent the 25th, 50th, and 75th percentiles, while the whiskers show the 5th and 95th percentiles. IC90, protein-adjusted 90% inhibitory concentration; EC90, 90% effective concentration.

FIG 4

Schematic of the dosing regimen and dolutegravir (DTG) pharmacokinetic (PK) sample collection for the different studies. This analysis excludes concentrations in arm B of the NCT01231542 study during weeks 2 and 3 (when participants received rifabutin). OD, once daily; BD, twice daily; RIF, rifampicin; TB, tuberculosis; HIV, human immunodeficiency virus; NRTI, nucleotide reverse transcriptase inhibitor.