Lopinavir/ritonavir plus lamivudine and abacavir or zidovudine dose ratios for paediatric fixed-dose combinations

Antivir Ther. 2015;20(2):225-33. doi: 10.3851/IMP2876. Epub 2014 Oct 3.

Abstract

Background: Lopinavir/ritonavir (LPV/r) is available in a liquid formulation that is far from ideal for treatment of children in resource-poor settings. Flexible, low-cost, solid, oral fixed-dose combinations (FDC) of LPV/r with nucleoside reverse transcriptase inhibitors (LPV/r/abacavir [ABC]/lamivudine [3TC] and LPV/r/zidovudine [ZDV]/3TC) are needed to improve both management and adherence of children. This work aimed to develop appropriate drug ratios and dosing for each FDC.

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/r: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 4-5.9 kg weight band (LPV/ZDV: 120/90 mg twice daily [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 ritonavir, 15 mg 3TC and 30 mg ABC or ZDV. According to the weight bands defined by WHO, 4-5.9 kg, 6-9.9 kg, 10-13.9 kg, 14-19.9 kg, 20-24.9 kg, therapeutic doses would be 2, 3, 4, 5 or 6 individual units administered by oral route bid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Age Factors
  • Antiretroviral Therapy, Highly Active
  • Biological Availability
  • Child
  • Child, Preschool
  • Clinical Trials as Topic
  • Computer Simulation
  • Dideoxynucleosides / administration & dosage
  • Dideoxynucleosides / blood
  • Dideoxynucleosides / pharmacokinetics*
  • Drug Combinations
  • Drug Dosage Calculations
  • Drug Monitoring
  • Female
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV-1 / drug effects
  • HIV-1 / growth & development
  • Humans
  • Infant
  • Lamivudine / administration & dosage
  • Lamivudine / blood
  • Lamivudine / pharmacokinetics*
  • Lopinavir / administration & dosage
  • Lopinavir / blood
  • Lopinavir / pharmacokinetics*
  • Male
  • Models, Statistical*
  • Ritonavir / administration & dosage
  • Ritonavir / blood
  • Ritonavir / pharmacokinetics*
  • Silybin
  • Silymarin / administration & dosage
  • Silymarin / pharmacokinetics*
  • Viral Load / drug effects
  • Zidovudine / administration & dosage
  • Zidovudine / blood
  • Zidovudine / pharmacokinetics*

Substances

  • Dideoxynucleosides
  • Drug Combinations
  • Silymarin
  • abacavir, lamivudine drug combination
  • Lopinavir
  • Lamivudine
  • Zidovudine
  • Silybin
  • Ritonavir