Optimizing Dolutegravir Initiation in Neonates Using Population Pharmacokinetic Modeling and Simulation

Abstract

Background: A knowledge gap exists for dolutegravir (DTG) pharmacokinetics and safety during the first 4 weeks of life, preventing safe and effective DTG use in neonates.Setting: Population pharmacokinetic modeling and simulation were used to assess newborn DTG dosing requirements during the first few days of life as a function of maternal DTG dosing history before delivery.Methods: DTG PK data were obtained from pregnant women and infants enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026S study. Maternal and neonate population pharmacokinetic models were separately developed. Monte Carlo simulations were performed to simulate neonatal concentrations after 2 doses of DTG after birth for infants born to mothers either receiving or not receiving DTG before delivery. Results:In DTG-naïve infants, a 5-mg DTG dose at birth with a second dose after 48 hours maintained median concentrations above the lower bound of the target range (0.77 mg/mL) and below the upper bound of the target range (7.34 mg/mL representing 2-fold above the adult C max value). In DTG-exposed infants, a 5-mg DTG dose at 24 hours after birth with a second dose after 48 hours maintained median concentrations within or nearly within the target range, even if the last maternal DTG dose was taken as soon as 6 hours or as long as 24 hours before delivery.Conclusions: Newborn DTG dosing requirements during the first few days of life depend on maternal DTG dosing history before delivery. These results may help the design of future clinical studies of DTG in the neonatal population.

Hemopexin Reverses Activation of Lung eIF2a and Decreases Mitochondrial Injury in Chlorine Exposed Mice

“…In the first set of experiments, we exposed adult male and female C57BL/6 mice to Cl2 (500 ppm for 30 m), returned them to room air and at 1h post exposure injected the mice with a bolus of human hemopexin (hHPX; 5 µg/ g BW) (Figure 1A). These data were fitted in a non-compartmental PK model (37). There were marked differences in the maximum concentration of hHPX in the plasma among air and Cl2 exposed mice (Cmax 9080±1482 vs. 2048±316 ng/ml; X± 1 SD; n=3; p<0.0013; unpaired two-tailed t-test) as well as in the daily area under the plasma drug concentration-time curve (AUC24; 174.6±21 vs. 49.6 at 24±5.3 hr*mg/L; X± 1 SD; n=3; p<0.0004; unpaired two-tailed t-test), which reflects the actual body exposure to hHPX.…”

Translating Clinical Pharmacology Data in Pregnancy to Evidence‐Based Guideline Recommendations: Perspectives From the HIV Field

“…Using dolutegravir as an example, there are global efforts to expand the availability of this medication across all ranges. Infant washout PK helped inform initial recommendations for how long to wait after the last maternal dose to start dolutegravir prophylaxis in the infant, 40 while also informing starting points for a neonatal study of dolutegravir from birth through up to 4 weeks of age.…”