Infant dolutegravir exposure through placental and breastmilk transfer

Dolutegravir (DTG) is expected to provide up to four days of additional prophylaxis to breastfed infants following maternal drug cessation. The estimate, based on data from the DolPHIN-1 study, suggests that breastfeeding contributes relatively little to infant plasma DTG exposures.

These findings from a population pharmacokinetic (PK) model, describing infant DTG exposure from residual intrapartum transfer and ongoing breastfeeding, werepresented at the 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs.

DolPHIN-1 looked at the PK of DTG in pregnant women and their infants presenting with HIV late in pregnancy (28 to 36 weeks gestation). In this study 28 women from Uganda and South Africa were randomised to receive daily DTG or efavirenz (EFV)-based ART. Incomparison to EFV-based standard of care the DTG-based regimen was significantly more likely to achieve maternal viral load <50 copies/mL by day 14 of ART.

The aims of the modelling study were: to develop a population PK model to describe DTG in maternal plasma, umbilical cord, breastmilk as well as in breastfeeding infants following DTG cessation and evaluate potential covariate effects; and to estimate time to DTG protein adjusted IC90 (0.064 mg/L) in breastfed infants.

Infants with recorded date and time of delivery (n=22) were included in the model. DTG dose at birth was simulated based on cord concentrations: 39.9 mg (range: 15.5 to 59.0) or 12.5 mg/kg (range: 5.0 to 19.6).

Predicted median infant half-life (n=21): 38.2 hours (range: 23.0 to 64.1). And predicted median time to PA-IC90 (n=13): 100.2 hours (range: 15.5 to 130.8).

The investigators noted that transplacental and breastmilk transfer of DTG and infant plasma half-life were consistent with results previously reported in the IMPAACT and PANNA studies. And that elimination of DTG in infants was prolonged, likely due to immaturity of metabolic pathways (UGT1A1).

Breastfeeding contributed relatively little to infant DTG exposures and the investigators suggested that breastfeeding alone is unlikely to provide adequate post-exposure prophylaxis. But high transplacental transfer of DTG offers additional infant post-exposure prophylaxis, which decreases with time postpartum.

They concluded that infants whose mothers discontinue DTG in the first week postpartum might have an additional 1–4 days of protection, but those whose mothers discontinue later are unlikely to have additional protection

The group are investigating the impact of prolonged infant exposure to DTG as part of DolPHIN-2.

Dickinson L et al. Infant exposure to dolutegravir through placental and breastmilk transfer: A population PK analysis of DolPHIN-1. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs. Noordwijk, the Netherlands. 14–16 May 2019. Oral abstract 9.
http://regist2.virology-education.com/presentations/2019/20AntiviralPK/26_Dickinson.pdf (PDF slides)