PI-045

B. Amore,1 V. Chow,1 M. Gibbs,2 L. Wienkers1; 1Amgen, Inc., Seattle, WA, 2Amgen, Inc., Thousand Oaks, CA

BACKGROUND: Regulatory guidance on the safety testing of drug metabolites recommends further evaluation when human plasma metabolites exceed a predefined threshold relative to total drug-related exposure. Additional safety testing may be required if a human metabolite is not formed in animal test species or is present at disproportionately higher levels in humans. This abstract presents the evaluation of a potential disproportionate human metabolite of AMG 853, a prostaglandin D2 pathway antagonist.
METHODS: In vitro AMG 853 metabolism was characterized in human, cynomolgus monkey and rat hepatocytes and liver microsomes to identify probable pathways of metabolic clearance. Metabolites were also measured in rat and monkey plasma using a validated bioanalytical method. Nonclinical data were compared with human metabolite exposures determined in Phase I, where pharmacokinetics (PK) of AMG 853 and metabolite were characterized in serial plasma samples from 6 healthy volunteers after multiple oral dosing. PK parameters were estimated using non-compartmental methods.
RESULTS: AMG 853 hepatocyte incubations revealed a glucuronide conjugate and minor oxidized metabolites. The rank order of AMG 853 glucuronidation intrinsic clearance in liver microsomes was human > monkey > rat. In vivo, area under the AMG 853 glucuronide-time curve (AUCm) in rat was <1% of AMG 853 AUC (AUCp). In cynomolgus monkey, AUCm was ~75% of AUCp. In vitro and in vivo glucuronide formation across species indicated that AUCm could be > 75% of AUCp in human (actual AUCm/AUCp ~0.8). Acyl glucuronide exposure in toxicology studies exceeded human glucuronide metabolite levels.
CONCLUSION: Nonclinical and early clinical data support the conclusion that AMG 853 glucuronide was not a disproportionate human metabolite.