SYNOPSIS. Final Clinical Study Report for Study CA Final Clinical Study Report

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1 Name of Sponsor/Company: Bristol-Myers Squibb Name of Finished Product: Sprycel Name of Active Ingredient: Dasatinib Individual Study Table Referring to the Dossier (For National Authority Use Only) SYNOPSIS for Study TITLE OF STUDY: The Effect of Omeprazole on the Pharmacokinetics of Dasatinib () in Healthy Subjects INVESTIGATORS/STUDY CENTERS: John Coumbis, MD, MSPH, Bristol-Myers Squibb Clinical Research Center, Hamilton, NJ PUBLICATIONS: None STUDY PERIOD: Study Initiation Date: 14-Apr-2008 CLINICAL PHASE: 1 Study Completion Date: 06-May-2008 OBJECTIVES: Primary Objective: The primary objective of this study was to assess the effect of omeprazole on the pharmacokinetics of dasatinib in healthy subjects. Secondary Objective: The secondary objective of this study was to assess the safety and tolerability of a single dose of dasatinib before and after 5 days of dosing with omeprazole in healthy subjects. METHODOLOGY: This study was an open-label, single-sequence design evaluating the effect of a 40-milligram (mg) daily dose of omeprazole on the pharmacokinetics of a single oral 100-mg dose of dasatinib in healthy subjects. Subjects underwent screening evaluations to determine eligibility within 21 days prior to study enrollment. Subjects were admitted to the clinical facility prior to dosing on Day -1. A single oral dose of 100-mg dasatinib was administered to subjects in the morning at approximately 9:00 am on Days 1 and 6 (fasted). Omeprazole was administered in the morning at approximately 11:00 am from Day 2 to Day 6. Subjects were confined to the clinical facility for the duration of the study. NUMBER OF SUBJECTS (Planned and Analyzed): There were 14 subjects planned and 14 subjects analyzed. DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: Healthy subjects, as determined by medical history, physical examination, 12-lead electrocardiogram (ECG), and clinical laboratory evaluations were eligible to participate in the study. Subjects had to be 18 to 50 years of age and have a body mass index (BMI) of 18 to 30 kg/m 2. Female subjects could not be

2 nursing, pregnant, or of childbearing potential. All women had to have a negative pregnancy test at screening and Day -1 prior to dosing. TEST PRODUCT, DOSE AND MODE OF ADMINISTRATION, DURATION OF TREATMENT, BATCH NUMBERS: Day 6: 100-mg (2x50 mg tablets) oral dose of dasatinib tablets in the fasted state in the morning (approximately at 9:00 am followed with omeprazole). Label batch number: 5M Days 2 through 6: 40-mg oral dose of omeprazole capsule in the fasted state in the morning (approximately at 11:00 am). On Day 6, omeprazole was given 2 hours after the dasatinib dose. Lot number: U2835. REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION, DURATION OF TREATMENT, BATCH NUMBERS: Day 1: 100-mg (2x50 mg tablets) oral dose of dasatinib tablets in the fasted state in the morning (approximately at 9:00 am). Label batch number: 5M CRITERIA FOR EVALUATION: Safety: Safety assessments were based on adverse event (AE) monitoring, clinical laboratory test assessments, ECGs, vital signs, physical examinations, and physical measurements. Pharmacokinetics: Dasatinib pharmacokinetic (PK) variables were Cmax, Tmax, AUC(0-T), AUC(INF), and T-HALF. Cmax Maximum observed plasma concentration Tmax Time of maximum observed plasma concentration AUC(0-T) Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration AUC(INF) Area under the plasma concentration-time curve from time zero extrapolated to infinite time STATISTICAL CONSIDERATIONS: Sample Size Determination: Although the number of subjects was not based on statistical power considerations, 12 subjects would provide 90% confidence that the estimate of the Day 6-to-Day 1 (dasatinib+omeprazole : dasatinib alone) ratio of geometric means would be within 26% of its true population value for dasatinib Cmax, and within 23% of its true population value for dasatinib AUC(INF). Fourteen (14) subjects were enrolled to allow for dropouts. Statistical Analysis: To assess the effect of omeprazole on the pharmacokinetics of dasatinib, analyses of variance were performed on log Cmax, log AUC(0-T), and log AUC(INF) of dasatinib. Point estimates and 90% confidence intervals were calculated for the Day 6-to-Day 1 (dasatinib+omeprazole : dasatinib alone) ratios of geometric means of dasatinib Cmax, AUC(0-T) and AUC(INF). s on the log-transformed scale were adjusted for imbalances among factors in the analysis model (SAS least square means) and then exponentiated to obtain adjusted geometric means. Summary statistics for the PK parameters of dasatinib were tabulated by treatment (with or without omeprazole).

