Successful Prediction of Human Fetal Exposure to P-Glycoprotein Substrate Drugs Using the Proteomics-Informed Relative Expression Factor Approach and PBPK Modeling and Simulation.
Drug Metab Dispos
; 49(10): 919-928, 2021 10.
Article
em En
| MEDLINE
| ID: mdl-34426410
ABSTRACT
Many women take drugs during their pregnancy to treat a variety of clinical conditions. To optimize drug efficacy and reduce fetal toxicity, it is important to determine or predict fetal drug exposure throughout pregnancy. Previously, we developed and verified a maternal-fetal physiologically based pharmacokinetic (m-f PBPK) model to predict fetal Kp,uu (unbound fetal plasma AUC/unbound maternal plasma AUC) of drugs that passively cross the placenta. Here, we used in vitro transport studies in Transwell, in combination with our m-f PBPK model, to predict fetal Kp,uu of drugs that are effluxed by placental P-glycoprotein (P-gp)-namely, dexamethasone, betamethasone, darunavir, and lopinavir. Using Transwell, we determined the efflux ratio of these drugs in hMDR1-MDCKcP-gpKO cells, in which human P-gp was overexpressed and the endogenous P-gp was knocked out. Then, using the proteomics-informed efflux ratio-relative expressive factor approach, we predicted the fetal Kp,uu of these drugs at term. Finally, to verify our predictions, we compared them with the observed in vivo fetal Kp,uu at term. The latter was estimated using our m-f PBPK model and published fetal [umbilical vein (UV)]/maternal plasma drug concentrations obtained at term (UV/maternal plasma). Fetal Kp,uu predictions for dexamethasone (0.63), betamethasone (0.59), darunavir (0.17), and lopinavir (0.08) were successful, as they fell within the 90% confidence interval of the corresponding in vivo fetal Kp,uu (0.30-0.66, 0.29-0.71, 0.11-0.22, 0.04-0.19, respectively). This is the first demonstration of successful prediction of fetal Kp,uu of P-gp drug substrates from in vitro studies. SIGNIFICANCE STATEMENT For the first time, using in vitro studies in cells, this study successfully predicted human fetal Kp,uu of P-gp substrate drugs. This success confirms that the m-f PBPK model, combined with the ER-REF approach, can successfully predict fetal drug exposure to P-gp substrates. This success provides increased confidence in the use of the ER-REF approach, combined with the m-f PBPK model, to predict fetal Kp,uu of drugs (transported by P-gp or other transporters), both at term and at earlier gestational ages.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Inibidores da Protease de HIV
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP
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Feto
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Glucocorticoides
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Female
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Humans
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Pregnancy
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article