The human inflammatory response can result in the alteration of drug clearance through effects on metabolizing enzymes or transporters. In this article we briefly review the theory of how cancer can lead to indirect changes in drug metabolism, review acute phase proteins and cytokines as markers of changes in cytochrome P450 (CYP) activity in cancer patients, and provide clinical case examples of how the inflammation in advanced cancer patients can lead to altered CYP‐mediated drug clearance.

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.

14076 Background: Enzastaurin (ENZ) targets the PKCβ and PI3K/AKT pathways to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. In vitro studies show ENZ solubility is highest at pH 2.0 and decreases with increasing pH. This study examined the effect of increased gastric pH by a proton pump inhibitor (lansoprazole) and the effect of food on the bioavailability of a single oral dose of ENZ in healthy subjects. Methods: In this open-label, three-period, fixed sequence, crossover study, healthy subjects received an oral, 500-mg single dose of ENZ in the fed state, alone (A) and with lansoprazole (B), and in the fasted state alone (C). Lansoprazole was dosed for 5 days, with ENZ administered 2 hours after the 5th dose. A two-week washout occurred between each period. Plasma samples were collected at predose and scheduled timepoints for up to 168 hours post-ENZ dose for pharmacokinetic (PK) characterization of ENZ and its active metabolites. Results: 22 subjects were enrolled in the study with 19 subjects completing all treatment periods. The table summarizes the PK results for enzastaurin and total analytes (enzastaurin + metabolites). ENZ Cmax and AUC(0–8) were unaffected by the administration of lansoprazole, when ENZ was then given in the fed state. Enzastaurin Cmax and AUC(0–8) increased significantly, respectively by 6.8 and 2.8 fold, when ENZ was administered after a standardized breakfast, compared to the fasted state. Median tmax increased from approximately 3 hours in the fed state to 6 hours in the fasted state, indicating slower absorption when ENZ was administered in the fasted state. Conclusions: No significant alterations in ENZ exposures were seen in the presence of lansoprazole, indicating that increased gastric pH did not decrease exposures of ENZ, when ENZ is administered in the fed state. Exposures of ENZ and its active metabolites were significantly enhanced by administration of ENZ after a meal. [Table: see text] No significant financial relationships to disclose.