Effect of carbamazepine on dolutegravir pharmacokinetics and dosing recommendation

European Journal of Clinical Pharmacology
Ivy SongStephen C Piscitelli

Abstract

Dolutegravir (DTG) is primarily metabolized by UGT1A1 with CYP3A as a minor route. Carbamazepine (CBZ) is a potent inducer of these enzymes; thus, the effect of oral extended-release CBZ on DTG pharmacokinetics (PK) was evaluated to provide dose recommendation when co-administered. This was a single-center, open-label, fixed-sequence, crossover study in healthy adults. Subjects received three treatments: DTG 50 mg every 24 h (q24h) × 5 days in period 1, followed by CBZ 100 mg every 12 h (q12h) × 3 days, then 200 mg q12h × 3 days, then 300 mg q12h × 10 days in period 2, and DTG 50 mg q24h + CBZ 300 mg q12h × 5 days in period 3. No washout intervals occurred. Each dose was administered with a moderate-fat meal. Serial PK samples for DTG were collected on day 5 of periods 1 and 3. Plasma DTG PK parameters were determined with non-compartmental analysis. Geometric least-squares mean ratios (GMRs) and 90 % confidence intervals (CIs) were generated by the mixed-effect model for within-subject treatment comparisons. Safety assessments were performed throughout the study. Sixteen subjects enrolled; 14 completed the study. CBZ significantly reduced DTG exposure: GMRs (90 % CI) for DTG + CBZ versus DTG alone were 0.51 (0.48-0.549), 0.67 ...Continue Reading

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Citations

Feb 2, 2019·Expert Opinion on Drug Metabolism & Toxicology·Dario CattaneoGiuliano Rizzardini
Nov 15, 2019·Clinical Pharmacology in Drug Development·Teodora Pene DumitrescuKimberly Adkison
May 24, 2019·The Journal of Antimicrobial Chemotherapy·Catalina BarceloUNKNOWN Swiss HIV Cohort Study

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Methods Mentioned

BETA
contraception

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NCT01967771

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