Disposition and metabolism of [¹⁴C]-galunisertib, a TGF-βRI kinase/ALK5 inhibitor, following oral administration in healthy subjects and mechanistic prediction of the effect of itraconazole on galunisertib pharmacokinetics

Abstract

1. The disposition and metabolism of galunisertib (LY2157299 monohydrate, a TGF-βRI Kinase/ALK5 Inhibitor) was characterized following a single oral dose of 150 mg of [¹⁴C]-galunisertib (100 µCi) to six healthy human subjects.

2. The galunisertib plasma half-life was 8.6 h, while the ¹⁴C half-life was 10.0 h. Galunisertib was abundant in circulation (40.3% of the ¹⁴C AUC024 h), with 7 additional metabolites detected in plasma. Two metabolites LSN3199597 (M5, mono-oxidation), and M4 (glucuronide of M3) were the most abundant circulating metabolites (10.7 and 9.0% of the 14C AUC024 h respectively). The pharmacological activity of LSN3199597 was tested and found to be significantly less potent than galunisertib.

3. The dose was recovered in feces (64.5%) and in urine (36.8%). Galunisertib was cleared primarily by metabolism, based on low recovery of parent in excreta (13.0% of dose). Due to the slow in vitro metabolism of galunisertib in suspended hepatocytes, a long term hepatocyte system was used to model the human excretion profile.

4. Expressed cytochromes P450 and hepatocytes indicated clearance was primarily CYP3A4-mediated. Mechanistic static modeling that incorporated small non-CYP-mediated metabolic clearance and renal clearance components predicted an AUC ratio of 4.7 for the effect of itraconazole, a strong CYP3A4 inhibitor, on galunisertib.

Keywords:

• ¹⁴C
• galunisertib
• Hµrel
• human ADME
• itraconazole

View correction statement:

Correction to: Cassidy et al., Disposition and metabolism of [14C]-galunisertib, a TGF-bRI kinase/ALK5 inhibitor, following oral administration in healthy subjects and mechanistic prediction of the effect of itraconazole on galunisertib pharmacokinetics

Acknowledgements

The authors would like to thank Chad Hadden, Ph.D. for NMR support, Boris Czeskis, Ph.D. for synthesis of [¹⁴C]-galunisertib and metabolites.

Declaration of interest

K. Cassidy, I. Gueorguieva, W. Ehlhardt, J. Rehmel, P. Yi and C. Miles are employees of Eli Lilly and Company, Indianapolis, IN, USA and may hold company stock. This study was supported by Eli Lilly and Company, Indianapolis, IN 46285.

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