Prasugrel and clopidogrel inhibit platelet aggregation through active metabolite formation. Prasugrel's active metabolite (R‐138727) is formed primarily by cytochrome P450 (CYP) 3A and CYP2B6, with ...roles for CYP2C9 and CYP2C19. Clopidogrel's activation involves two sequential steps by CYP3A, CYP1A2, CYP2C9, CYP2C19, and/or CYP2B6. In a randomized crossover study, healthy subjects received a loading dose (LD) of prasugrel (60 mg) or clopidogrel (300 mg), followed by five daily maintenance doses (MDs) (15 and 75 mg, respectively) with or without the potent CYP3A inhibitor ketoconazole (400 mg/day). Subjects had a 2‐week washout between periods. Ketoconazole decreased R‐138727 and clopidogrel active metabolite Cmax (maximum plasma concentration) 34–61% after prasugrel and clopidogrel dosing. Ketoconazole did not affect R‐138727 exposure or prasugrel's inhibition of platelet aggregation (IPA). Ketoconazole decreased clopidogrel's active metabolite AUC0–24 (area under the concentration–time curve to 24 h postdose) 22% (LD) to 29% (MD) and reduced IPA 28% (LD) to 33% (MD). We conclude that CYP3A4 and CYP3A5 inhibition by ketoconazole affects formation of clopidogrel's but not prasugrel's active metabolite. The decreased formation of clopidogrel's active metabolite is associated with reduced IPA.
Clinical Pharmacology & Therapeutics (2007) 81, 735–741. doi:10.1038/sj.clpt.6100139; published online 14 March 2007
This study was designed to compare the degree of inhibition of platelet aggregation (IPA) of prasugrel with that of clopidogrel in stable aspirin-treated patients with coronary artery disease (CAD).
...Subjects (n=101) were randomly assigned to the following loading dose (LD) (day 1)/maintenance dose (MD) (days 2-28) combinations: prasugrel, 40 mg/5 mg; 40 mg/7.5 mg; 60 mg/10 mg; 60 mg/15 mg; or clopidogrel, 300 mg/75 mg. Turbidometric platelet aggregation was measured at multiple timepoints during the study. At 4 h after dosing, with 20 microM ADP, both prasugrel LDs achieved significantly higher mean IPA levels (60.6% and 68.4 vs. 30.0%, respectively; all P<0.0001) and lower percentage (3 vs. 52%, P<0.0001) of pharmacodynamic non-responders (defined as IPA <20%) than clopidogrel. Prasugrel 10 and 15 mg MDs achieved consistently higher mean IPA than clopidogrel 75 mg at day 28 (all P<0.0001). At pre-MD on day 28, there were no non-responders in the 10 and 15 mg prasugrel group, compared with 45% in the clopidogrel group (P=0.0007).
In this population, prasugrel (40-60 mg LD and 10-15 mg MD) achieves greater IPA and a lower proportion of pharmacodynamic non-responders compared with the approved clopidogrel dosing.
Background: Preclinically, protein kinase C and AKT activation can be inhibited by enzastaurin and reduce tumor growth of colorectal cancer cells. In asymptomatic patients with metastatic colorectal ...cancer (mCRC), enzastaurin activity was evaluated by measuring the 6-month progression-free survival (PFS) rate in a window study design.
Patients and methods: Chemonaive patients with asymptomatic mCRC who did not require immediate chemotherapy-induced tumor reduction received a 400-mg thrice daily loading dose of enzastaurin on day 1 of cycle 1, followed by 500mg once daily for the remaining 28-day cycles. Progression was assessed on the basis of radiographic imaging, rise in carcinoembryonic antigen or lactate dehydrogenase (LDH) levels or by appearance of clinical symptoms.
Results: Twenty-eight patients received daily enzastaurin. The 6-month PFS rate was 28% 95% confidence interval (CI) 13%–45% and median PFS was 1.9 months (95% CI 1.8–4.5 months). Twelve (43%) patients had stable disease with a median duration of 6.1 months. The survival rate at 20 months was 77% (95% CI 47%–92%). No grade 4 toxicity was reported and grade 3 toxic effects were observed in three patients with one patient showing probable drug-related elevation of liver transaminases.
Conclusion: The window design in asymptomatic patients with mCRC can be safely applied to assess the activity and safety of novel cytostatic agents like enzastaurin.
Abstract only
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.
