Pharmacogenetics of Plasma Dolutegravir Exposure During 1-Month Rifapentine/Isoniazid Treatment of Latent Tuberculosis

Authors

Nia Covington
Anne F Luetkemeyer
Marjorie Z Imperial
Rodney Dawson
Yoninah Cramer
Sue Rosenkranz
Susan Swindells
Irina Gelmanova
Anchalee Avihingsanon
Roberto C Arduino
Wadzanai Samaneka
Kelly E Dooley
Rada Savic
Anthony T Podany
David W Haas

Publication Date

6-1-2025

Journal

Pharmacogenetics and Genomics

Abstract

In Advancing Clinical Therapeutics Globally protocol A5372, a pharmacokinetic study of dolutegravir with 1-month of daily rifapentine/isoniazid, twice-daily dolutegravir offset the induction effects of rifapentine on plasma dolutegravir trough concentrations (C trough ). Here, we characterize the impact on dolutegravir C trough of UGT1A1 , AADAC , and NAT2 polymorphisms that affect dolutegravir, rifapentine, and isoniazid, respectively. People with HIV receiving dolutegravir-based antiretroviral therapy with an indication to treat latent tuberculosis underwent pharmacokinetic sampling during dolutegravir 50 mg once daily alone, and on day 28 of dolutegravir 50 mg twice daily with rifapentine/isoniazid. Multivariable linear regression models characterized genetic associations with dolutegravir C trough . Among 30 participants evaluable for genetic associations, median (Q1, Q3) day 0 dolutegravir C trough was 1745 (1099, 2694) ng/ml, and day 28 was 2146 (1412, 2484) ng/ml. Day 28 C trough was higher with UGT1A1 rs887829 TT [geometric mean ratio (GMR) = 1.65; 90% confidence interval (CI): 0.97-2.78] and CT (GMR = 1.38; 90% CI: 1.02-1.86) than with CC, and was higher with AADAC rs1803155 GG (GMR = 1.79; 90% CI: 1.09-2.93) and AG (GMR = 1.48; 90% CI: 1.14-1.90) than with AA. Median day 28 C trough ranged from 1205 (1063, 1897) ng/ml with 4 total UGT1A1 and AADAC risk alleles, to 3882 and 3717 ng/ml with only one risk allele. Individuals with concomitant AADAC slow metabolizer and UGT1A1 normal metabolizer genotypes may be at greater risk for clinically significant drug-drug interactions between rifapentine/isoniazid and dolutegravir.

Keywords

Pharmacogenomic Testing, HIV Integrase Inhibitors, HIV Infections, Latent Tuberculosis, Antibiotics, Antitubercular, Isoniazid, Humans, Male, Female, Young Adult, Adult, Middle Aged, Glucuronosyltransferase, Carboxylic Ester Hydrolases, Rifampin, Piperazines, Pyridones, Heterocyclic Compounds, 3-Ring, Oxazines, CYP3A, HIV-1, UGT1A1, dolutegravir, isoniazid, pharmacogenetics, rifapentine, tuberculosis

DOI

10.1097/FPC.0000000000000562

PMID

39960813

PMCID

PMC12043259

PubMedCentral® Posted Date

2-12-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes