Background: Lopinavir/ritonavir (LPV/r) is available in a liquid formulation far from ideal for treatment of children in resource poor settings. Flexible, low-cost, solid, fixed-dose oral combinations (FDC) of LPV/r with nucleoside reverse transcriptase inhibitors (NRTI) (LPV/ABC/3TC and LPV/ZDV/3TC) is needed to improve both management and adherence of children. This work was aimed to develop appropriate drug ratios and dosing for each FDCs.
Methods: Data from 25 combined datasets included therapeutic drug monitoring and clinical studies from IMPAACT and PENTA. Population pharmacokinetic analyses were performed using Monolix. Monte-Carlo simulations of WHO and FDA dosing recommendations were performed to assess their ability to provide optimal exposure in children weighing 4 to 25 kg based on consensus plasma targets. The LPV:3TC:ZDV(ABC) dose ratios were 2.67: 1: 2(2) respectively.
Results: Using WHO dosage, LPV efficacy target was reached in all weight-bands. Given the recommended drug ratios, the dosage for the 4-6 kg weight band (LPV/ZDV: 120/90 mg BID) showed more than 20% of subjects had ZDV levels at high risk of neutropenia. Reducing the LPV/ZDV dose to 80/60 mg BID decreased frequency of high ZDV concentrations but retained the LPV efficacy criteria.
Conclusions: This defined a flexible and simple FDC containing 40 mg LPV, 10 mg RTV, 15 mg 3TC and 30 mg ABC or ZDV. According to the weight-bands defined by WHO, 4-6 kg, 6-10 kg, 10-14 kg, 14-20 kg, 20-25 kg, therapeutic doses would be 2, 3, 4, 5, or 6 individual units administered by oral route twice-daily.
Bouazza, N.; Foissac, F.; Fauchet, F.; Burger, D.; Kiechel, J.R.; Treluyer, J.M.; Capparelli, E.V.; Lallemant, M.; Urien, S. Lopinavir/ritonavir plus lamivudine and abacavir or zidovudine dose ratios for paediatric fixed-dose combinations. Antiviral Therapy (2014) : [DOI: 10.3851/IMP2876]