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

Abstract

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.

Figure 1.

Simulated pharmacokinetic profile of raltegravir for typical individual treated by dose regimen scenario 10: 1.5 mg/kg once daily from day-1 to day-7, 3 mg/kg twice daily from day-8 to day-28 and 6 mg/kg twice daily from day-29 to day-42.

Figure 2.

Simulated C_trough and AUC profiles for dosing regimen no. 10. C_trough is plotted against the left axis and AUC against the right axis. Black dots represent C_trough values, red squares represent AUC_0–24 for days 1–7 and red triangles represent AUC_0–12 for days 8–42. Dotted lines present the C_trough criterion ≥0.033 mg/L, AUC_0–24 criterion ≤ 40 mg*hr/L and AUC _0–12 criterion ≤ 20 mg*hr/L.