Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial
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 ,   EMPIRICAL Clinical Trial Group, Sacarlal Jahit , Sidat Muhammad , Manjate Elias , Martins Sónia , Langa Stella , Nipaco Natália , Machava Sara , Chirindza Anastância , Martins Luzidina , Nhaca Mércia , Nathoo Kusum J , Chitsamatanga Moses , Marange Ruth , Mudzingwa Shepherd , Murungu Dorothy , Namuziya Natasha , Zulu Idah , Shankalala Perfect , Mukubesa Mulima , Namwinwa Juliet , Chibuye Chalwe , Chipoya Terence , Mulenga Veronica , Simunyola Bwalya , Tembo John , Inambao Muleya , Chitondo Salome , Mumba Wyclef , Mankushe Endreen , Musukwa Henry , Sondashi Davies , Kamugisha Albert , Econi Karen , Kiggwe Andrew , Beinomugisha Judith , Nkinzi Sharafat , Kakooza Lawrence , Namisanvu Henriator , Mark Nancy Lajara , Mwesige Josam Thembo , Segawa Ivan , Ssessanga Joseph , Mbavu Paul , Kafufu Bosco , Nansera Denis , Najjingo Elizabeth , Mbabazi Bashira T , Lugemwa Abbas , Kasozi Mariam , Ankunda Rogers , Manukyan Lilit 
Published: October 2023

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 &lt;0.32 mg/L, and none had Ctrough &lt;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 &lt;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.