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Application of structural and functional pharmacokinetic analogs for physiologically based pharmacokinetic model development and evaluation.
Regul Toxicol Pharmacol. 2020 Jul; 114:104667.RT

Abstract

This work provides case studies for the pharmacokinetic (PK) analog approach, where a physiologically based pharmacokinetic (PBPK) model for a target chemical (has no PK data) is evaluated using PK data from a source chemical (has existing PK data). A bottom up PBPK modeling approach (using in vitro and in silico inputs) is used to develop human oral PBPK models for caffeine and diphenhydramine. Models are evaluated using in vivo data from structural and functional PK analogs. At the end of the case studies, in vivo PK data for caffeine and diphenhydramine is introduced and both models were able to simulate plasma concentrations which agreed with the in vivo PK data. To further demonstrate that structural analogs can serve as PK analogs, in vitro metabolism and plasma protein binding was compared for a subset of structurally similar ToxCast chemicals and shown to be similar. Next steps for the PK analog approach should focus on evaluating this concept for a broader set of compounds. Using PK analogs for evaluating and establishing confidence in a PBPK model will ensure that PBPK modeling remains a viable option in animal alternative safety assessments.

Authors+Show Affiliations

The Procter & Gamble Company, Cincinnati, OH, 45040, USA. Electronic address: Ellison.ca@pg.com.The Procter & Gamble Company, Cincinnati, OH, 45040, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32387187

Citation

Ellison, Corie A., and Shengde Wu. "Application of Structural and Functional Pharmacokinetic Analogs for Physiologically Based Pharmacokinetic Model Development and Evaluation." Regulatory Toxicology and Pharmacology : RTP, vol. 114, 2020, p. 104667.
Ellison CA, Wu S. Application of structural and functional pharmacokinetic analogs for physiologically based pharmacokinetic model development and evaluation. Regul Toxicol Pharmacol. 2020;114:104667.
Ellison, C. A., & Wu, S. (2020). Application of structural and functional pharmacokinetic analogs for physiologically based pharmacokinetic model development and evaluation. Regulatory Toxicology and Pharmacology : RTP, 114, 104667. https://doi.org/10.1016/j.yrtph.2020.104667
Ellison CA, Wu S. Application of Structural and Functional Pharmacokinetic Analogs for Physiologically Based Pharmacokinetic Model Development and Evaluation. Regul Toxicol Pharmacol. 2020;114:104667. PubMed PMID: 32387187.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Application of structural and functional pharmacokinetic analogs for physiologically based pharmacokinetic model development and evaluation. AU - Ellison,Corie A, AU - Wu,Shengde, Y1 - 2020/05/05/ PY - 2020/02/06/received PY - 2020/04/09/revised PY - 2020/04/17/accepted PY - 2020/5/11/pubmed PY - 2020/5/11/medline PY - 2020/5/11/entrez KW - Analog KW - Biokinetics KW - IVIVE KW - Modeling KW - Pharmacokinetics KW - Physiologically based pharmacokinetics KW - Read across KW - Structural activity relationship KW - Toxicokinetics SP - 104667 EP - 104667 JF - Regulatory toxicology and pharmacology : RTP JO - Regul. Toxicol. Pharmacol. VL - 114 N2 - This work provides case studies for the pharmacokinetic (PK) analog approach, where a physiologically based pharmacokinetic (PBPK) model for a target chemical (has no PK data) is evaluated using PK data from a source chemical (has existing PK data). A bottom up PBPK modeling approach (using in vitro and in silico inputs) is used to develop human oral PBPK models for caffeine and diphenhydramine. Models are evaluated using in vivo data from structural and functional PK analogs. At the end of the case studies, in vivo PK data for caffeine and diphenhydramine is introduced and both models were able to simulate plasma concentrations which agreed with the in vivo PK data. To further demonstrate that structural analogs can serve as PK analogs, in vitro metabolism and plasma protein binding was compared for a subset of structurally similar ToxCast chemicals and shown to be similar. Next steps for the PK analog approach should focus on evaluating this concept for a broader set of compounds. Using PK analogs for evaluating and establishing confidence in a PBPK model will ensure that PBPK modeling remains a viable option in animal alternative safety assessments. SN - 1096-0295 UR - https://www.unboundmedicine.com/medline/citation/32387187/Application_of_structural_and_functional_pharmacokinetic_analogs_for_physiologically_based_pharmacokinetic_model_development_and_evaluation L2 - https://linkinghub.elsevier.com/retrieve/pii/S0273-2300(20)30093-3 DB - PRIME DP - Unbound Medicine ER -
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