There are limited abacavir (ABC) pharmacokinetic (PK) data in African children living with HIV (CLHIV) <14 kg receiving pediatric fixed-dose combinations (FDC) dosed by WHO weight-bands (WB). WB dosing with FDC tablets leads to higher than FDA-approved mg/kg daily doses of ABC in the lower WBs. We developed an ABC population PK model using clinical data from Kenyan and Ugandan CLHIV to assess ABC exposures across WBs.
Children enrolled in the LIVING study in Kenya and Uganda [NCT02346487] who received ABC/3TC (60/30 mg) dispersible tablets and LPV/r (40/10 mg) pellets BID according to WHO WB were included. Sparse PK samples were collected after 1 month, and every 6 months for up to 30 months. PK parameters were estimated using a population approach. Using the final model, simulations were performed using a standardized in silico paediatric population with demographics representative of African CLHIV to predict ABC exposure across WBs. Target daily ABC exposures (AUC[sub]0-24[/sub]) were those reported in older children (6.4 to 50.4 mg.h/L).
A total of 2,254 ABC plasma samples were available from 387 children (49.6% female). At baseline, mean (range) age was 2.91 (0.3-9.7) years, body weight was 11.95 (4.4-23) kg, 16% were moderately and 10% severely underweight. ABC PK was described by a 1-compartment model. Body weight influenced clearance (CL/F) and volume of distribution (V/F) and was allometrically scaled. Maturation of ABC CL/F was described using a sigmoid model dependent on post-natal age (50% adult CL/F achieved by 0.48 yrs old). ABC CL/F, V/F and Ka were 21.4 L/h, 7.2 L (standardized to a 12.9 kg child) and 0.37 h-1, respectively. ABC exposures were within target for children 6.0-24.9 kg but higher exposures were seen for children 3-5.9 kg (Figure 1). Reducing the ABC dose to 30 mg BID or 60 mg OD for children 3-5.9 kg achieved a higher proportion within target.
Twice daily WHO WB dosing of FDC tablets containing 60 mg ABC provide adequate exposure in children ?6 kg; however, higher exposures are expected for children 3.0-5.9 kg. While no safety concerns have been reported with the current dosing, lower ABC doses (30 mg BID or 60 mg OD) in WB 1 would be optimal to achieve comparable exposures.