Raltegravir (RAL) in Neonates: Dosing, Pharmacokinetics (PK), and Safety in HIV-1–Exposed Neonates at Risk of Infection (IMPAACT P1110)

Abstract

Background: Adequate pharmacokinetic and safety data in neonates are lacking for most antiretroviral agents. Raltegravir is a selective HIV-1 integrase strand transfer inhibitor available in a granule formulation suitable for use in neonates and young infants as prophylaxis or treatment of HIV infection. Methods: IMPAACT P1110 is a phase 1, multicenter, noncomparative dose-finding study of raltegravir in infants exposed to HIV-1 infection. A 2-cohort adaptive design was utilized where pharmacokinetic data from infants in cohort 1 who received 2 single doses of raltegravir 3 mg/kg were included in population modeling and simulations to guide selection of a daily dose for infants in cohort 2. Results: A total of 52 infants enrolled in IMPAACT 1110: cohort 1 (N = 16) and cohort 2 (N = 36). Using simulations based on population PK modeling incorporating cohort 1 data, the following daily dosing regimen was selected for study: 1.5 mg/kg daily from birth through day 7; 3 mg/kg twice daily from days 8–28 of life; and 6 mg/kg twice daily after 4 weeks of age through 6 weeks of age. The geometric mean protocol exposure targets for AUC, Ctrough, and Cmax were met or slightly exceeded in all infants. The chosen neonatal raltegravir dosing regimen was safe and well tolerated in full-term neonates during treatment over the first 6 weeks of life and follow-up to age 24 weeks. Conclusions: Raltegravir can be safely administered to full-term infants using the daily dosing regimen studied. This regimen is not recommended for use in premature infants in a new version of P1110.

Low raltegravir transfer into the breastmilk of a woman living with HIV

“…Raltegravir and bilirubin are both metabolized by UGT1A1 and compete for albumin binding sites [ 18 ]. In this case, the UGT1A1 activity of the infant was probably matured at the time of sampling, whereas low UGT1A1 activity in neonates may result in higher raltegravir concentrations [ 18 , 19 ].…”

“…Raltegravir and bilirubin are both metabolized by UGT1A1 and compete for albumin binding sites [ 18 ]. In this case, the UGT1A1 activity of the infant was probably matured at the time of sampling, whereas low UGT1A1 activity in neonates may result in higher raltegravir concentrations [ 18 , 19 ]. The observed hyperbilirubinemia could, therefore, be not only attributed to the raltegravir exposure via breastmilk but also to intrauterine raltegravir exposure as reported in nonbreastfed infants after intrauterine integrase inhibitor exposure [ 20 – 22 ].…”

A Health Literate Patient-focused Approach to the Redesign of the Raltegravir (ISENTRESS) Pediatric Kit and Instructions for Use

“…However, the old raltegravir pediatric kit was not designed for use in neonates who required doses below 20 mg and who present a very different metabolic environment. The IMPAACT P1110 14 study developed pharmacokinetic and safety data for raltegravir in neonates, and in 2017, raltegravir received FDA approval for use in full-term infants from birth to 28 days old (neonates) weighing at least 2 kg. 15 The recommended raltegravir dosing for neonates begins as low as 4 mg once daily and is modified based upon the age (by week) and body weight of the neonate (Table 1 ).…”

Optimising neonatal antiretroviral therapy using raltegravir: a qualitative analysis of healthcare workers’ and caregivers’ perspectives

“…At this visit, the dose is doubled and administration changes from once a day to two times a day, to adjust for the rapid changes in RAL metabolism that occur in the first few weeks of life. 6 At 28 days of life, current guidance recommends switching from a RAL granule-based regimen to a dolutegravir (DTG)-based or lopinavir/ritonavir (LPV/r)-based regimen, depending on the country’s available paediatric formulations. The additional visits, dosing changes and regimen switch required for the use of neonatal RAL, add significant levels of complexity to service delivery.…”

“…On day 8 of life, the dose must be adjusted for weight, which usually requires the caregiver to bring their baby back to the facility to make this adjustment. At this visit, the dose is doubled and administration changes from once a day to two times a day, to adjust for the rapid changes in RAL metabolism that occur in the first few weeks of life 6. At 28 days of life, current guidance recommends switching from a RAL granule-based regimen to a dolutegravir (DTG)-based or lopinavir/ritonavir (LPV/r)-based regimen, depending on the country’s available paediatric formulations.…”