Disposition of [¹⁴C]LY2606368 following intravenous administration in patients with advanced and/or metastatic solid...

The disposition and metabolism of prexasertib, a CHK-1 inhibitor was characterised over a 120 h period following a single 170-mg intravenous dose of [¹⁴C]prexasertib (50 µCi) to 6 patients with advanced/metastatic solid tumours.The prexasertib safety profile was consistent with prior studies. Plasma, urine, and faeces were analysed for radioactivity, prexasertib, and metabolites. Geometric mean t_1/2 in plasma was 34.2 h for prexasertib and 73.8 h for total radioactivity. Unchanged prexasertib accounted for approximately 9% of plasma total radioactivity, indicating extensive metabolism by the presence of circulating metabolites. Both renal and faecal excretion were identified as important routes of elimination since 41.8% (±12.9%) of the total administered radioactivity was recovered in the renal excretions and 32.2% (±7.28%) in the faecal excretions. Mean renal clearance was approximately 15% of the total systemic clearance, while biliary clearance was also low. Prexasertib was cleared predominantly by metabolism with only 23% of the dose recovered in excreta as intact drug. Radioactivity was eliminated predominantly within 72 h in urine, but faecal elimination was protracted.The metabolism of prexasertib was complex while primary metabolic clearance pathways involved were oxidative deamination, O-dealkylation, mono-oxidation, and possibly direct glucuronide conjugation. Although prexasertib was the major component in plasma, up to 11 metabolites were observed. The most abundant metabolites identified in plasma were glucuronides and none of these are expected to contribute to the pharmacological activity or pose a safety concern.