Impact of Low Birth Weight and Prematurity on Neonatal Raltegravir Pharmacokinetics: Impaact P1097

Abstract

Background: HIV treatment of neonates requires identifying appropriate antiretroviral dosing regimens. Our aims were to characterize raltegravir elimination kinetics in low birth weight (LBW) neonates after maternal dosing and to develop a pharmacokinetic model to predict raltegravir plasma concentrations for term and preterm neonates.

Methods: Mothers living with HIV who received raltegravir during pregnancy and their LBW neonates participated in IMPAACT P1097 study. Up to 6 serial plasma samples were collected from each infant over the first 2 postnatal weeks to characterize raltegravir elimination. Safety laboratory evaluations were obtained, and infants were monitored for 6 weeks for signs of raltegravir toxicity. An integrated maternal-neonatal pharmacokinetic model was developed to predict neonatal raltegravir plasma concentrations.

Results: Sixteen mothers and their 18 LBW neonates were enrolled. The median (range) raltegravir elimination half-life was 24.4 (10.1-83) hours (N = 17 neonates). No adverse events related to raltegravir in utero exposure were observed. Pharmacokinetic modeling revealed that raltegravir clearance in full-term LBW neonates was well described by allometric scaling but clearance in preterm LBW neonates was better described using slower clearance maturation kinetics. Simulations suggest receipt of the current dosing recommendations in a 34-week gestation neonate would result in plasma concentrations up to 2.5-fold higher than those observed in full-term LBW infants.

Conclusions: Modeling suggests that prematurity reduces raltegravir clearance and a modified raltegravir dosing regimen will be necessary to avoid elevated plasma raltegravir concentrations.

Figure 1.. Raltegravir elimination kinetics.

(A) Mean (SE) raltegravir plasma concentration (ng/mL) versus time from birth. The sampling time intervals are 1–6 hours (N = 5), 12–24 hours (N = 11), 36–48 hours (N = 16), 72–84 hours (N = 16), 108–132 hours (N = 16), and 7-14 days (N = 16). (B) raltegravir plasma concentration over time for individual low birth weight (LBW) neonates.

Figure 2.. Comparison of the modified maternal-neonatal model results to empirical raltegravir clearance data from LBW neonates.

Shown are the raltegravir plasma concentrations for individual LBW neonates (blue symbols) superimposed on the integrated maternal-neonatal model predictions for the mother (green lines) and full term neonates (blue lines). GA, gestational age (weeks); BW, birth weight (kg). Preterm: ≤ 35 weeks; transitional preterm: 35 weeks < gestational age ≤ 38 weeks, full term: > 38 weeks.

Figure 3.. Validation of the pharmacokinetic model with empirical data from case studies.

The predicted raltegravir concentrations from the pharmacokinetic model (blue lines) are shown in response to the dosing regimen described by (A) Kreutzwiser et al.[22] or (B) Trahan et al.[21] Case A: GA= 34 weeks; BW= 1.91 kg. Case B: GA= 25 weeks; BW= 0.800 kg. Red symbols indicate empirical data.

Figure 4.. Simulation of the response to neonatal raltegravir dosing.

The neonatal raltegravir dosing regimen approved for full term neonates (week 1: 1.5 mg/kg QD; weeks 2-4: 3 mg/kg BID; weeks 5-6: 6 mg/kg BID) was used in a simulation to predict the plasma raltegravir concentrations. Blue = full term; red = preterm.