Abstract only
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 5
th
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 C
max
and AUC
(0–8)
were unaffected by the administration of lansoprazole, when ENZ was then given in the fed state. Enzastaurin C
max
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 t
max
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.
Abstract only
2048
Background: Enzastaurin (ENZ), an oral inhibitor of protein kinase C (PKC), affects signal transduction associated with angiogenesis, proliferation, and survival. The combination ...of ENZ and capecitabine (CAPE) has the potential for additive or synergistic anticancer effects without excessive toxicity. Methods: Patients (pts) with advanced, refractory, solid tumors received lead-in treatment with ENZ for 7–14 days (cycle 1), to achieve steady-state exposures. In subsequent 21-day cycles, ENZ was given once daily, orally, on days 1–21 and CAPE twice daily (bid), orally, on days 1–14 in 3 dose levels (L): L 1 = ENZ 350 mg + CAPE 750 mg/m
2
; L 2 = ENZ 350 mg + CAPE 1000 mg/m
2
; L 3 = ENZ 525 mg (some pts received 500 mg tablets) + CAPE 1000 mg/m
2
. PK for ENZ was assessed on day 1–3 and 7 in cycle 1 and day 8 in cycle 2 and for CAPE on day 1, 8 in cycle 2. Therapy continued until disease progression or unacceptable toxicity occurred. Results: 27 pts (13 males; 14 females, ECOG ≤1) with a median age of 58 yrs (range: 38–74 yrs), received a median number of 3 cycles (range: 2–14 cycles). High interpatient PK variability was noted for total ENZ analytes. Ratio of geometric mean AUC (90% CI) of ENZ with CAPE versus ENZ alone at 500/525 mg was 0.65 (0.38–1.11, n=6) and of Cmax was 0.66 (0.42–1.10, n=4). PK parameters of CAPE in the presence of ENZ were similar to those previously reported for CAPE alone. No grade (Gr) 4 toxicities occurred. Gr 3 toxicities were anemia (1 pt), headache (1 pt), intestinal perforation (1 pt with gastric carcinoma), fatigue (1 pt), hand-foot syndrome (2 pts), and cardiac ischemia (1 pt). PBMCs demonstrated PKC inhibition following exposure to ENZ. Plasma VEGF and bFGF levels did not reflect any significant changes. No objective tumor responses were seen. Five pts had stable disease (lung, breast, pancreas, head/neck, and hemangiopericytoma) for ≥ 6 months (range: 6–9.7 months). Conclusions: The recommended phase II dose is ENZ 500 mg, qd and Cape 1000 mg/m
2
bid, days 1–14 every 21 days. This regimen was well tolerated, and exposures of ENZ and CAPE did not appear to be significantly altered when given in combination.
Table: see text
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14021
Background: Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCβ and the PI3K/AKT pathway to induce tumor cell apoptosis, reduce ...proliferation, and suppress tumor-induced angiogenesis. Objectives of this phase 1b study included the comparison of safety and PK data for enzastaurin and its active metabolites in the QD (once daily) and BID (twice daily) regimens. Methods: Patients (pts) with advanced or metastatic cancer were enrolled. In cycle 1, pts received 500 mg enzastaurin QD from days 1–15 and 250 mg BID from days 16–30. In subsequent 21-day cycles, 500 mg/m
2
pemetrexed was administered as a 10-minute intravenous infusion on day 1, with 250 mg enzastaurin BID. Folic acid and vitamin B
12
supplementation was given to pts prior to and during pemetrexed administration. For comparison of enzastaurin QD versus BID, PK sampling was performed on days 15 and 29 of cycle 1. Results: Interim data for cycle 1 are presented for 26 patients who received 1 dose of enzastaurin. Twenty patients (9 F, 17 M; median age 60 years range: 43–80; ECOG =2) completed cycle 1. Hematological toxicities (grade Gr =3) were reported on a total of 9 pts. Lymphopenia occurred in 8 pts in BID regimen (1 Gr 3) and 2 pts in QD. Leukopenia (n=1), neutropenia (n=1), hypokalemia (n=1) and SGPT increase (n=1) were reported only in BID regimen. Chromaturia (n=15) was observed in both regimens. Hypoalbuminemia (n=2) and fatigue (n=2) were equally common in both regimens. Pharmacokinetic data for the two regimens is shown in the table . Exposures increased by approximately 50% and 40% for enzastaurin and total analyte (enzastaurin + metabolites), respectively. Conclusions: In comparison to QD dosing, enzastaurin exposures are increased modestly after BID dosing. This increase in exposure did not cause any clinically significant worsening of toxicities in most patients.
