Pharmacokinetic modeling to support WHO-weight band dosing of a new pediatric darunavir/ritonavir (120/20 mg) fixed-dose combination tablet for children at least 3 years old and weighing 10 to less than 35 kg

Background: Darunavir boosted with ritonavir (DRV/r) is the preferred HIV protease inhibitor for children, but no child-friendly fixed-dose combination (FDC) exists. A generic DRV/r 120/20 mg FDC tablet (6:1 ratio) is under development; however, dosing guidance across WHO weight bands is lacking. We performed a pharmacokinetic (PK) modeling/simulation study to inform dosing of the DRV/r FDC tablet in children. Methods: Darunavir/ritonavir plasma concentration data from three pediatric HIV trials (DELPHI, ARIEL and CHAPAS-4), administered as separate formulations, were pooled to update a pediatirc population PK model. Simulations were performed for children ≥3 years old weighing 10-<35 kg, evaluating doses of the 120/20 mg DRV/r tablets once- and twice daily per WHO-weight bands. The PK target was a geometric mean DRV exposure (AUC 0-tau ) within 80%-130% of adult values. Results: Data from 162 children 3-16 years old were included. Darunavir PK was described using a 2-compartment model, with differing absorption lag-time between formulations. Clearance and volume of distribution were allometrically scaled according to weight. Alpha-1-acid glycoprotein concentrations inversely influenced DRV clearance. Simulations predicted the following DRV/r doses achieved target exposures: DRV/r once daily: 480/80 mg (4 tablets) from 10 to <14 kg and 600/100 mg (5 tablets) from 14 to <35 kg. DRV/r twice daily: 240/40 mg (2 tablets) from 10 kg to <14 kg; 360/60 mg (3 tablets) from 14 kg to <25 kg; and 480/80 mg (4 tablets) from 25kg to <35 kg. Conclusion: Model-based dosing supports once- and twice-daily of the pediatric DRV/r 120mg/20mg FDC tablet across WHO-weight bands.