There are limited data to guide dosing of antiretrovirals in neonates (and limited approved drugs for this age group).
There is an urgent need for new options both for prophylaxis for neonates at high risk of infection and to treat vertically infected young infants.
Raltegravir (RAL) was recently approved by the FDA for use in children aged two years and above; pharmacokinetics (PK) in infants aged four weeks to two years is under evaluation.
RAL primarily uses the UGT1A1 pathway. UGT1A1 is reduced in neonates but increases in the first weeks to months of life. This pathway is the same as that used by bilirubin and competition for protein binding sites might result in kernicterus. This effect is unlikely unless RAL exceeds typical peak concentrations (approx 4500 ng/mL) by 50 to 100 fold. The toxicity profile of RAL in infants is currently unknown.
At the PK workshop, 2012, Diana Clarke from Boston Medical Centre presented data from IMPAACT P1097. This is an ongoing phase 4 multicentre trial designed to determine washout PK in infants born to HIV positive women who received RAL in pregnancy and to evaluate the safety of in utero/intrapartum exposure in infants. These data will help develop neonatal dosing regimens for future study.
Women who received at least two weeks of RAL (400 mg twice daily) prior to study entry and continued in labour were enrolled.
Maternal and cord blood samples were obtained within one hour of delivery as well as neonatal blood samples at four time points: 1-5, 8-14, 18-24, and 30-36 hours after birth. RAL concentrations were determined using a validated HPLC-MS-MS method. The neonatal half-life was estimated using the terminal 3 concentration- time points. Safety of in utero/intrapartum exposure to RAL was evaluated through 20 weeks follow up. Data are geometric mean (%CV).
Twelve mother/infant pairs were enrolled and data were available for nine pairs. The mean gestational age of the infants was 37.5 weeks and mean birth weight was 3.33 kg. The majority 8/12 were delivered by planned caesarean section, three by spontaneous vaginal delivery and one by forceps/vacuum.
Mean maternal RAL concentration at delivery was 772 ng/mL (113%). Mean cord blood RAL concentration (at mean 3.6 hours after maternal dosing) was 880 ng/mL (78%). Mean cord blood to maternal delivery concentration ratio was 1.14 (55%). Cord blood to maternal plasma concentration increased by approximately 1.5 by 2 to 4 hours after maternal dosing.
Mean last infant RAL concentration at 30 to 36 hours was 407 ng/mL(range 42.1 to 1401 ng/mL). Mean infant RAL half-life was 23.2 hours (range 9.3-87.8 hours). RAL elimination was highly variable.
No safety issues were observed in the first 20 weeks of life.
Simulations combining these data plus PK from 4 weeks to 6 months in P1066 will be used to determine dose and dosing frequency for neonates.
Raltegravir has important characteristics that make its potential use in pregnancy and for uninfected (and infected) infants compelling.
Because of its rapid first and second phase viral decay plus good transplacental transfer, new BHIVA guidelines recommend women who are untreated in pregnancy or do not initiate treatment until after 28 weeks receive it as part of their regimen. There are limited reports from the UK, presented at the recent BHIVA meeting, which we will cover in the next issue of HTB as we have with previous presentations.2-4
Investigation into use of raltegravir in neonates is ongoing.
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