Abstract
GDC-0425 is an orally bioavailable small molecule inhibitor of checkpoint kinase 1 (Chk1) that was investigated as a novel co-therapy to potentiate chemotherapeutic drugs such as gemcitabine. In the radiolabeled ADME study in Sprague-Dawley rats, trace level but long-lived 14C-labeled plasma thiocyanate was observed. This thiocyanate originated from metabolic decyanation of GDC-0425 and rapid conversion of cyanide to thiocyanate. Excretion studies indicated decyanation was a minor metabolic pathway, but placing 14C at nitrile magnified its observation. P450s catalyzed the oxidative decyanation reaction in vitro when tested with liver microsomes and, in the presence of 18O2, one atom of 18O was incorporated into the decyanated product. To translate this finding to a clinical risk assessment, the total circulating levels of thiocyanate (endogenous plus drug-derived) were measured following repeated administration of GDC-0425 to rats and cynomolgus monkeys. No overt increases were observed with thiocyanate concentrations of 121-154 μM in rats and 71-110 μM in monkeys receiving vehicle and all tested doses of GDC-0425. These findings were consistent with results from the radiolabel rat study where decyanation accounted for conversion of <1% of the administered GDC-0425 and contributed less than 1 μM thiocyanate to systemic levels. Further, in vitro studies showed only trace oxidative decyanation for humans. These data indicated that though cyanide was metabolically released from GDC-0425 and formed low levels of thiocyanate, this pathway was a minor route of metabolism and GDC-0425-related increases in systemic thiocyanate were unlikely to pose safety concern for subjects of clinical studies.
- animal/nonclinical/preclinical
- anticancer agents
- cytochrome P450
- drug development/discovery
- mass spectrometry/MS
- metabolite identification
- The American Society for Pharmacology and Experimental Therapeutics