3 SUMMARY OF RESULTS: Disposition, Demographics, and Other Pertinent Baseline Characteristics: Table 1 summarizes subject disposition. Table 1: Subject Disposition All Subjects () Total No. of Subjects Enrolled 49 No. of Subjects Treated 14 No. of Subjects Completed 13 No. of Subjects Discontinued, treated 1 Withdrew consent 1 No. of Subjects Discontinued, not treated 35 No longer met study criteria 26 Withdrew consent 6 Group full, not needed 3 Table 2 lists the baseline and demographic characteristics. Table 2: Baseline and Demographic Characteristics Characteristic All Subjects () Age (years) (SD) Range Gender, n (%) Male Female Race, n (%) Black White Asian BMI, kg/m 2 37 (6) (93) 1 (7) 8 (57) 5 (36) 1 (7) (SD) 25.4 (2.9) Abbreviations: BMI = body mass index, SD = standard deviation

4 Safety Results: Safety findings are shown in Table 3. Four (4, 28.6%) subjects reported 6 AEs: headache (3, 21.4%), flatulence (1, 7.1%), nausea (1, 7.1%), and vomiting (1, 7.1%). All AEs were mild to moderate in intensity. No marked laboratory abnormality was reported in this study. There was no clinically-relevant change in vital signs or ECG parameters. Table 3: Safety Results Adverse Events Dasa (Day 1) No. (%) Subjects with at least 1 AE Number (%) of Subjects Omp (Days 2-5) Dasa+Omp (Day 6) N = 13 All Subjects 3 (21.4) 2 (14.3) 2 (15.4) 4 (28.6) Death SAE Discontinuation due to AEs Abbreviations: AE = adverse event, Dasa = dasatinib, Omp = omeprazole, SAE = serious adverse event Pharmacokinetic Results: Dasatinib PK parameters are summarized by treatment in Table 4. Table 4: Summary Statistics for Dasatinib PK Parameters Treatment Dasa (n = 14) Dasa+Omp (n = 13) Cmax (ng/ml) (51) (76) AUC(0-T) (ng h/ml) (46) (72) AUC(INF) (ng h/ml) (45) (68) Tmax (h) Median (Min, Max) 0.75 (0.47, 2.02) 1.00 (0.50, 1.92) T-HALF (h) (SD) 4.00 (1.35) 4.29 (1.62) Abbreviations: AUC(0-T) = area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration, AUC(INF) = area under the plasma concentration-time curve from time zero extrapolated to infinite time, Cmax = maximum observed plasma concentration, CV = coefficient of variation, Dasa = dasatinib, Omp = omeprazole, SD = standard deviation, T-HALF = plasma half-life, Tmax = time of maximum observed plasma concentration Details of the statistical analyses of dasatinib PK parameters are presented in Table 5. Table 5: Results of Statistical Analyses for Dasatinib Cmax, AUC(0-T) and AUC(INF) Treatment Adjusted s a (90% CI) Cmax AUC(0-T) AUC(INF)

5 Table 5: Results of Statistical Analyses for Dasatinib Cmax, AUC(0-T) and AUC(INF) Dasa (40.26, ) Dasa+Omp (20.14, 72.20) Dasa+Omp : Dasa Geo. Ratios Adjusted s a (90% CI) (ng/ml) (ng h/ml) (ng h/ml) 0.58 (0.25, 1.38) (176.36, ) (83.66, ) 0.54 (0.27, 1.07) (191.68, ) (96.90, ) 0.57 (0.30, 1.06) a s on the log-transformed scale were adjusted for imbalances among factors in the analysis model (SAS least square means) and then exponentiated to obtain adjusted geometric means. Abbreviations : CI = confidence interval, Dasa = dasatinib, Omp = omeprazole CONCLUSIONS: Dasatinib bioavailability was reduced by approximately 40% when dasatinib was administered 22 hours after a 4-day, 40-mg omeprazole daily dose [QD] and 2 hours before the next dose of omeprazole There was 42% decrease in Cmax and 43% reduction in AUC(INF) of dasatinib as administered in this study Dasatinib single dose was safe and well tolerated by healthy subjects when given in the absence or presence of omeprazole DATE OF REPORT: 06-Jan-2009