Use of Modeling and Simulations to Determine Raltegravir Dosing in Neonates: A Model for Safely and Efficiently Determining Appropriate Neonatal Dosing Regimens: IMPAACT P1110

J Acquir Immune Defic Syndr. 2019 Dec 1;82(4):392-398. doi: 10.1097/QAI.0000000000002149.


Background: Population modeling and simulations can be used to facilitate the conduct of phase I studies to develop safe and effective dosing regimens in neonates.

Setting: P1110 is an international, multicenter trial to determine safe and effective raltegravir doses in neonates at risk for HIV infection.

Methods: P1110 used a 2-cohort adaptive design incorporating population pharmacokinetic modeling and simulations. An initial cohort of neonates received 2 single oral doses of raltegravir with standard-of-care therapy for prevention of perinatal transmission-one within 48 hours of birth and a second at 7-10 days of life. Raltegravir concentration data after administration of these doses were combined with data from a previous study of infants aged 4 weeks to 2 years. The combined database was used for population pharmacokinetic modeling and simulations to select a daily dosing regimen for investigation in a second cohort of neonates.

Results: Raltegravir concentration data from 6 neonates were combined with data from infants aged 4 weeks to 2 years receiving raltegravir twice daily. The combined data set allowed for successful development of a population pharmacokinetic model with reasonable precision of parameter estimates. Monte Carlo simulations were run to evaluate potential daily dosing regimens from birth to 6 weeks of age, allowing for selection of a regimen to be evaluated in a subsequent cohort of neonates receiving chronic raltegravir dosing.

Conclusions: An adaptive design incorporating population pharmacokinetic modeling and simulations was used to select a developmentally appropriate neonatal raltegravir dosing regimen in the first 6 weeks of life.

Publication types

  • Multicenter Study

MeSH terms

  • Adolescent
  • Adult
  • Anti-HIV Agents / administration & dosage*
  • Child
  • Drug Administration Schedule
  • Female
  • HIV Infections / drug therapy*
  • Humans
  • Infant
  • Infant, Newborn
  • Infectious Disease Transmission, Vertical
  • Male
  • Models, Biological
  • Monte Carlo Method
  • Raltegravir Potassium / administration & dosage*
  • Raltegravir Potassium / adverse effects
  • Raltegravir Potassium / pharmacokinetics
  • Young Adult


  • Anti-HIV Agents
  • Raltegravir Potassium