Physiologically based pharmacokinetic model combined with a clinical lactation study to determine doravirine...

To determine breastmilk concentrations of doravirine via PBPK modelling in combination with a clinical lactation study. As women living with HIV are not able to cease antiretroviral therapy during lactation, it is necessary to establish drug transfer into breastmilk to determine exposure of the infant to antiretroviral drugs and potential risk of drug-induced toxicity.

PBPK modelling was performed with Simcyp v22 with the lactation module as an add-on. Model predictions were compared with observed data, and model performance was considered adequate if predicted: observed ratios for AUC_0-24, C_max and half-life fell between 0.7 and 1.43. Observed data originated from a study performed in healthy, lactating women from whom a full pharmacokinetic curve over 24 h was obtained in both plasma and breastmilk after a single dose of 100 mg doravirine. Concentrations were measured using validated LC-MS/MS assays. Noncompartmental analysis was performed within Phoenix Winnonlin.

The lactation model predicted a geometric mean (CV%) breastmilk to maternal plasma ratio of 0.39,²⁰ whereas it was 0.26²¹ in the clinical part of the study. The median (IQR) predicted and observed daily infant dose based on an estimated breastmilk intake of 150 mL/day was 0.18 (0.12-0.29) and 0.18 (0.15-0.26) mg/day. The relative infant dose based on an estimated intake of 150 mL/day was predicted to be 2.27 (1.31-3.94)% and was 1.90 (1.50-2.44) % in the clinical part of the study.

We present in silico and clinical evidence of the transfer of doravirine into breastmilk. However, based on these data, the infant's exposure to doravirine through breastmilk is not expected to be hazardous.