Comparison of Maximum Drug Concentration and Area Under the Time‐Concentration Curve Between Humans and Animals for Oral and Intravenous Investigational Drugs

Abstract

The study compared maximum drug concentration (C(max)) and area under the time-concentration curve (AUC) after normalization of doses to body weight and to body surface area and developed relationships for C(max) and AUC between humans and animals for 75 oral and 10 intravenous investigational drugs. For the oral drugs, animal-human ratios of C(max) were different among animals in both normalizations. Surface area-normalized AUC ratios were not different, whereas weight-normalized ones were different. For both normalizations for intravenous drugs, AUC ratios were not different. Drugs exhibiting 1/10 or smaller ratios tended to have low bioavailability. Regression of the relationships for dose-normalized C(max) and AUC transformed logarithmically between humans and animals were significant for the drugs with relatively high bioavailability. As approaches for predicting human C(max) and AUC from animals, surface area normalization seems to surpass weight normalization, and the equation obtained can be applied to drugs with high bioavailability.

Evolution of chemical-specific adjustment factors (CSAF) based on recent international experience; increasing utility and facilitating regulatory acceptance

“…Based on experience to date, the following distinction is suggested: (JMPR 2006(JMPR , 2007(JMPR , 2008JECFA 2011b) for some pesticide residues in food, such as the picolinic acid derivative, aminopyralid, the Nmethyl carbamate, carbofuran, some pyrethroids (cyfluthrin, cyhalothrin, and deltamethrin), and the mycotoxin, deoxynivalenol, illustrate principles relevant to both CSAF and categorical approaches. Adjustment factors of two-fold instead of the default TK subfactors were applied for both interspecies differences and human variability in TK, based principally on data from 75 pharmaceutical compounds (Fujita et al 2006) in which there was less variation in C max (which reflects less variable oral absorption) than in AUC (which reflects more variable clearance). Thus, the two-fold adjustment for these specific pesticides and food contaminants was related to class-specific (i.e.…”

Pharmacokinetic comparison of nalbuphine with single injection and patient‐controlled analgesia mimic method in healthy Chinese volunteers

“…Pharmacokinetic parameters were further calculated by dose and bodyweight normalization to evaluate the influence of gender. Specifically, as previous studies reported, 21,22 the dose and bodyweight normalized maximum plasma concentration ( C max,norm ) and area under the curve ( AUC 0‐t,norm and AUC inf,norm ) values were estimated by dividing by dose per kilogram of bodyweight. The dose and bodyweight normalized clearance ( CL norm ) and apparent volume of distribution ( Vd norm ) values were derived by dividing by the bodyweight.…”

Method of variability optimization in pharmacokinetic data analysis

“…Until now, only a few methods of transforming the values of PK parameters were proposed (Abdallah 1998; Fujita et al 2006). Frequently, these methods were based on data transformation through the normalization of pharmacokinetic parameters, value of the dose or physiological parameters (body weight, dose, body surface, normalization etc.…”