Women diagnosed with HIV late in pregnancy (≥28wks) require safe and effective treatment to quickly reduce viral load and prevent neonatal transmission. DolPHIN-1 (NCT02245022) examined the PK and safety of dolutegravir (DTG) in pregnant women and their infants presenting with untreated HIV late in pregnancy (28-36wks gestation).
Women recruited from Uganda and South Africa (SA) were randomised to receive DTG-based therapy (50mg OD) or efavirenz-based standard of care (SoC). DTG PK sampling (0-24h) was undertaken 14days after therapy initiation (third trimester; T3) and within 2wks of delivery (postpartum; PP). Where possible, matched maternal and cord samples were taken at delivery. Breastmilk (BM) was sampled PP, 2-6h and 24h post-dose. After PP sampling, patients switched to SoC and a plasma and BM sample was taken 1-3days post-switch. Nonlinear mixed effects (NONMEM v. 7.3) was used to describe DTG PK in maternal plasma, cord and BM. Covariates included maternal age, weight, pregnancy (T3 [i]vs.[/i] PP), gestational age, delivery (vaginal [i]vs.[/i] C-section), site (Uganda [i]vs.[/i] SA) and wks PP. Model evaluation was performed by visual predictive check (VPC).
Twenty-eight women [14 Uganda, 14 SA; median (range) age, weight: 27yr (19-42), 67kg (44-160), respectively] contributed 528 plasma, 7 cord and 80 BM samples to the model; 27 had paired T3/PP visits [gestational age: 39wks (35-43)]. A 2-compartment model described DTG in plasma, which was linked to a fetal compartment of negligible volume and a BM compartment of fixed volume (0.125L) by first-order processes. Apparent oral clearance (CL/F) was higher than previously reported for HIV+, treatment-naïve patients (1.47 vs. 0.90L/h) but not significantly different between T3 and PP. Model VPC and measured DTG are shown (Figure). Median (range) simulated cord AUC0-24 was 37.7mg.h/L (27.7-6.9; n=7) and was 107% (105-112) that of plasma. BM AUC0-24 was 1.13mg.h/L (0.64-4.22; n=27) and was consistently 3% (2-7) that of plasma when simulated 48-240h post-switch. BM Cav was 0.047mg/L (0.027-0.18) corresponding to a relative infant dose (RID) to that of the mother of 0.26% (0.11-0.97).
Rich and sparse data collection allowed estimation of DTG disposition in maternal plasma, cord and BM by population PK modelling. RID of DTG from BM was within the suggested safety threshold of 10%, although accumulation in the infants was observed, potentially due to delayed excretion.