Collections > Electronic Theses and Dissertations > Integration of preclinical and clinical data with pharmacokinetic modeling and simulations to characterize the disposition of orally-active antiparasitic prodrugs and metabolites: prediction of the dose-exposure relationship in humans
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Prediction of the disposition and selection of the appropriate dosage regimen of drug candidates prior to clinical studies presents a major challenge in drug development. In this dissertation project, a multiexperimental approach, including Caco-2 cells, rat isolated perfused livers (IPLs), rat and human sandwich-cultured hepatocytes (SCH), a plasma/tissue binding assay, and pharmacokinetic modeling was employed to 1) examine mechanisms underlying differences in systemic exposure of two active metabolites (furamidine and CPD-0801) of respective antiparasitic prodrugs (pafuramidine and CPD-0868), and 2) quantitatively integrate preclinical and clinical data to elucidate the dose-plasma/exposure relationship in humans using pafuramidine/furamidine as a model prodrug/active metabolite pair. Pafuramidine and CPD-0868 exhibited similar permeability properties in Caco-2 monolayers when the basolateral compartment was supplemented with 4% bovine serum albumin, suggesting that the difference in systemic exposure of active metabolites was not due to the difference in intestinal permeabilities between the prodrugs. Hepatic accumulation of both active metabolites was extensive (>95% of total formed) in rat IPLs and SCH. Compared to furamidine, the extent of formation and perfusate/medium exposure of CPD-0801 was greater, by ≤ 2.5- and ≥ 7-fold, respectively. The unbound fraction of both active metabolites in rat liver (fu,L) was lower than that in plasma and perfusate by ≥ 24-fold; fu,L of CPD-0801 was 5-fold higher than that of furamidine (1.6 versus 0.3%). These observations suggested that intrahepatic binding influences the disposition of these active metabolites. A higher fu,L) mostly explained the enhanced perfusate exposure of CPD-0801 compared to furamidine in rat IPLs. A strong concordance between rat IPL and SCH data substantiated SCH as a useful tool to study the hepatobiliary disposition of these compounds. Pafuramidine/furamidine preclinical and clinical data were used as a training set to develop whole-body semi-physiologically-based pharmacokinetic (PBPK) models for rats and humans. The PBPK models suggested that the intestine may contribute to pre-systemic furamidine formation. Based on the prodrug dose-plasma/exposure relationship predicted by the human model, a dosage regimen of pafuramidine, 40 mg/day, was proposed. This dissertation project, through integration of preclinical and clinical data with pharmacokinetic modeling and simulations, provided a framework to guide dose-ranging studies in humans for next-in-class antiparasitic compounds.