Dolutegravir (DTG), a second-generation integrase strand transfer inhibitor, is recommended as first-line treatment for people living with HIV (PLWH) in low- and middle-income countries (1). However, co-administering DTG with rifampicin (RIF), a potent inducer, may reduce DTG concentrations, potentially leading to treatment failure (2). This study aimed to determine the population pharmacokinetics of DTG and RIF in Thai PWH and optimize the DTG dosing regimen using Monte Carlo simulations.
A total of 194 PWH were included, with 1,076 DTG, and 309 RIF plasma concentrations available for analysis. Population pharmacokinetics of DTG and RIF were separately analyzed using a nonlinear mixed-effects modeling approach with NONMEM®. A stepwise covariate selection was used to identify factors impacting DTG’s and RIF’s pharmacokinetics (3, 4). The impact of RIF exposure was investigated. The area under the curve (AUC) of RIF was calculated by dividing the dose by individual apparent clearance (CL/F).
Participants were 59% male, with a median age of 48 years, median weight of 60 kg (range 35.0 – 97.0 kg), and total bilirubin of 0.38 mg/L. A one-compartment model with 4 and 10 transit compartments, respectively, and first-order elimination best described DTG and RIF pharmacokinetics. Allometric scaling with exponents fixed to 0.75 and 1 for CL/F and volume of distribution (V/F) was incorporated. The AUC of RIF and total bilirubin significantly influenced DTG CL/F, while RIF AUC affected DTG bioavailability (F). Simulations indicated that without RIF co-administration, all DTG dosing regimens (50 mg once daily (OD), 50 mg twice daily (BID), and 100 mg OD) provided DTG trough concentrations (Ctrough) exceeding 99% of the in vitro protein-adjusted 90% inhibitory concentration (IC90; > 0.064 mg/L) and the in vivo 90% effective concentration (EC90; > 0.3 mg/L) in all weight groups (5, 6). When co-administered with RIF standard dose (450 mg or 600 mg OD), DTG concentrations dropped significantly, with the median DTG 50 OD concentrations decreasing from 1.781 mg/L to 0.187 mg/L in the low-weight group (35.0–60.0 kg) and from 1.330 mg/L to 0.100 mg/L in the high-weight group (60.1–97.0 kg). Moreover, the simulations showed that the 50 mg OD of DTG co-administration with RIF had attained percentage of achieving IC90 only 82.20% and 65.95% in the low-weight group and high-weight group, respectively. While the percentage of archiving EC90 in this co-administration regimen had decreased to 31.65% and 10.53% in the low-weight group and high-weight group, respectively. However, increasing the dose of DTG to 50 mg BID or 100 mg OD when using them with RIF had shown a higher percentage of achieving IC90 in the low-weight group, more than 95% in both regimens. Nevertheless, the DTG 50 mg BID had still achieved EC90 more than 95%, while DTG 100 mg OD had achieved EC90 only 58.03%. Lastly, DTG 50 mg BID remained a higher percentage of achieving IC90 and EC90 (99.70% and 84.22%, respectively) when compared to DTG 100 mg OD (84.22% and 33.07%, respectively) in the high-weight group.
Rifampicin co-administration significantly decreased DTG exposure. In the absence of RIF, 50 mg of OD DTG dosing provided sufficient DTG concentrations for HIV viral suppression. However, higher doses of DTG are required when co-administered with RIF, especially in PLWH with high weight.
Reference
(1) Thailand National guidelines on Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) Diagnosis, Treatment and Prevention 2020/2021 [Internet]. Bureau of AIDS, TB and STIs Department of Disease control, Ministry of Public Health. 2021
(2) Chen J, Raymond K. Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor. Ann Clin Microbiol Antimicrob. 2006;5:3.
(3) Bonate PL. Pharmacokinetic-Pharmacodynamic Modeling and Simulation. 2011.
(4) Joel S. Owen JF-K. Introduction to Population pharmacokinetic/pharmacodynamics analysis with Nonlinear Mixed Effects Models. 2014.
(5) Cottrell ML, Hadzic T, Kashuba AD. Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir. Clin Pharmacokinet. 2013;52(11):981-994.
(6) Van Lunzen J, Maggiolo F, Arribas JR, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2012;12(2):111-118.