Successful Prediction of Human Fetal Exposure to P-Glycoprotein Substrate Drugs Using the Proteomics-Informed Relative Expression Factor Approach and PBPK Modeling and Simulation

Abstract

5 th percentile: 5 th percentile confidence value; 95 th percentile: 95 th percentile confidence value; AAFE: absolute average fold error; AUC f : area under the curve of total fetal plasma concentration-time profile; AUC m : area under the curve of total maternal plasma concentration-time profile; BCRP: breast cancer resistance protein; BID: Bis in die, twice daily; CI 90% : 90% confidence interval spanning between 5th and 95th percentiles; CL int,PD,placenta : intrinsic placental passive diffusion clearance; CL int,Pgp,placenta : In vivo P-gp mediated efflux clearance from the placenta; C max : maximum plasma drug concentration; C-T profile: drug plasma concentration-time profile; CYP: cytochrome P450; DEX: dexamethasone; DRV: darunavir; ER: This article has not been copyedited and formatted. The final version may differ from this version.

Prediction of Hepatobiliary Clearances and Hepatic Concentrations of Transported Drugs in Humans Using Rosuvastatin as a Model Drug

“…Before an approach can be used with confidence, it must be validated with additional transporter substrates for key transporters important in drug disposition/distribution and the corresponding tissue concentrations obtained by PET imaging. In this regard, we have already validated the ability of the REF approach to predict the unbound tissue‐to‐plasma concentration ratio of human brain and fetus (at term) for MDR1 substrate drugs 30,31 . Thus, we propose that the REF approach can now be used with confidence to predict tissue drug concentrations when transporters are present at the tissue‐blood barrier provided these transporters are known and can be quantified in the tissue of interest.…”

“…In this regard, we have already validated the ability of the REF approach to predict the unbound tissue-to-plasma concentration ratio of human brain and fetus (at term) for MDR1 substrate drugs. 30,31 Thus, we propose that the REF approach can now be used with confidence to predict tissue drug concentrations when transporters are present at the tissue-blood barrier provided these transporters are known and can be quantified in the tissue of interest.…”

Non‐clinical considerations for supporting accelerated inclusion of pregnant women in pre‐licensure clinical trials with anti‐HIV agents

“…In a drug development setting, the PBPK approach may be used to predict human maternal and foetal exposure during pregnancy in an early stage of drug trials and, therefore, can help inform the probability that the dose selected for phase 2b/3 in pregnancy generates effective plasma concentrations in the mother. With respect to foetal exposure, PBPK models have also been successfully extended and parameterized with data from ex vivo human placenta perfusion studies or data from human cellular systems that mimic the human placental barrier in vitro [ 19 , 20 , 21 , 22 , 23 ]. Further standardization of the experimental approaches, consensus on how such data can be best incorporated in PBPK models and systematic evaluation of the models will help further advance this field in the coming years.…”

Mechanistic Modeling of Placental Drug Transfer in Humans: How Do Differences in Maternal/Fetal Fraction of Unbound Drug and Placental Influx/Efflux Transfer Rates Affect Fetal Pharmacokinetics?

“…Hence, the overall suitability of this approach for parameterizing placental transfer in PBPK models remains inconclusive. Importantly, a refined version of this approach has been proposed very recently ( 54 ) and merits further evaluation with additional drugs.…”