Background:
Abacavir (ABC)/dolutegravir (DTG)/lamivudine (3TC) is a fixed-dose combination (FDC) tablet approved for adults and children with HIV weighing ≥6kg and aged ≥3 months. We evaluated whether ABC/DTG/3TC (60mg/5mg/30mg) dispersible tablet (DT) once daily would achieve therapeutic targets in children weighing 3-<6kg (aged ≥4 weeks).
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 pediatric drug exposures. Simulations were performed with 1000 replicate trials of 200 participants. Exposure metrics (AUC0-24, Cmax, 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 AUC0-24 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 pediatric 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-<6kg receiving a single FDC of ABC/DTG/3TC DT (Table 1) were within the target ranges for each component. AUC0-24, Cmax and C24h of ABC, DTG and 3TC were also comparable to prior pediatric and adult studies. Review of pediatric 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 60mg and ABC 120mg for this WB.
Conclusions:
Predicted drug exposures support the potential use of a single FDC of ABC/DTG/3TC DT in infants weighing 3-<6kg (aged ≥4 weeks), with efficacy and safety expected to be comparable to prior pediatric studies in children ≥6kg. The once daily single tablet treatment option may be a practical solution for infants with early HIV diagnosis.
