RT Journal Article
SR Electronic
T1 A Semiphysiologically Based Pharmacokinetic Modeling Approach to Predict the Dose-Exposure Relationship of an Antiparasitic Prodrug/Active Metabolite Pair
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 6
OP 17
DO 10.1124/dmd.111.040063
VO 40
IS 1
A1 Grace Zhixia Yan
A1 Claudia N. Generaux
A1 Miyoung Yoon
A1 Rachel B. Goldsmith
A1 Richard R. Tidwell
A1 James E. Hall
A1 Carol A. Olson
A1 Harvey J. Clewell
A1 Kim L. R. Brouwer
A1 Mary F. Paine
YR 2012
UL http://dmd.aspetjournals.org/content/40/1/6.abstract
AB 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.