Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial
Author:
Jacobs Tom G1ORCID, Mumbiro Vivian2, Cassia Uneisse3, Zimba Kevin4, Nalwanga Damalie5, Ballesteros Alvaro6, Domínguez-Rodríguez Sara6ORCID, Tagarro Alfredo678ORCID, Madrid Lola69, Mutata Constantine2, Chitsamatanga Moses2, Bwakura-Dangarembizi Mutsa2, Passanduca Alfeu3, Buck W Chris310, Nduna Bwendo11, Chabala Chishala41213, Najjingo Elizabeth14, Musiime Victor515, Moraleda Cinta616, Colbers Angela1ORCID, Mujuru Hilda A2, Rojo Pablo61617, Burger David M1, 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,
Affiliation:
1. Department of Pharmacy, Radboudumc Institute for Medical Innovation, Radboud University Medical Center , Nijmegen , The Netherlands 2. University of Zimbabwe Clinical Research Centre , Harare , Zimbabwe 3. Universidade Eduardo Mondlane Faculdade de Medicina , Maputo , Mozambique 4. University Teaching Hospitals-Children’s Hospital , Lusaka , Zambia 5. Department of Paediatrics and Child Health, School of Medicine, College of Health Sciences, Makerere University , Kampala , Uganda 6. Pediatric Unit for Research and Clinical Trials, Hospital 12 de Octubre Health Research Institute, Biomedical Foundation of Hospital Universitario 12 de Octubre , Madrid , Spain 7. Pediatric Service, Infanta Sofia University Hospital, Servicio Madrileño de Salud , Madrid , Spain 8. Universidad Europea de Madrid , Madrid , Spain 9. London School of Hygiene and Tropical Medicine , London , United Kingdom 10. David Geffen School of Medicine, University of California–Los Angeles , Los Angeles, California , USA 11. Arthur Davidson Children’s Hospital , Ndola , Zambia 12. School of Medicine, University of Zambia , Lusaka , Zambia 13. HerpeZ , Lusaka , Zambia 14. Mbarara Regional Referral Hospital , Mbarara , Uganda 15. Joint Clinical Research Centre , Kampala , Uganda 16. Pediatric Service, Hospital Universitario 12 de Octubre, Servicio Madrileño de Salud , Madrid , Spain 17. Complutense University of Madrid , Madrid , Spain
Abstract
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 living 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.
Funder
European Union Mozambique EMPIRICAL PediCAP)
Publisher
Oxford University Press (OUP)
Subject
Infectious Diseases,Microbiology (medical)
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