The clinical trial information provided in this public disclosure synopsis is supplied for informational purposes only.

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1 The clinical trial information provided in this public disclosure synopsis is supplied for informational purposes only. Please note that the results reported in any single trial may not reflect the overall potential risks or benefits of a product which are based on an evaluation of an entire research program. Before prescribing any Takeda products, healthcare professionals should consult prescribing information for the product approved in their country.

2 Study No. _ SYNOPSIS in Healthy Adult Subjects Name of Sponsor: Takeda Global Research & Development Center, Inc. Name of Finished Product: Investigator: Matthew M. Medlock, MD Publications Based on the Study: None Study Period: 04 June 2008 to 14 August 2008 OBJECTIVES Study Center: PPD Development, LP 7551 Metro Center Drive, Suite 200 Austin, TX Phase of Development: Phase 1 Primary: The primary objective of this study was to examine the single-dose pharmacokinetics of (10 mg) and its metabolites Lu AA34443 and Lu AA39835 in the presence of multiple doses of fluconazole (200 mg once daily [QD]) or ketoconazole (400 mg QD), in healthy subjects. Secondary: The secondary objective of the study was to compare the safety and tolerability of a single dose of alone, and in the presence of multiple doses of fluconazole or ketoconazole, in healthy subjects. METHODS This was a phase 1, open-label, randomized, single-center, pharmacokinetic drug interaction study to evaluate the effect of multiple doses of fluconazole or ketoconazole on the single-dose pharmacokinetic profile of. Thirty-six healthy male or female subjects aged 18 to 55 years, inclusive, were planned for enrollment into the study. Subjects were randomized to 1 of 2 treatment groups (1:1 ratio) in which a single oral dose of 10 mg QD was administered before and after administration of multiple doses of fluconazole 200 mg QD or ketoconazole 400 mg QD. A schematic of the study design is included below: Screening Days -21 to -2 Checkin Day -1 Treatment Day 1 10 mg Source: Appendix ET=early termination, PK=pharmacokinetics. Washout Days 2-14 Group 1 Group 2 Treatment Days Fluconazole alone 200 mg QD Ketoconazole alone 400 mg QD OR Treatment Day 21 Fluconazole 200 mg + 10 mg Ketoconazole 400 mg + 10 mg PK Days 2-26 Final Visit/ ET Day 27 Final Visit procedures

3 Study No. _103 in Healthy Adult Subjects The study consisted of a Screening Period (Days -21 to -2), Check-in and Recheck-in (Day -1 and Day 14, respectively), Treatment Period (single dose of 10 mg on Day 1, multiple doses of fluconazole 200 mg QD or ketoconazole 400 mg QD on Days 15 through 20, and a single dose of 10 mg + fluconazole 200 mg or ketoconazole 400 mg on Day 21), Washout (Days 2 to 14 and Days 22 to 26), and the Final Visit or Early Termination (Day 27). Eligible subjects reported to the clinical research unit on the morning of Day -1, remained confined until the morning of Day 6, were readmitted to the clinic on Day 14, and subsequently remained confined until the final pharmacokinetic blood samples were collected and all Final Visit procedures were performed on Day 27. A follow-up phone call was made 30 days after administration of the last dose of study medication (Day 51). Number of Subjects (Planned and Analyzed): Planned: 36 subjects. Analyzed: Pharmacokinetics 36 subjects; Safety 36 subjects. Diagnosis and Main Criteria for Inclusion: To qualify for study participation, subjects must have been healthy men or nonpregnant, nonlactating healthy women; aged 18 to 55 years, inclusive; weighing at least 50 kg and with a body mass index of 19 to 30 kg/m 2, inclusive; with a resting pulse within the normal range of 45 to 100 bpm; in good health as determined by the investigator per medical history, physical examination, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory evaluations (hematology, serum chemistry, and urinalysis); testing negative for hepatitis B surface antigen and hepatitis C virus antibody; and willing to sign the informed consent form, and comply with the protocol requirements. Test Product, Dose and Mode of Administration, Lot Number: Drug Dose Form Route Lot No. Fluconazole Ketoconazole 10 mg 200 mg 400 mg Tablet Tablet Tablet (200 mg) Oral Oral Oral Y Duration of Treatment: The total duration of the study was approximately 48 days, consisting of Screening (Days -21 to -2), Check-in and Recheck-in (Day -1 and Day 14, respectively), Treatment Period (Day 1, Days 15 to 20, and Day 21), Washout (Days 2 to 14 and Days 22 to 26), and the Final Visit/Early