Physiologically based pharmacokinetic model combined with a clinical lactation study to determine doravirine concentrations in human breastmilk

Women living with HIV cannot discontinue antiretroviral therapy during lactation, making it essential to understand how these drugs transfer into breastmilk and the resulting exposure risk to breastfed infants. This publication combines a physiologically based pharmacokinetic (PBPK) model built in Simcyp with its lactation module and a clinical lactation study to predict and measure doravirine concentrations in human breastmilk, with observed plasma and milk pharmacokinetics obtained by non-compartmental analysis in Phoenix WinNonlin. The PBPK model predicted a breastmilk-to-maternal-plasma ratio of 0.39, compared with an observed clinical value of 0.26, and predicted and observed estimated infant daily doses were closely aligned at roughly 0.18 mg/day, corresponding to a relative infant dose of about 2%. Combining in silico and clinical evidence, the authors conclude that infant exposure to doravirine through breastfeeding is not expected to pose a hazard. The work illustrates how PBPK modeling can complement clinical lactation studies to inform breastfeeding safety assessments for antiretroviral therapy.