Abstract
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.
Footnotes
This work was supported by the National Institutes of Health National Institute of General Medical Sciences [R01-GM41935, R25-GM74088]; and the Consortium for Parasitic Drug Development. G.Z.Y. was supported by an Eli Lilly Predoctoral Fellowship in Pharmacokinetics and Drug Disposition.
Dr. Kim Brouwer is a cofounder and Chair of the Scientific Advisory Board for Qualyst, Inc., which has exclusively licensed the sandwich-cultured hepatocytes technology for quantification of biliary excretion (B-CLEAR®).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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ABBREVIATIONS:
- HAT
- human African trypanosomiasis
- PBPK
- physiologically based pharmacokinetic
- semi-PBPK
- semiphysiologically based pharmacokinetic
- IPL
- isolated perfused liver
- SCH
- sandwich-cultured hepatocyte(s)
- HBSS
- Hanks' balanced salt solution
- PBS
- phosphate-buffered saline
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- B/P
- blood/plasma
- TFA
- trifluoroacetic acid
- ECG
- electrocardiogram
- HPLC
- high-performance liquid chromatography
- Cl
- clearance
- AUC
- area under the concentration-time curve
- GFR
- glomerular filtration rate
- NOAEL
- no observable adverse effect level.
- Received April 9, 2011.
- Accepted September 27, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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