Physiologically based pharmacokinetic (PBPK) modeling of disposition of epiroprim in humans.
The objective of this study was to use in synergy physiologically based and empirical approaches to estimate the drug-specific input parameters of PBPK models of disposition to simulate the plasma concentration-time profile of epiroprim in human. The estimated input parameters were the tissue:plasma partition coefficients (Pt:p) for distribution and the blood clearance (CL) for the in vivo conditions. Epiroprim represents a challenge for such methods, because it shows large interspecies differences in its pharmacokinetic properties. Two approaches were used to predict the human Pt:p values: the tissue composition model (TCM) and the "Arundel approach" based on the volume of distribution at steady state (Vdss) determined in vivo in the rat. CL in human was predicted by (1) conventional allometric scaling of in vivo animal clearances (CAS), (2) physiologically based direct scaling up of in vitro hepatocyte data (DSU), and (3) allometric scaling of animal intrinsic in vivo blood CL normalized by the ratios of animal:human intrinsic clearances determined in vitro with hepatocytes (NAS). The performance of prediction was assessed by comparing separately the above pharmacokinetic parameters (Vdss estimated from the Pt:p values and blood CL) with the corresponding in vivo data obtained from the plasma kinetic profiles. These input parameters were used in PBPK models, and the resulting plasma concentration-time profiles of epiroprim were compared with those observed in rat and human. Previously to the construction of the human PBPK model, a model for the rat was also developed to gain more confidence on the model structure and assumptions. Overall, using the TCM and the NAS for the parameterization of the distribution and clearance, respectively, the PBPK model gave the more accurate predictions of epiroprim's disposition in human. This study represents therefore an attractive approach, which may potentially help the clinical candidate selection.
D000818:Animals; D001835:Body Weight; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008251:Macaca; D008297:Male; D051379:Mice; D008954:Models, Biological; D013045:Species Specificity; D013997:Time Factors; D014018:Tissue Distribution; D014295:Trimethoprim / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
C082896:epiroprim; D014295:Trimethoprim