Dolutegravir pharmacokinetics in Ugandan patients with TB and HIV receiving standard- versus high-dose rifampicin

Author:

Kengo Allan1ORCID,Nabisere Ruth2,Gausi Kamunkhwala1,Musaazi Joseph2,Buzibye Allan2,Omali Denis2,Aarnoutse Rob3,Lamorde Mohammed2,Dooley Kelly E.4ORCID,Sloan Derek James5,Denti Paolo1ORCID,Sekaggya-Wiltshire Christine2

Affiliation:

1. Department of Medicine, Division of Clinical Pharmacology, University of Cape Town , Cape Town, South Africa

2. Infectious Disease Institute, College of Health Sciences, Makerere University , Kampala, Uganda

3. Department of Pharmacy, Radboud University Medical Center , Nijmegen, the Netherlands

4. Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Centre , Nashville, Tennessee, USA

5. Division of Infection and Global Health, School of Medicine, University of St. Andrews , St Andrews, United Kingdom

Abstract

ABSTRACT Higher rifampicin doses may improve tuberculosis treatment outcomes. This could however exacerbate the existing drug interaction with dolutegravir. Moreover, the metabolism of dolutegravir may also be affected by polymorphism of UGT1A1, a gene that codes for uridine diphosphate glucuronosyltransferase. We used population pharmacokinetic modeling to compare the pharmacokinetics of dolutegravir when coadministered with standard- versus high-dose rifampicin in adults with tuberculosis and HIV, and investigated the effect of genetic polymorphisms. Data from the SAEFRIF trial, where participants were randomized to receive first-line tuberculosis treatment with either standard- 10 mg/kg or high-dose 35 mg/kg rifampicin alongside antiretroviral therapy, were used. The dolutegravir model was developed with 211 plasma concentrations from 44 participants. The median (interquartile range) rifampicin area under the curve (AUC) in the standard- and high-dose arms were 32.3 (28.7–36.7) and 153 (138−175) mg·h/L, respectively. A one-compartment model with first-order elimination and absorption through transit compartments best described dolutegravir pharmacokinetics. For a typical 56 kg participant, we estimated a clearance, absorption rate constant, and volume of distribution of 1.87 L/h, 1.42 h −1 , and 12.4 L, respectively. Each 10 mg·h/L increase in the AUC of coadministered rifampicin from 32.3 mg·h/L led to a 2.3 (3.1–1.4) % decrease in dolutegravir bioavailability. Genetic polymorphism of UGT1A1 did not significantly affect dolutegravir pharmacokinetics. Simulations of trough dolutegravir concentrations show that the 50 mg twice-daily regimen attains both the primary and secondary therapeutic targets of 0.064 and 0.3 mg/L, respectively, regardless of the dose of coadministered rifampicin, unlike the once-daily regimen.

Funder

EC | H2020 | ERA-LEARN | European and Developing Countries Clinical Trials Partnership

HHS | NIH | NIH Office of the Director

Scottish Funding Council

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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