A semiphysiologically based pharmacokinetic modeling approach to predict the dose-exposure relationship of an antiparasitic prodrug/active metabolite pair

Grace Zhixia Yan; Claudia N Generaux; Miyoung Yoon; Rachel B Goldsmith; Richard R Tidwell; James E Hall; Carol A Olson; Harvey J Clewell; Kim L R Brouwer; Mary F Paine

doi:10.1124/dmd.111.040063

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A semiphysiologically based pharmacokinetic modeling approach to predict the dose-exposure relationship of an antiparasitic prodrug/active metabolite pair

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A semiphysiologically based pharmacokinetic modeling approach to predict the dose-exposure relationship of an antiparasitic prodrug/active metabolite pair

Grace Zhixia Yan, Claudia N Generaux, Miyoung Yoon, Rachel B Goldsmith, Richard R Tidwell, James E Hall, Carol A Olson, Harvey J Clewell, Kim L R Brouwer and Mary F Paine

Drug metabolism and disposition, Vol.40(1), pp.6-17

01/2012

DOI: https://doi.org/10.1124/dmd.111.040063

Handle:

https://hdl.handle.net/2376/116717

PMCID: PMC3250045

PMID: 21953913

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Abstract

Tissue Distribution - physiology

Predictive Value of Tests

Tissue Distribution - drug effects

Antiparasitic Agents - pharmacokinetics

Rats, Wistar

Humans

Middle Aged

Rats

Male

Rats, Sprague-Dawley

Dose-Response Relationship, Drug

Animals

Prodrugs - pharmacokinetics

Models, Biological

Antiparasitic Agents - pharmacology

Prodrugs - pharmacology

Dose selection during antiparasitic drug development in animal models and humans traditionally has relied on correlations between plasma concentrations obtained at or below maximally tolerated doses that are efficacious. The objective of this study was to improve the understanding of the relationship between dose and plasma/tissue exposure of the model antiparasitic agent, pafuramidine, using a semiphysiologically based pharmacokinetic (semi-PBPK) modeling approach. Preclinical and clinical data generated during the development of pafuramidine, a prodrug of the active metabolite, furamidine, were used. A whole-body semi-PBPK model for rats was developed based on a whole-liver PBPK model using rat isolated perfused liver data. A whole-body semi-PBPK model for humans was developed on the basis of the whole-body rat model. Scaling factors were calculated using metabolic and transport clearance data generated from rat and human sandwich-cultured hepatocytes. Both whole-body models described pafuramidine and furamidine disposition in plasma and predicted furamidine tissue (liver and kidney) exposure and excretion profiles (biliary and renal). The whole-body models predicted that the intestine contributes significantly (30-40%) to presystemic furamidine formation in both rats and humans. The predicted terminal elimination half-life of furamidine in plasma was 3- to 4-fold longer than that of pafuramidine in rats (170 versus 47 h) and humans (64 versus 19 h). The dose-plasma/tissue exposure relationship for the prodrug/active metabolite pair was determined using the whole-body models. The human model proposed a dose regimen of pafuramidine (40 mg once daily) based on a predefined efficacy-safety index. A similar approach could be used to guide dose-ranging studies in humans for next-in-class compounds.

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Title: A semiphysiologically based pharmacokinetic modeling approach to predict the dose-exposure relationship of an antiparasitic prodrug/active metabolite pair
Creators: Grace Zhixia Yan - Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7569, USA
Claudia N Generaux
Miyoung Yoon
Rachel B Goldsmith
Richard R Tidwell
James E Hall
Carol A Olson
Harvey J Clewell
Kim L R Brouwer
Mary F Paine
Publication Details: Drug metabolism and disposition, Vol.40(1), pp.6-17
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: United States
Grant note: R01 GM041935 / NIGMS NIH HHS R01-GM41935 / NIGMS NIH HHS R25-GM74088 / NIGMS NIH HHS R25 GM074088 / NIGMS NIH HHS
Identifiers: 99900547764601842
Language: English
Resource Type: Journal article