Twice-daily dosing of dolutegravir in infants on rifampicin treatment: a pharmacokinetic substudy of the EMPIRICAL trial

Abstract Introduction We evaluated dolutegravir pharmacokinetics in infants with HIV receiving dolutegravir twice-daily with rifampicin-based TB-treatment compared to once-daily without rifampicin. Methods This pharmacokinetic substudy was nested in the EMPIRICAL trial for infants with HIV admitted with severe pneumonia. Infants aged 1-12 months, weighing ≥3 kg, and receiving dolutegravir twice-daily with rifampicin or once-daily without rifampicin were eligible. Six bloodsamples were taken over 12 (twice-daily dosing) or 24 hours (once-daily dosing). Dolutegravir pharmacokinetic parameters were calculated and compared for infants with and without rifampicin, and HIV viral load data and adverse events (AEs) were reported descriptively. Results 27/30 enrolled infants on dolutegravir had evaluable pharmacokinetic curves. The median (IQR) age was 7.1 (6.1-9.9) months, weight was 6.3 (5.6-7.2) kilograms, 21/27 (78%) received rifampicin, and 11/27 (41%) were female. Geometric mean ratios comparing dolutegravir twice-daily with rifampicin versus once-daily without rifampicin were AUC0–24h 0.91 (95%CI 0.59-1.42); Ctrough 0.95 (0.57-1.59); Cmax 0.87 (0.57-1.33). 1/21 infants receiving rifampicin versus 0/6 without rifampicin had dolutegravir Ctrough <0.32 mg/L, and none had Ctrough <0.064 mg/L. Dolutegravir metabolic ratio (dolutegravir-glucuronide AUC/dolutegravir AUC) was 2.3-fold higher in combination with rifampicin versus without rifampicin. 5/82 reported AEs were possibly related to rifampicin or dolutegravir and resolved without treatment discontinuation. Upon TB-treatment completion, HIV viral load was <1,000 copies/mL in 76% and 100% of infants, and undetectable in 35% and 20% of infants with and without rifampicin, respectively. Conclusion Dolutegravir twice-daily in infants receiving rifampicin-based TB-treatment resulted in adequate dolutegravir exposure, supporting this treatment approach for infants with HIV-TB coinfection.