Raltegravir (RAL) in Neonates

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

Diana F. Clarke, PharmD; Edward P. Acosta, PharmD; Mae Cababasay, MS; Jiajia Wang, MS; Anne Chain, PHD; Hedy Teppler, MD; Stephanie Popson, PhD; Bobbie Graham, BS; Betsy Smith, MD; Rohan Hazra, MD; Kat Calabrese, MPH; Yvonne Bryson, MD; Stephen A. Spector, MD; Jos Lommerse, PhD; Mark Mirochnick, MD


J Acquir Immune Defic Syndr. 2020;84(1):70-77. 

In This Article

Abstract and Introduction


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.


Limited data exist to provide dosing recommendations for combination antiretroviral regimens to prevent or treat HIV infection in neonates. The Department of Health and Human Services Perinatal Guidelines recommend the administration of a 3-drug antiretroviral regimen for empiric treatment of newborns at highest risk of HIV acquisition and for treatment of neonates with documented HIV infection. However, sufficient neonatal pharmacokinetic and safety data with formulations appropriate for use in neonates are available for only a few antiretroviral agents in neonates—zidovudine, lamivudine, and nevirapine at birth plus lopinavir/ritonavir after 2 weeks of age.[1]

Raltegravir is a potent and selective HIV-1 integrase strand transfer inhibitor available in a granule formulation suitable for use in neonates and young infants with HIV infection.[1] The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1097 protocol demonstrated that raltegravir readily crosses the placenta and that elimination of transplacentally acquired raltegravir in infants whose mothers received raltegravir during pregnancy is highly variable and prolonged.[2] Raltegravir is metabolized by uridine diphosphate glucuronosyltransferase (UGT) 1A1, whose activity is known to be extremely low immediately after birth followed by a dramatic increase over the first weeks of life.[3,4] Raltegravir and bilirubin are both metabolized by UGT1A1 and compete for albumin-binding sites.[5] Neonatal plasma raltegravir concentrations that exceed typical peak raltegravir concentrations of 4500 ng/mL by 50–100 fold could displace sufficient unconjugated bilirubin from albumin to lead to bilirubin-induced neurologic dysfunction, including kernicterus, as was seen with sulfisoxazole.[5,6]

Although traditional phase I pharmacokinetic and safety studies are difficult to conduct in neonates, population pharmacokinetic modeling and simulations can be used to inform selection of initial dosing regimens for study in this vulnerable population, improving study safety and efficiency. In this study, an adaptive design with population pharmacokinetic modeling and simulations was used to determine an appropriate raltegravir dose for use in neonates and assess the safety of the dosing regimen selected.