Termination (Day 27). Reference Therapy, Dose and Mode of Administration, Lot Number: None. Criteria for Evaluation: Pharmacokinetic: The following plasma pharmacokinetic parameters of and its metabolites, Lu AA34443 and Lu AA39835, were determined for Day 1 and Day 21: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC[0-tlqc]), area under the plasma concentration-time curve from time 0 to infinity (AUC[0-inf]), area under the plasma concentration-time curve from time 0 to 120 hours postdose (AUC[0-120]), maximum observed plasma concentration (Cmax), time at which Cmax occurred (Tmax), terminal elimination rate c-life (T1/2), mean residence time (MRT), apparent oral clearance (CL/F) (for only), apparent volume of distribution (Vd/F) (for only), and apparent volume of distribution at steady-state (Vss/F) (for only). Metabolic ratios of Lu AA34443 and Lu AA39835 (AUC-Lu AA34443[0-inf]/AUC-[0-inf] and AUC-Lu AA39835[0-inf]

4 Study No. _103 in Healthy Adult Subjects /AUC-[0-inf], respectively) were also calculated. The following urine pharmacokinetic parameters of and its metabolites, Lu AA34443 and Lu AA39835, were calculated from the Day 1 and Day 21 urine concentration values: amount of drug excreted in urine from time 0 to 120 hours postdose (Ae[0-120]), renal clearance (CLr), and the fraction of drug excreted in urine (Fe). The following plasma pharmacokinetic parameters were calculated for the interacting drugs fluconazole and ketoconazole on Day 21: area under the blood concentration-time curve from time 0 to 24 hours postdose (AUC[0-24]), Cmax, Tmax, CL/F, Vss/F, MRT; observed predose plasma concentrations during multiple dosing (Ctrough) on Days 18, 19, 20, and 21 were also determined. Pharmacokinetic blood samples (6 ml each) were collected for and its metabolites, Lu AA34443 and Lu AA39835, on Days 1 and 21 at predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96, and 120 hours postdose. Pharmacokinetic blood samples (6 ml each) for fluconazole and ketoconazole were collected on Days 18 to 20 at predose; and on Day 21 at predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours postdose. Urine samples were collected for and its metabolites, Lu AA34443 and Lu AA39835, on Days 1 and 21 at predose (-12 to 0 hours), and at 0 to 24, 24 to 48, and 48 to 72 hours postdose. Safety Safety variables included adverse events, clinical laboratory evaluations (hematology, serum chemistry, and urinalysis), vital signs, physical examination results, and 12-lead ECG findings. Genotype Analysis: Subjects were genotyped for common cytochrome P450 (CYP) 2C9, CYP2C19, and CYP2D6 allelic variants associated with drug disposition. Statistical Methods: Pharmacokinetic Measures: To examine the single-dose pharmacokinetics of after multiple doses of fluconazole or ketoconazole, a paired t-test based on within-subject differences was performed on the natural logarithms of AUC(0-tlqc), AUC(0-inf), and Cmax for and its metabolites Lu AA34443 and Lu AA The Wilcoxon signed rank test was used for Tmax. The statistical analysis of each pharmacokinetic parameter was performed using only those subjects with nonmissing values on both Days 1 and 21. There was no imputation of missing data. Within the framework of the paired t-test analysis, using the natural logarithms of AUC(0-tlqc), AUC(0-inf), and Cmax, the ratio of the central values of the test treatment ( + fluconazole or + ketoconazole on Day 21) to the reference treatment ( alone on Day 1) was obtained by taking the antilog of the difference between the means of the test and reference treatments on the natural logarithmic scale. The 90% confidence interval (CI) of the ratio of the central values was obtained by taking the antilog of the 90% CI for the difference between the means of the test and reference treatments on the natural logarithmic scale. Attainment of steady state of fluconazole or ketoconazole plasma concentrations was evaluated by analysis of each of the Ctrough concentrations collected on Days 18, 19, 20, and 21. The following analysis of variance (ANOVA) model was used for fluconazole or ketoconazole: Log(concentration)=subject + day. Subject was considered as a random effect while day was a fixed effect. Within the ANOVA model, a pairwise t-test was used to assess the achievement of steady state by comparing the Ctrough values between study days for each of fluconazole and ketoconazole. In the event that there was statistical significance regarding steady state, the statistical analysis was used in conjunction with clinical judgment in assessing the overall impact of the nonattainment of steady state on the primary conclusions of the results of the pharmacokinetic analysis.

