Effects of a potent CYP3A inhibitor on the pharmacokinetics and safety of enzastaurin
2572 Background: Enzastaurin (ENZ) targets the PKCβ and PI3K/AKT pathways to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. ENZ is metabolized by CYP3A in vitro. This study examined the potential clinical effects of a potent CYP3A4 inhibitor, ketoconazole (KETO), on the pharmacokinetics and safety of ENZ. Methods: In this open-label, fixed-sequence, three-period, crossover study (duration = 6 weeks), healthy subjects received an oral, 200- mg, single dose of ENZ (period 1); 400-mg daily doses of KETO for 4 days to assess QT (period 2); and 400-mg daily doses of KETO for 14 days, with a 200-mg single dose of ENZ given on day 4 (period 3). Plasma samples for PK analysis were collected predose and after ENZ administration in periods 1 and 3 at scheduled intervals. Results: Of the 16 women enrolled, 13 completed the study. Changes in PK parameters of ENZ and its metabolite, LY326020, in the presence of KETO are summarized in the table . No serious adverse events (AEs) occurred. A similar number of AEs possibly related to enzastaurin occurred in period 1 (6) and period 3 (7). Headache (n=4) and nausea (n=3) were more frequent in period 3, but were also the most common AEs related to KETO. Three patients had hepatic transaminase elevations, but no consistent pattern with dosing period or ENZ exposures was observed. At 4 hours post-dose, QT intervals were prolonged by a mean 5.88 (95% CI: 1.767–10.00) msec after four daily doses of KETO and by a mean 9.29 (95% CI: 5.165–13.41) msec when coadministered with ENZ. Conclusion: In the presence of KETO, plasma concentrations of ENZ and its metabolites increased significantly. ENZ alone did not increase QT intervals. Ketoconazole plus ENZ caused a slightly greater increase in QT intervals compared to KETO alone, but this very small change may not be clinically significant. ENZ was generally well tolerated, alone or with KETO. [Table: see text] No significant financial relationships to disclose.