Using PBPK modeling to supplement clinical data and support the safe and effective use of dolutegravir in pregnant and lactating women

Ning, Jia, Pansari, Amita, Rowland Yeo, Karen, Heikkinen, Aki T, Waitt, Catriona ORCID: 0000-0003-0134-5855 and Almond, Lisa M (2024) Using PBPK modeling to supplement clinical data and support the safe and effective use of dolutegravir in pregnant and lactating women CPT: Pharmacometrics & Systems Pharmacology, 13 (11). pp. 1924-1938. ISSN 2163-8306, 2163-8306

Text Ning - dolutegravir pregnancy and lacation - submission - accepted.docx - Author Accepted Manuscript Available under License Creative Commons Attribution. Download (247kB)

Abstract

AbstractOptimal dosing in pregnant and lactating women requires an understanding of the pharmacokinetics in the mother, fetus, and breastfed infant. Physiologically‐based pharmacokinetic (PBPK) modeling can be used to simulate untested scenarios and hence supplement clinical data to support dosing decisions. A PBPK model for the antiretroviral dolutegravir (mainly metabolized by UGT1A1) was verified using reported exposures in non‐pregnant healthy volunteers, pregnant women, and the umbilical cord, lactating mothers, and breastfed neonates. The model was then applied to predict the impact of UGT1A1 phenotypes in extensive (EM), poor (PM), and ultra‐rapid metabolizers (UM). The predicted dolutegravir maternal plasma and umbilical cord AUC in UGT1A1 PMs was 1.6‐fold higher than in EMs. The predicted dolutegravir maternal plasma and umbilical cord AUC in UGT1A1 UMs mothers was 1.3‐fold lower than in EMs. The predicted mean systemic and umbilical vein concentrations were in excess of the dolutegravir IC90 at 17, 28, and 40 gestational weeks, regardless of UGT1A1 phenotype, indicating that the standard dose of dolutegravir (50 mg q.d., fed state) is generally appropriate in late pregnancy, across UGT1A1 phenotypes. Applying the model in breastfed infants, a 1.5‐, 1.7‐, and 2.2‐fold higher exposure in 2‐day‐old neonates, 10‐day‐old neonates, and infants who were UGT1A1 PMs, respectively, compared with EMs of the same age. However, it should be noted that the exposure in breastfed infants who were UGT1A1 PMs was still an order of magnitude lower than maternal exposure with a relative infant daily dose of <2%, suggesting safe use of dolutegravir in breastfeeding women.

Item Type:	Article
Uncontrolled Keywords:	Humans, HIV Infections, Oxazines, Piperazines, Pyridones, Heterocyclic Compounds, 3-Ring, Glucuronosyltransferase, HIV Integrase Inhibitors, Breast Feeding, Lactation, Pregnancy, Models, Biological, Adult, Infant, Newborn, Female, Young Adult, UGT1A1 Enzyme, Dolutegravir
Divisions:	Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	04 Nov 2024 09:00
Last Modified:	28 Feb 2026 20:41
DOI:	10.1002/psp4.13251
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3187017
Disclaimer:	The University of Liverpool is not responsible for content contained on other websites from links within repository metadata. Please contact us if you notice anything that appears incorrect or inappropriate.