5 Study No. _103 in Healthy Adult Subjects SUMMARY OF RESULTS Subject Disposition: Thirty-six subjects were enrolled in the study and randomized to 1 of 2 treatment groups (18 subjects per treatment group). The mean age in this study was 28.6 years for subjects in the fluconazole treatment group and 26.5 years for subjects in the ketoconazole treatment group. Thirty-three subjects completed the study and 3 subjects prematurely discontinued from the study: 2 subjects (fluconazole treatment group) prematurely discontinued from the study due to protocol deviation and voluntary withdrawal, respectively; and 1 subject (ketoconazole treatment group) discontinued from the study due to a reason listed as adverse event/protocol deviations. Pharmacokinetic Results: The statistical analyses of the single dose plasma pharmacokinetic parameters of and its metabolites, Lu AA34443 and Lu AA39835, following administration of multiple doses of fluconazole or ketoconazole, are summarized in the table below. Statistical Analysis of the Plasma Pharmacokinetic Parameters of and its Metabolites Lu AA34443 and Lu AA39835 Treatment Group: Fluconazole Geometric Mean 10 mg + Fluconazole 200 mg (Test) 10 mg Alone (Reference) Geometric Mean Ratio (100*Test/ Reference) 90% CI for Geometric Mean Ratio Analyte Parameter (units) (a) N (b) AUC(0-tlqc) (nghr/ml) (132.64, ) Cmax (ng/ml) (106.64, ) Tmax (hr) (c) Lu AA34443 AUC(0-tlqc) (nghr/ml) (95.72, ) Cmax (ng/ml) (71.70, ) Tmax (hr) (c) Lu AA39835 AUC(0-tlqc) (nghr/ml) (143.14, ) Cmax (ng/ml) (119.63, ) Tmax (hr) (c)

6 Study No. _103 in Healthy Adult Subjects Treatment Group: Ketoconazole Geometric Mean 10 mg + Ketoconazole 400 mg (Test) 10 mg Alone (Reference) Geometric Mean Ratio (100*Test/ Reference) 90% CI for Geometric Mean Ratio Analyte Parameter (units) (a) N (b) AUC(0-tlqc) (nghr/ml) (122.34, ) Cmax (ng/ml) (119.20, ) Tmax (hr) (c) Lu AA34443 AUC(0-tlqc) (nghr/ml) (102.57, ) Cmax (ng/ml) (103.80, ) Tmax (hr) (c) Lu AA39835 AUC(0-tlqc) (nghr/ml) (131.56, ) Cmax (ng/ml) (138.97, ) Tmax (hr) (c) Source: Table and Appendix =not applicable. (a) The analysis for AUC(0-inf) of and its metabolites, Lu AA34443 and Lu AA39835, was not performed because of limited paired data available (<50% of number of subjects) in each treatment group. (b) All subjects (N=18) in both treatment groups had a complete dataset for AUC(0-tlqc), Cmax, and Tmax of and its metabolites on Day 1, whereas, 3 of 36 subjects (who prematurely discontinued from the study and did not receive treatment during the Days 15 to 26 Treatment Period) did not have a complete dataset for the aforementioned parameters on Day 21. Only N for Day 21 is presented in this table. (c) Median values are reported for Tmax. Analysis of Tmax was performed using the Wilcoxon signed rank test (fluconazole treatment group: P=0.488, 0.694, and for, Lu AA34443, and Lu AA39835, respectively; ketoconazole treatment group: P=0.011, 0.106, and for, Lu AA34443, and Lu AA39835, respectively). Fluconazole Treatment Group For, the 90% CI for the geometric mean ratio of the test ( 10 mg + fluconazole 200 mg) to reference ( 10 mg alone) treatments for Cmax was within the 80% to 125% no-effect boundary. The 90% CI for the geometric mean ratio of the test to reference treatments for AUC(0-tlqc) was outside the 80% to 125% no-effect boundary (132.64, ). An increase of approximately 46% in AUC(0-tlqc) of was observed when was coadministered with fluconazole compared with administered alone. However, this change is not considered clinically meaningful. For