Physiologically Based Pharmacokinetic Modeling to Determine the Impact of CYP2B6 Genotype on Efavirenz Exposure in Children, Mothers and Breastfeeding Infants.
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| Abstract |
The antiretroviral drug efavirenz remains widely used in children and mothers during breastfeeding in tuberculosis-endemic areas. Evaluating the safety of efavirenz during breastfeeding requires an understanding of its pharmacokinetics (PKs) in breast milk, its exposure in the breastfed infant, and the potential influence of polymorphisms in drug disposition genes. The interplay of these factors between the mother and the nursing infant is a complex scenario that can be readily investigated using physiologically-based PK (PBPK) modeling. A verified PBPK model for efavirenz describing the CYP3A4- and CYP2B6-mediated auto-induction during multiple dosing was reported previously and was applied in this study to predict the exposure of efavirenz in vulnerable populations, including children (down to the age of 3 months), mothers, and breastfeeding infants, accounting for the various CYP2B6 genotypes. Predicted pharmacokinetic parameters for mothers, breastfeeding infants, and children aged ≥ 3 months were reasonably consistent with observed data, irrespective of CYP2B6 genotype. The clinically significant trend toward higher infant efavirenz exposure from GG/GG to TT/TT composite maternal/infant CYP2B6 genotypes was captured reasonably well by the PBPK model. Thereafter, simulations were performed to determine the adequacy of the current World Health Organization (WHO; ≥ 3 years) and the US Food and Drug Administration (FDA; ≥ 3 months) weight-based dosing regimens for efavirenz in children according to CYP2B6 genotype. The findings of this study indicate that PBPK models can be used in designing studies in vulnerable populations and providing guidance on optimal doses based on developmental physiology and pharmacogenetics.
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| Authors | Xian Pan, Karen Rowland Yeo |
| Journal | Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 114 Issue 1 Pg. 182-191 (07 2023) ISSN: 1532-6535 [Electronic] United States |
| PMID | 37078251 (Publication Type: Journal Article) |
| Copyright | © 2023 Certara. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. |
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