RT Journal Article
SR Electronic
T1 In Silico Prediction of the Absorption and Disposition of Cefadroxil in Humans using an Intestinal Permeability Method Scaled from Humanized PepT1 Mice
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.118.084236
DO 10.1124/dmd.118.084236
A1 Yongjun Hu
A1 David E Smith
YR 2018
UL http://dmd.aspetjournals.org/content/early/2018/12/28/dmd.118.084236.abstract
AB It is difficult to predict the pharmacokinetics and plasma concentration-time profiles of new chemical entities in humans based on animal data. Some pharmacokinetic parameters, such as clearance and volume of distribution, can be scaled allometrically from rodents, mammals and non-human primates with good success. However, it is far more challenging to predict the oral pharmacokinetics of experimental drug candidates. In the present study, we used in situ estimates of intestinal permeability, obtained in silico and from rat, wildtype (WT) and humanized PepT1 (huPepT1) mice, to predict the systemic exposure of cefadroxil, an orally administered model compound, under a variety of conditions. Using GastroPlus® simulation software, we found that the Cmax and AUC0-t of cefadroxil were better predicted using intestinal permeability estimates (both segmental and jejunal) from huPepT1 than from WT mice, and that intestinal permeabilities based on in silico and rat estimates gave poor predictions. We also observed that good predictions were possible for cefadroxil during oral dose escalation (i.e., 5, 15 and 30 mg/kg cefadroxil), a drug-drug interaction study (i.e., 5 mg/kg oral cefadroxil plus 45 mg/kg oral cephalexin), and during an oral multiple dose study (i.e., 500 mg cefadroxil every six hours). Finally, the great majority of cefadroxil was absorbed in the duodenal and jejunal segments of the small intestine after a 5 mg/kg oral dose. Thus, by combining a humanized mouse model and in silico software, the present study offers a novel strategy for better translating preclinical pharmacokinetic data to oral drug exposure during first-in-human studies.