Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial

• Published in: Clinical infectious diseases Vol. 78; no. 3; pp. 702 - 710
• Main Authors: Jacobs, Tom G, Mumbiro, Vivian, Cassia, Uneisse, Zimba, Kevin, Nalwanga, Damalie, Ballesteros, Alvaro, Domínguez-Rodríguez, Sara, Tagarro, Alfredo, Madrid, Lola, Mutata, Constantine, Chitsamatanga, Moses, Bwakura-Dangarembizi, Mutsa, Passanduca, Alfeu, Buck, W Chris, Nduna, Bwendo, Chabala, Chishala, Najjingo, Elizabeth, Musiime, Victor, Moraleda, Cinta, Colbers, Angela, Mujuru, Hilda A, Rojo, Pablo, Burger, David M
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 20.03.2024
• Subjects: Female; Heterocyclic Compounds, 3-Ring - pharmacokinetics; HIV; HIV Infections; Humans; Infant; Male; Oxazines; Piperazines; Pyridones; Rifampin - therapeutic use; rifampicin; infants; dolutegravir; drug–drug interaction; HIV
• ISSN: 1058-4838; 1537-6591
• DOI: 10.1093/cid/ciad656

Abstract Background We evaluated dolutegravir pharmacokinetics in infants with human immunodeficiency virus (HIV) receiving dolutegravir twice daily (BID) with rifampicin-based tuberculosis (TB) treatment compared with once daily (OD) without rifampicin. Methods Infants with HIV aged 1–12 months, weighing ≥3 kg, and receiving dolutegravir BID with rifampicin or OD without rifampicin were eligible. Six blood samples were taken over 12 (BID) or 24 hours (OD). Dolutegravir pharmacokinetic parameters, HIV viral load (VL) data, and adverse events (AEs) were reported. Results Twenty-seven of 30 enrolled infants had evaluable pharmacokinetic curves. The median (interquartile range) age was 7.1 months (6.1–9.9), weight was 6.3 kg (5.6–7.2), 21 (78%) received rifampicin, and 11 (41%) were female. Geometric mean ratios comparing dolutegravir BID with rifampicin versus OD without rifampicin were area under curve (AUC)0–24h 0.91 (95% confidence interval, .59–1.42), Ctrough 0.95 (0.57–1.59), Cmax 0.87 (0.57–1.33). One infant (5%) receiving rifampicin versus none without rifampicin had dolutegravir Ctrough <0.32 mg/L, and none had Ctrough <0.064 mg/L. The dolutegravir metabolic ratio (dolutegravir-glucuronide AUC/dolutegravir AUC) was 2.3-fold higher in combination with rifampicin versus without rifampicin. Five of 82 reported AEs were possibly related to rifampicin or dolutegravir and resolved without treatment discontinuation. Upon TB treatment completion, HIV viral load was <1000 copies/mL in 76% and 100% of infants and undetectable in 35% and 20% of infants with and without rifampicin, respectively. Conclusions Dolutegravir BID in infants receiving rifampicin resulted in adequate dolutegravir exposure, supporting this treatment approach for infants with HIV–TB coinfection. Dolutegravir trough concentrations in plasma were adequate for infants with human immunodeficiency virus receiving dolutegravir twice daily with rifampicin following World Health Organization weight-band dosing recommendations and comparable to trough concentrations in infants receiving dolutegravir once daily without rifampicin.