the inactive metabolite Lu AA34443, the 90% CIs for the geometric mean ratios of the test to reference treatments for AUC(0-tlqc) and Cmax were outside the 80% to 125% no-effect boundary (95.72, and 71.70, , respectively). An increase of approximately 10% in AUC(0-tlqc) and a decrease of 12% in Cmax were seen when was coadministered with fluconazole compared with administered alone. These changes are not considered clinically meaningful. The metabolic ratio of Lu AA34443 increased from 1.46 on Day 1 ( 10 mg alone) to 1.52 on Day 21 ( 10 mg + fluconazole 200 mg). For the active metabolite Lu AA39835, the 90% CIs for the geometric mean ratios of the test to reference treatments for AUC(0-tlqc) and Cmax were outside the 80% to 125% no-effect boundary (143.14, and , , respectively). Increases of approximately 86% in AUC(0-tlqc) and 42% in Cmax were

7 Study No. _103 in Healthy Adult Subjects observed when was coadministered with fluconazole compared with administered alone. The metabolic ratio of Lu AA39835 on Day 1 was not evaluable; the metabolic ratio of Lu AA39835 on Day 21 was Since plasma concentrations of Lu AA39835 were very low compared with plasma concentrations of the parent compound, the 86% increase in AUC(0-tlqc) and the 42% increase in Cmax of Lu AA39835 did not have any significant impacts on the pharmacological profile of. Therefore, these changes are not considered clinically meaningful. Median Tmax values of and its metabolite Lu AA34443 were identical for the test and reference treatments. Median Tmax values of Lu AA39835 were different for the test and reference treatments (24.00 and hours, respectively); however, this difference was not statistically significant (P=0.173). Ketoconazole Treatment Group For, the 90% CIs for the geometric mean ratios of the test ( 10 mg + ketoconazole 400 mg) to reference ( 10 mg alone) treatments for AUC(0-tlqc) and Cmax were outside the 80% to 125% no-effect boundary (122.34, , and , , respectively). Increases of approximately 30% in AUC(0-tlqc) and 26% in Cmax were observed when was coadministered with ketoconazole compared with administered alone. These changes are not considered clinically meaningful. For the inactive metabolite Lu AA34443, the 90% CIs for the geometric mean ratios of the test to reference treatments for AUC(0-tlqc) and Cmax were within the 80% to 125% no-effect boundary. The metabolic ratio of Lu AA34443 decreased from 1.23 on Day 1 ( 10 mg alone) to 1.05 on Day 21 ( 10 mg + ketoconazole 400 mg). For the active metabolite Lu AA39835, the 90% CIs for the geometric mean ratios of the test to reference treatments for AUC(0-tlqc) and Cmax were outside the 80% to 125% no-effect boundary (131.56, and , , respectively). Increases of approximately 46% in AUC(0-tlqc) and 47% in Cmax were seen when was coadministered with ketoconazole compared with administered alone. These changes are not considered clinically meaningful. The metabolic ratio of Lu AA39835 on Day 1 was not evaluable; the metabolic ratio of Lu AA39835 on Day 21 was Median Tmax values of and its metabolite Lu AA34443 were different for the test and reference treatments (10.00 and hours [P=0.011] and 5.00 and 6.00 hours [P=0.106], respectively); however, these differences are not considered clinically meaningful. Median Tmax values of Lu AA39835 were identical for the test and reference treatments. Steady State Plasma concentrations of ketoconazole achieved steady state by Day 19. Plasma concentrations of fluconazole appeared to have reached near steady state. Safety Results: Eight