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

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Rapid Screening of HIV Reverse Transcriptase and Integrase Inhibitors
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Rapid Screening of HIV Reverse Transcriptase and Integrase Inhibitors

Published on: April 9, 2014

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Naïm Bouazza1, Frantz Foissac, Floris Fauchet

  • 1EA 7323, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.

Antiviral Therapy
|October 4, 2014
PubMed

Insights

Fixed-dose combinations of lopinavir/ritonavir (LPV/r) with nucleoside reverse transcriptase inhibitors offer improved pediatric HIV treatment. New dosing strategies ensure optimal drug exposure and safety in children weighing 4 to 25 kg.

Area of Science:

  • Pharmacology
  • Pediatric Infectious Diseases
  • Drug Development

Background:

  • Liquid lopinavir/ritonavir (LPV/r) formulations are suboptimal for children in resource-limited settings.
  • Need for flexible, low-cost, solid oral fixed-dose combinations (FDCs) of LPV/r with nucleoside reverse transcriptase inhibitors (NRTIs) for improved pediatric HIV management and adherence.
  • Development of LPV/r/abacavir (ABC)/lamivudine (3TC) and LPV/r/zidovudine (ZDV)/3TC FDCs is crucial.

Purpose of the Study:

  • To develop appropriate drug ratios and dosing for fixed-dose combinations (FDCs) of LPV/r with ABC/3TC and ZDV/3TC.
  • To optimize therapeutic drug exposure in pediatric populations based on established plasma targets.
  • To ensure safety and efficacy of new pediatric antiretroviral formulations.

Main Methods:

  • Population pharmacokinetic analyses utilizing data from 25 combined datasets (IMPAACT and PENTA).
  • Monte-Carlo simulations of World Health Organization (WHO) and Food and Drug Administration (FDA) dosing recommendations.
  • Assessment of dosing strategies for children weighing 4 to 25 kg to achieve optimal drug exposure.

Main Results:

  • WHO dosage achieved LPV efficacy targets across all weight bands.
  • Initial dosing for the 4-5.9 kg weight band (LPV/ZDV: 120/90 mg twice daily) showed a high risk of neutropenia (>20% of subjects).
  • Reduced LPV/ZDV dose to 80/60 mg twice daily mitigated neutropenia risk while maintaining LPV efficacy.

Conclusions:

  • A flexible and simple FDC was defined, containing 40 mg LPV, 10 mg ritonavir, 15 mg 3TC, and 30 mg ABC or ZDV.
  • Therapeutic doses, administered orally twice daily, were established for WHO weight bands (4-5.9 kg to 20-24.9 kg) using 2 to 6 individual FDC units.
  • This FDC formulation provides a simplified and effective treatment option for pediatric HIV management.
Abstract

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