Population pharmacokinetics of dolutegravir co-administered with rifampicin in Thai people living with HIV and TB
Anan Chanruang (1), Baralee Punyawudho (1), Pajaree Chariyaviladkul (2), Sasiwimol Ubolyam (3), Sivapon Gatechumpol (3,5), YS Cho (4), Jae Gook Shin (4), Anchalee Avihingsanon (3,5)
(1) Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand, (2) Clinical Pharmacokinetics and Pharmacogenomics Research Unit and Center of Excellence for Pediatric Infectious Diseases and Vaccines, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, (3) HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand, (4) Center for Personalized Precision Medicine of Tuberculosis, Inje University College of Medicine, Busan, Republic of Korea, (5) Center of Excellence in Tuberculosis, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Introduction/Objectives
Dolutegravir (DTG), a second-generation integrase strand transfer inhibitor (INSTI), is recommended as the first-line treatment for people living with HIV (PLWH), including those co-infected with TB (1). The standard dose of DTG is 50 mg once daily. However, when used in conjunction with rifampicin, the DTG 50 mg twice daily is recommended (1). Fixed-dosed combination of tenofovir disoproxil fumarate/lamivudine/DTG (TLD) as one pill a day is widely used in low/middle-income countries (LMICs), including Thailand. Extra dose of DTG is challenging and twice-daily dose regimens would affect the patients’ adherence. A once-daily regimen of 100 mg may increase adherence (2). This study aimed to determine the population pharmacokinetics of DTG in Thai HIV/TB co-infected participants on rifampicin. The optimal dose of DTG for co-administration with rifampicin was determined by examining the different dosing regimens.
Method
Forty HIV/TB co-infected adults on rifampicin were randomized to receive either DTG 50 mg once (OD) or twice daily (BID). At week 4, intensive pharmacokinetics of DTG were performed. A population pharmacokinetic model was developed using NONMEM®. One- and two-compartment models were evaluated during structural model development to define DTG pharmacokinetic parameters. The transit or lag-time model was tested to describe DTG delayed absorption. The inter-individual variability (IIV) was modeled using an exponential error model. The typical bioavailability (F) was fixed to 1. A stepwise covariate selection was used to identify factors impacting DTG’s pharmacokinetics. The covariates tested were age, weight, serum creatinine, total bilirubin, and sex. The bootstrapping and prediction-corrected visual predictive checks (pcVPC) were performed for the final model evaluation (3, 4). The optimal dose of DTG was investigated by Monte Carlo simulations. The final population pharmacokinetic model of DTG was used to simulate trough concentrations of DTG from different DTG dosing regimens (DTG 50 mg OD, 50 mg BID, and 100 mg OD co-administered with rifampicin). The percentage of simulated patients participants achieving the target concentration (protein-adjusted 90% inhibitory concentration; IC90 > 0.064 mg/L) for each dosage regimen was obtained (5).
Result
A total of 300 steady-state DTG plasma concentrations from 40 HIV/TB co-infected participants (87.5% male) were included in the analysis. The mean age was 38.16 (range, 21.6–60.5) years, and the weight was 59.69 (range, 41.1–86.0) kg. The median total bilirubin was 0.38 (range, 0.14–17.5) mg/dl. DTG pharmacokinetics could be best described by a one-compartment model with first-order elimination. The delayed absorption was characterized by a lag-time model. The addition of a second-compartment or transit absorption model did not improve the model fit. The population estimates of DTG apparent clearance (CL/F), apparent volume of distribution (V/F), absorption rate constant (KA), and lag time were 2.95 L/h, 21.5 L, 1.55 h-1, and 0.61 h, respectively. The IIV of CL/F, KA, and F were 17.41%, 98.54%, and 72.78%, respectively. The proportional error model best characterized the residual unexplained variability (RUV) of DTG. Total bilirubin was a significant covariate for CL/F of DTG. The impact of total bilirubin on DTG CL/F was described by an exponential function with a coefficient of -0.276. Age, weight, sex, and serum creatinine were not found to affect the pharmacokinetics of DTG. The goodness-of-fit plots revealed no explicit bias in the model. The parameter estimates of the final model from NONMEM were comparable to the values obtained from the bootstrap analysis. The pcVPC demonstrated a good description of observed data and adequate predictive performance of the final model. The simulations showed that when DTG at doses of 50 mg OD, 50 mg BID and 100 mg OD were co-administered with rifampicin, the median DTG trough concentrations were 0.08, 0.58, and 0.15 mg/L, respectively. The percentage of the participants who achieved the DTG IC90 target was 60.95%, 99.45%, and 83.26% when DTG doses were 50 mg OD, 50 mg BID, and 100 mg OD, respectively.
Conclusions
This is the first population pharmacokinetic model of DTG established in Thai HIV/TB co-infected population. Total bilirubin was the only significant covariate that impacted DTG CL/F. The DTG 50 mg BID provided the highest percentage of patients achieving DTG target concentrations.
References:
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