A single once daily ABC/DTG/3TC tablet predicts safe and effective exposures in children 3 to <6 kg

31

A single once daily ABC/DTG/3TC tablet predicts safe and effective exposures in children 3 to <6 kg

Hardik Chandasana¹, Kristina Brooks², Ann Buchanan³, Lionel Tan⁴, Hilda Mujuru⁴, Angela Colbers⁵, Judy Hopking¹, Marika Ciuffa¹, Michael McKenna¹, Andrew Wiznia⁶, Sean Brummel⁷, Adrie Bekker⁸, Tim Cressey⁹ and Helena Rabie⁸

¹GSK; ²Anschutz Medical Campus, University of Colorado; ³ViiV Healthcare; ⁴University of Zimbabwe; ⁵Radboud University Medical Center; ⁶Jacobi Medical Center, Albert Einstein College of Medicine; ⁷Harvard T.H. Chan School of Public Health; ⁸Stellenbosch University; ⁹AMS-PHPT, Chiang Mai University

Background: Abacavir (ABC)/dolutegravir (DTG)/lamivudine (3TC) is a fixed-dose combination (FDC) tablet approved for adults and children with HIV weighing ≥6 kg and aged ≥3 months. We evaluated whether ABC/DTG/3TC (60 mg/5 mg/30 mg) dispersible tablet (DT) once daily would achieve therapeutic targets in children weighing 3 to <6 kg (aged ≥4 weeks).

Materials and methods: We used a population pharmacokinetic (PopPK) model-based approach leveraging existing data with single entities and FDC formulations from adults, infants and children with HIV. Drug-specific PopPK models incorporating expected enzyme and renal maturation functions were developed for ABC, DTG and 3TC and used to predict paediatric drug exposures. Simulations were performed with 1000 replicate trials of 200 participants. Exposure metrics (AUC_0–24, C_max and C24) were calculated for each drug and compared with pre-defined exposure target range (DTG C24 geometric mean [GM] 0.697–2.26 μg/mL, ABC AUC0–24 GM 6.3–50.4 μg*h/mL and 3TC AUC_0–24 GM 6.3–26.5 μg*h/mL). We reviewed safety findings for ABC, DTG and 3TC in the lowest weight bands (WBs) of three paediatric trials (P1093, ODYSSEY and IMPAACT 2019), alongside available literature describing PK and safety of ABC and 3TC in neonates and infants under 3 months (including PETITE study).

Results: Predicted GM steady-state plasma exposures of ABC, DTG and 3TC in children 3 to <6 kg receiving a single FDC of ABC/DTG/3TC DT were within the target ranges for each component. AUC_0–24, C_max and C24h of ABC, DTG and 3TC were also comparable to prior paediatric and adult studies. Review of paediatric safety data showed similar safety profiles across WBs and were consistent with the known safety profile of the individual drugs. Most children in these studies were on the higher WHO doses of 3TC 60 mg and ABC 120 mg for this WB.

Conclusions: Predicted drug exposures support the potential use of a single FDC of ABC/DTG/3TC DT in infants weighing 3 to <6 kg (aged ≥4 weeks), with efficacy and safety expected to be comparable to prior paediatric studies in children ≥6 kg. The once-daily single tablet treatment option may be a practical solution for infants with early HIV diagnosis.