Dataset Information

Infant exposure to dolutegravir through placental and breastmilk transfer: a population pharmacokinetic analysis of DolPHIN-1.

ABSTRACT:

Background

Rapid reduction of HIV viral load is paramount to prevent peripartum transmission in women diagnosed late in pregnancy. We investigated dolutegravir population pharmacokinetics in maternal plasma, cord, breastmilk and infant plasma of DolPHIN-1 participants (NCT02245022) presenting with untreated HIV late in pregnancy (28-36 weeks gestation).

Methods

Pregnant women from Uganda and South Africa were randomised (1:1) to daily dolutegravir (50 mg) or efavirenz-based therapy. Dolutegravir pharmacokinetic sampling (0-24 hours) was undertaken 14 days after treatment initiation and within 1-3 weeks of delivery, with matched maternal and cord samples at delivery. Mothers switched to efavirenz and maternal and infant plasma and breastmilk samples taken 24, 48 or 72 hours post-switch. Nonlinear mixed effects (NONMEM v. 7.4) was used to describe dolutegravir in all matrices and to evaluate covariates.

Results

Twenty-eight women and 22 infants were included. Maternal dolutegravir was described by a two-compartment model linked to a fetal and breastmilk compartment. Cord and breastmilk to maternal plasma ratios were 1.279 (1.209-1.281) and 0.033 (0.021-0.050), respectively. Infant dolutegravir was described by breastmilk-to-infant and infant elimination rate constants. No covariate effects were observed. Predicted infant dolutegravir half-life and time to protein adjusted-IC90 (0.064 mg/L) for those above this threshold were 37.9 hours (22.1-63.5) and 108.9 hours [(18.6-129.6); 4.5 days (0.8-5.4); n=13].

Conclusions

Breastfeeding contributed relatively little to infant plasma exposures but a median of 4.5 days additional prophylaxis to some of the breastfed infants was observed following maternal dolutegravir cessation (3-15 days postpartum), which waned with time postpartum as transplacental dolutegravir cleared.

SUBMITTER: Dickinson L

PROVIDER: S-EPMC8423479 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundFetal antiretroviral exposure is usually derived from the cord-to-maternal concentration ratio. This static parameter does not provide information on the pharmacokinetics in utero, limiting the assessment of a fetal exposure-effect relationship.ObjectiveThe aim of this study was to incorporate placental transfer into a pregnancy physiologically based pharmacokinetic model to simulate and evaluate fetal darunavir exposure at term.MethodsAn existing and validated pregnancy physiologically based pharmacokinetic model of maternal darunavir/ritonavir exposure was extended with a feto-placental unit. To parameterize the model, we determined maternal-to-fetal and fetal-to-maternal darunavir/ritonavir placental clearance with an ex-vivo human cotyledon perfusion model. Simulated maternal and fetal pharmacokinetic profiles were compared with observed clinical data to qualify the model for simulation. Next, population fetal pharmacokinetic profiles were simulated for different maternal darunavir/ritonavir dosing regimens.ResultsAn average (±standard deviation) maternal-to-fetal cotyledon clearance of 0.91 ± 0.11 mL/min and fetal-to-maternal clearance of 1.6 ± 0.3 mL/min was determined (n = 6 perfusions). Scaled placental transfer was integrated into the pregnancy physiologically based pharmacokinetic model. For darunavir 600/100 mg twice a day, the predicted fetal maximum plasma concentration, trough concentration, time to maximum plasma concentration, and half-life were 1.1, 0.57 mg/L, 3, and 21 h, respectively. This indicates that the fetal population trough concentration is higher or around the half-maximal effective darunavir concentration for a resistant virus (0.55 mg/L).ConclusionsThe results indicate that the population fetal exposure after oral maternal darunavir dosing is therapeutic and this may provide benefits to the prevention of mother-to-child transmission of human immunodeficiency virus. Moreover, this integrated approach provides a tool to prevent fetal toxicity or enhance the development of more selectively targeted fetal drug treatments.

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