RT Journal Article
SR Electronic
T1 Assessment of Metabolites Exposure in Preclinical Species and Humans at Steady State from the Single Dose Radiolabelled ADME Studies: A Case Study
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.112.044933
DO 10.1124/dmd.112.044933
A1 Chandra Prakash
A1 Zhaoyang Li
A1 Cesare Orlandi
A1 Lewis Klunk
YR 2012
UL http://dmd.aspetjournals.org/content/early/2012/04/03/dmd.112.044933.abstract
AB The exposure of a drug candidate and its metabolites in humans and preclinical species during drug development needs to be determined to ensure that the safety of drug-related components in humans is adequately assessed in the standard toxicology studies. The in vivo radiolabeled studies in preclinical species and human volunteers provide total fate of the drug-derived radioactivity including the relative abundance of metabolites. Here we describe how the single dose radiolabeled human studies could provide the exposure of circulating metabolites at steady state using a case study of an extensively metabolized drug, lixivaptan. Following an oral dose of [14C]lixivaptan to humans, a total of nine metabolites were detected in systemic circulation; eight of them exceed 10% of the parent exposure (2 to 41% of total radioactivity). The plasma samples were profiled for all subjects at each time point by HPLC and metabolites were quantified using a radioactive detector. Based on single dose AUC values, exposure of six human metabolites was greater at least in one preclinical species used in toxicology evaluation. Based on T1/2 of lixivaptan and two major metabolites from single dose in humans, their AUC and Cmax values were simulated at the steady state. The simulated exposures (Cmax and AUC) values of parent drug and the two most abundant metabolites were similar to those of from a 7 day clinical study obtained using a validated LC-MS/MS assay, suggesting that a well-designed single dose radiolabeled human study can help in addressing the metabolites in safety testing-related issues