Physiologically-based pharmacokinetic modelling of infant exposure to efavirenz through breastfeeding

Olagunju, A ORCID: 0000-0002-6588-5749, Rajoli, Rajith KR ORCID: 0000-0002-6015-5712, Atoyebi, Shakir Adeyinka, Khoo, Saye ORCID: 0000-0002-2769-0967, Owen, Andrew and Siccardi, Marco ORCID: 0000-0002-3539-7867
(2018) Physiologically-based pharmacokinetic modelling of infant exposure to efavirenz through breastfeeding. AAS Open Research, 1 (16). 16-.

Access the full-text of this item by clicking on the Open Access link.
[img] Text
2018 - Physiologically-based pharmacokinetic modelling of infant exposure to efavirenz through breastfeeding.pdf - Published version

Download (4MB)


Background: Very little is known about the level of infant exposure to many drugs commonly used during breastfeeding. The aim of this study was to develop a physiologically-based pharmacokinetic (PBPK) model for predicting infant exposure to maternal efavirenz through breastmilk. Methods: A breastfeeding PBPK model combining whole-body maternal and infant sub-models was constructed from drug-specific and system parameters affecting drug disposition using mathematical descriptions. The model was validated against published data on the pharmacokinetics of efavirenz in nursing mother-infant pairs. Further simulations were conducted to assess exposure in the context of the 400 mg reduced dose of efavirenz as well as best- and worse-case scenarios. Results: The model adequately described efavirenz pharmacokinetics, with over 80% of observed data points (203 matched breast milk and plasma pairs) within the predictive interval. All parameters were within 2-fold difference of clinical data. Median (range) predicted versus observed breast milk AUC0-24, Cmax and Cmin at the standard 600 mg dose were 75.0 (18.5-324) versus 68.5 (26.3-257) µ, 4.56 (1.17-16.0) versus 5.39 (1.43-18.4) µg/mL, and 2.11 (0.38-12.3) versus 1.68 (0.316-9.57) µg/mL, respectively. Predicted plasma AUC0-24, Cmax and Cmin at 400 mg reduced dose were similar to clinical data from non-breastfeeding adults. Model-predicted infant plasma concentrations were similar to clinical data, 0.15 (0.026–0.78) μg/mL at the 400 mg maternal dose in pooled analysis, approximately 25% lower than simulated exposure at 600 mg. The maximum exposure index was observed in the youngest infants, 5.9% (2.2-20) at 400 mg and 8.7% (3.2-29) at 600 mg. Thirteen and 36% of 10 days-1 month old infants were predicted to have exposure index above the 10% recommended threshold at 400 mg and 600 mg maternal dose, respectively. Conclusions: This application of PBPK modelling opens up opportunities for expanding our understanding of infant exposure to maternal drugs through breastfeeding.

Item Type: Article
Uncontrolled Keywords: breastfeeding,, PBPK modelling, efavirenz, infant
Depositing User: Symplectic Admin
Date Deposited: 07 Jun 2018 15:37
Last Modified: 14 Mar 2024 17:54
DOI: 10.12688/aasopenres.12860.1
Open Access URL:
Related URLs: