Background:
There is an increasing emphasis on reducing toxicity and improving acceptability of HIV-treatment. Two-drug regimens, consisting of two different antiretroviral drug classes, are recommended as an alternative to standard three-drug regimens, with dolutegravir and lamivudine (DTG/3TC) included in a number of adult treatment guidelines. This nested pharmacokinetics (PK) sub-study within the D3/Penta21 randomized controlled trial (#NCT04337450) is evaluating DTG and 3TC concentrations in children and adolescents, previously suppressed on a three-drug first-line regimen, who switched to once-daily DTG/3TC fixed dose combinations (FDC).
Methods:
Eligible children aged 2 to <15 years weighing 6-<40kg received either 5/30mg DTG/3TC dispersible tablets (DT) or 50/300mg film-coated tablets (FCT). Children in weightband (WB) 10-<14kg took 20/120mg; WB 14-<20kg 25/150mg DT; WB 20-<25kg took either 30/180mg DT or 50/300mg FCT; WB 25-<40kg took 50/300mg FCT, respectively. We aimed for ≥8 evaluable PK curves per WB/formulation. Seven blood samples were taken at steady-state after an overnight fast at t=0, and 1, 2, 3, 4, 6 and 24 h post dosing. PK parameters for DTG and 3TC and the number of children with DTG Ctrough below EC90 (0.32 mg/L) and PA-IC90 (0.064 mg/L) were summarised.
Results:
53 participants were included in this preliminary PK analysis (~70% of sub-study participants with successful PK sampling). Median(range) age was 7.1(2.8-13.8) years and weight 21.5(12.6-39.5) kg. DTG Ctrough, AUC0-24h and Cmax geometric mean(GM) (%CV) were 0.77(52) mg/L, 64(35) h*mg/L and 6.38(31) mg/L. 3TC Ctrough, AUC0-24h and Cmax GM(%CV) were 0.06(35) mg/L, 17(38) h*mg/L and 3.25(37) mg/L. Figure shows PK parameters by WB. Only 3 children had DTG Ctrough<0.32mg/L (1 in WB 10-<14kg; 2 in WB 25-<40kg). All children had Ctrough ≥0.064mg/L. In the 20-<25kg WB, 3TC AUC0-24h GM was 1.5 times higher in children receiving 50/300mg FCT versus 30/180mg DT; however, the AUC0-24h GM was not much higher than the AUC0-24hGM in participants weighing ≥25kg.
Conclusions:
Preliminary PK results demonstrate that DTG and 3TC concentrations after administration of a DTG/3TC FDC in virologically suppressed children living with HIV are comparable with previous paediatric PK studies of DTG (ODYSSEY) and 3TC (IMPAACT2019). As expected, because of a higher dose/kg in the 20-25kg WB in the FCT group in D3/Penta 21 compared to IMPAACT2019, (300mg v180mg), increased 3TC exposures were observed. Further PK data and safety data are awaited.