Table: see text
Table: see text
BACKGROUND:
Drotrecogin alfa (activated) DrotAA is approved for the reduction of mortality in adults with severe sepsis (sepsis with acute organ dysfunction) and high risk of death. Patients whose ...actual body weight was >135 kg were excluded from the Phase III PROWESS trial.
OBJECTIVE:
To compare exposure to DrotAA in patients with severe sepsis weighing >135 kg with those weighing ⩽135 kg in an open-label, Phase IV trial, and quantify the elimination half-life (t1/2) of DrotAA in these patients.
METHODS:
PROWESS inclusion/exclusion criteria were used, except that patients >135 kg were enrolled. Blood samples were collected for steady-state plasma concentration (Css) analysis of activated protein C once each day and for t1/2 analysis after infusion. Weight-normalized clearance (Clp) and t1/2 estimates for DrotAA were calculated and compared between weight groups.
RESULTS:
Patient weight range was 59–227 kg. There were 32 patients ⩽135 kg and 20 patients >135 kg enrolled. Median Clp was 0.45 L/h/kg (interquartile range IQR 0.37–0.54) for patients ⩽135 kg and 0.42 L/h/kg (IQR 0.33–0.54) for patients >135 kg (p = 0.692). Median estimates of Css were 51.9 ng/mL (IQR 43.4–62.0) and 56.5 ng/mL (IQR 44.9–71.1; p = 0.570). In patients ⩽135 kg, DrotAA had a median t1/2 of 16.7 minutes (IQR 13.9–20.0) compared with 16.0 minutes (IQR 12.9–19.8) in patients >135 kg (p = 0.767), for a composite median t1/2 of 16.3 minutes (IQR 14.2–18.8).
CONCLUSIONS:
There is no statistically significant difference in Css concentrations or t1/2 of DrotAA between patients weighing ⩽135 kg and >135 kg. DrotAA should be dosed by actual body weight.
Abstract only
2047
Background: Enzastaurin, an orally administered potent PKC inhibitor, is an anti-angiogenic agent that also suppresses PI3K/AKT to inhibit tumor cell proliferation and induce tumor ...cell death. Preclinical data suggest that the combination of enzastaurin and pemetrexed (Alimta) produced additive or synergistic antitumor activity in tumor specimens. This phase 1b study evaluated the safety, pharmacokinetic (PK) interaction, and antitumor activity of enzastaurin when combined with pemetrexed. Methods: Patients (pts) with advanced or metastatic cancer and an ECOG status of 0–2 received an intravenous dose of 500 mg/m
2
pemetrexed on day 1 and an oral dose of 500 mg enzastaurin once daily, (after day 4 in cycle 1) in repeat 21-day cycles for up to 6 cycles. In cycle 1, a loading dose of 1200 mg enzastaurin (400 mg/3×/day) was given on day 4. Pts were also given oral folic acid daily and vitamin B
12
every 9 weeks for the duration of pemetrexed therapy, and 5–7 days before cycle 1. Results: Blood samples for PK analysis of enzastaurin (n = 21) were collected on day 21 of cycle 1 and day 1 of cycle 2, and for analysis of pemetrexed (n = 22) on day 1 of cycle 1 and cycle 2. Steady-state concentration geometric mean (%CV) of total analytes (enzastaurin and its metabolites) was 1270 nM (126%) when administered alone and 1130 nM (100%) when administered with pemetrexed. Thus, no significant differences in exposures were observed when combined with pemetrexed. Clearance of pemetrexed was the same when dosed either with enzastaurin (2.48 L/h/m
2
) or as a single agent (2.62 L/h/m
2
). Safety data from the first 2 cycles are consistent with the known toxicity profile of pemetrexed. No grade 3 or 4 toxicity was reported following the loading dose of 1200 mg enzastaurin. Conclusions: Preliminary data suggest that there is no significant PK interaction between enzastaurin and pemetrexed, and that the combination is well tolerated. The current study is ongoing and subsequent analyses will document tumor responses and safety for longer-term treatment of enzastaurin combined with pemetrexed. This first PK study of enzastaurin and pemetrexed will help determine if enzastaurin has an additive clinical benefit to pemetrexed treatment and support future studies in NSCLC and mesothelioma.
Table: see text
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