Raltegravir (RAL) has potential for use as prophylaxis of perinatal transmission and early intensive treatment of neonates with HIV infection. Safety and pharmacokinetics (PK) of RAL was studied to determine the appropriate dose of RAL oral granules for suspension during the first 6 weeks of life.
IMPAACT P1110 is a phase I multicenter trial enrolling full-term HIV-1 exposed neonates at high risk of acquiring HIV-1-infection, with or without in utero RAL exposure. Study design included two cohorts: cohort 1 infants received 2 single RAL doses 1 week apart; cohort 2 infants received daily RAL dosing for first 6 weeks of life. PK data from Cohort 1 (previously reported) and from older infants and children were combined in a population PK model and simulations were used to select this daily RAL dosing regimen for evaluation in RAL naïve infants in Cohort 2: 1.5 mg/kg daily starting within 48 hours of life through day 7; 3 mg/kg twice daily on days 8-28 of life; 6 mg/kg twice daily after 4 weeks of age. Four plasma samples were collected after the initial dose and on the 3 mg/kg dose between 15-18 days of life; sparse sampling was obtained when doses were changed. Samples were analyzed for RAL concentrations using a validated HPLC-MS-MS method. AUC was estimated using the trapezoidal method. Protocol exposure targets for each subject are AUC24 12-40mg*h/L, AUC12 6-20 mg*h/L, C12 or C24 > 33ng/mL. Safety was assessed based on clinical and laboratory evaluations.
Twenty-six RAL-naïve infants were enrolled in Cohort 2. Evaluable PK results and 6 week safety data are available for 25 infants. After the first dose of 1.5 mg/kg, geometric mean (GM) RAL AUC24 was 38.2 mg*h/L and C24 was 948 ng/mL. On 3 mg/kg twice daily the GM RAL AUC12 was 14.3 mg*h/L and Cl2 estimated to be 176.1 ng/mL. There were no safety concerns associated with daily RAL administration through 6 weeks of life.
Daily RAL was safe and well tolerated during the first 6 weeks’ of life. All GM protocol exposure targets were met. In some infants AUC24 following the initial dose was slightly above target range but this was considered acceptable given the rapid increase in RAL metabolism over the first week of life. The PK targets and the safety guidelines have been met for RAL-unexposed infants in cohort 2 using the specified dosing regimen.