of 18 subjects (44.4%) in the fluconazole treatment group safety set experienced a total of 20 adverse events during the study; and 10 of 18 subjects (55.6%) in the ketoconazole treatment group safety set experienced a total of 26 adverse events during the study. The highest incidence of adverse events in the fluconazole treatment group occurred during Days 21 to 27 ( 10 mg + fluconazole 200 mg QD; 5 of 16 subjects [31.3%]). The highest incidence of adverse events in the ketoconazole treatment group occurred during Days 1 to 14 ( 10 mg alone; 9 of 18 subjects [50.0%]).

8 Study No. _103 in Healthy Adult Subjects Most subjects who experienced 1 or more adverse events, experienced adverse events that were considered by the investigator to be possibly related to study drug (6 of 8 subjects in the fluconazole treatment group; 8 of 10 subjects in the ketoconazole treatment group). No adverse events were considered probably or definitely related to study drug. The majority of adverse events reported during the study in either treatment group were considered mild in intensity (7 of 18 subjects [38.9%] in the fluconazole treatment group; 10 of 18 subjects [55.6%] in the ketoconazole treatment group). Two subjects (11.1%) in the fluconazole treatment group and 3 subjects (16.7%) in the ketoconazole treatment group experienced adverse events judged by the investigator as being moderate in intensity. Adverse events with the greatest incidence ( dizziness, and headache. Nausea was reported more frequently during Days 21 to 27 ( 10 mg + fluconazole 200 mg QD) compared with Days 1 to 14 ( 10 mg alone) and Days 15 to 20 (fluconazole 200 mg QD alone); all adverse events of nausea in the fluconazole treatment group were considered possibly related to study drug. Adverse events with the greatest incidence ( nausea, headache, diarrhea, toothache, vomiting, and dysmenorrhea. Nausea was reported with similar frequency during Days 1 to 14 ( 10 mg alone) and Days 21 to 27 ( 10 mg + ketoconazole 400 mg QD), and less frequently during Days 15 to 20 (ketoconazole 400 mg QD alone). Headache was experienced by subjects only during Days 15 to 20. All adverse events of headache and nausea experienced by subjects in the ketoconazole treatment group were considered possibly related to study drug. One subject (ketoconazole treatment group) permanently discontinued from the study due to a reason specified as adverse event/protocol deviations (the subject took a prohibited antibiotic for the adverse event of toothache). No deaths or serious adverse events occurred during the study. No result from clinical laboratory tests, vital signs, physical examination, or ECGs was reported as an adverse event and no subject discontinued from the study because of an abnormal value. CONCLUSIONS: An increase of approximately 46% in AUC of when a single dose of 10 mg was administered in the presence of multiple doses of fluconazole 200 mg QD (an inhibitor of the CYP2C9 and CYP3A4/5 isoforms, administered for 7 days) was not considered clinically meaningful. Increases of approximately 30% and 26% in AUC and Cmax of, respectively, when a single dose of 10 mg was administered in the presence of multiple doses of ketoconazole 400 mg QD (a potent inhibitor of the CYP3A4/5 and P-glycoprotein isoforms, administered for 7 days) were not considered clinically meaningful. Administration of 10 mg alone and concomitant treatment with 10 mg and fluconazole 200 mg QD or ketoconazole 400 mg QD were generally well tolerated in this study. Date of Report: 29 March 2010