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Page 3 of 1660 2.0 SYNOPSIS Name of Sponsor: Takeda Pharmaceuticals North America, Inc. Name of Finished Product: Ramelteon (TAK-375) Investigator: Aziz L. Laurent, MD Publication (reference): None Study Period (years): 22 April 2003 to 29 May 2003 OBJECTIVES Study Center: PPD Development, LLC, Clinics 706A Ben White Boulevard West Austin, TX 78704 Phase of Development: Phase I Primary: To evaluate the effect of concomitant fluoxetine administration on the single dose pharmacokinetics of ramelteon in healthy men and women. Secondary: To evaluate the safety of concomitant fluoxetine administration with ramelteon in healthy men and women. METHODOLOGY This was a Phase I, single-site, open-label study with a single sequence of treatment administration. Subjects received study drug once daily (QD) as presented in the following study schematic. Screening Baseline Treatment Period Discharge Day 21 to Day -2 Day -1 Day 1 Day 2 Day 3 to Day 12 Day 13 Day 14 16 mg QD Ramelteon Washout 40 mg QD Fluoxetine Ramelteon 16 mg QD + Fluoxetine 40 mg QD
Page 4 of 1660 Number of Subjects (Planned and Analyzed): Planned: 28 subjects Analyzed: Pharmacokinetics 27 subjects; Safety 28 subjects Diagnosis and Main Criteria for Inclusion: To qualify for study participation, subjects must have had/been: healthy men or nonpregnant, nonlactating women; 18 to 55 years of age, inclusive; at least 50 kg (110 pounds) with a body mass index (BMI) of less than or equal to 30 kg/m 2 ; able to comprehend and willing to sign an informed consent form; clinical laboratory results within the reference ranges or that were acceptable to the investigator or sponsor; negative urine test results for selected substances of abuse at Screening and at Check-in on Study Day -1; a negative hepatitis panel at Screening (or proof of hepatitis B vaccination if positive for hepatitis B surface antibody); had negative human immunodeficiency virus (HIV) antibody at Screening; and deemed in good health as determined by the investigator (ie, via medical history and physical examination). Study Drugs, Dose and Mode of Administration: Ramelteon 16 mg tablet, oral Fluoxetine 40 mg pulvule, oral Lot Number: Z515A021 6RD49M Duration of Treatment: The study duration was 14 days; subjects received a single dose of ramelteon 16 mg on Day 1, followed by multiple doses of fluoxetine 40 mg administered QD from Day 3 through Day 12, and a single coadministration of fluoxetine 40 mg and ramelteon 16 mg on Day 13. Reference Therapy, Dose and Mode of Administration, Lot Number: None. Criteria for Evaluation: Pharmacokinetic: The following pharmacokinetic values were calculated using serum concentration values of ramelteon and its metabolites (M-I, M-II, M-III, and M-IV): area under concentration-time curve from time 0 to time of last quantifiable concentration (AUC [0-tlqc]), area under concentration-time curve from time 0 to infinity (AUC[0-inf]), maximum observed concentration (Cmax), time at which maximum concentration is observed (Tmax), terminal elimination rate constant (λz), and half-life (T1/2). For fluoxetine and its metabolite, norfluoxetine, the following parameters were calculated using plasma concentrations; area under the curve from time 0 to tau (AUC[0-τ], where τ is the dosing interval), Cmax, minimum observed concentration (Cmin), and Tmax. The apparent oral clearance corrected for bioavailability (CL/F) was calculated for unchanged ramelteon and unchanged fluoxetine only. Safety: Safety variables included adverse events, clinical laboratory test results, vital signs, electrocardiograms (ECGs), and physical examinations.
Page 5 of 1660 Statistical Methods for Pharmacokinetic Endpoints: A paired t-test was performed on Cmax, AUC(0-tlqc), AUC(0-inf), and λz of ramelteon and its metabolites. Cmax, AUC(0-tlqc), and AUC(0-inf) were transformed into their natural logarithm prior to the analysis. The Wilcoxon Signed Rank Test was performed on Tmax. The 90% confidence intervals (CIs) for the ratio of geometric means of the test treatment (ramelteon + fluoxetine) relative to the reference treatment (ramelteon alone) are provided. Fluoxetine steady state concentration assessment was based on the natural logarithms of predose concentrations on Day 10 through Day 13. In the analysis of variance model (ANOVA), the fixed effect was Day, and the random effect was Subject. A pairwise t-test was used to evaluate steady state by comparing the predose concentration levels between study days. SUMMARY OF RESULTS Subject Disposition: A total of 28 subjects (mean age of 30.9 years), including 19 men and 9 women, were enrolled in the study, and 27 subjects, including 19 men and 8 women, completed the study. One subject was withdrawn from the study due to the investigator s discretion. Pharmacokinetic Results: Assessment of Steady State of Fluoxetine Statistical analysis on fluoxetine and norfluoxetine predose data on Day 10 through Day 13 in subjects who received fluoxetine alone showed that steady state was not achieved by Day 13. Levels of the parent and metabolite increased on each day from Day 10 through Day 13.
Page 6 of 1660 Effect of Fluoxetine on Ramelteon and Metabolites The serum pharmacokinetics of ramelteon and its metabolites were assessed after administration of ramelteon alone and after coadministration of ramelteon with fluoxetine. Statistical comparison results for selected pharmacokinetic parameters of interest for ramelteon, its active metabolite M-II, and minor metabolites M-I, M-III, and M-IV are shown in the following table. Geometric Means Pharmacokinetic Ramelteon Ramelteon + Mean Ratio 90% CI of Analyte Parameter N Alone (R) Fluoxetine (T) (100 T/R) (a) Ratio(a) Ramelteon Cmax (ng/ml) 27 3.85 5.38 139.81 (117.92, 165.77) AUC(0-tlqc) (ng hr/ml) 27 4.43 6.67 150.52 (127.49, 177.70) AUC(0-inf) (ng hr/ml) 26 4.66 7.00 150.09 (127.11, 177.21) M-I Cmax (ng/ml) 27 7.68 8.49 110.57 (100.93, 121.12) AUC(0-tlqc) (ng hr/ml) 27 8.44 10.6 125.50 (120.08, 131.16) AUC(0-inf) (ng hr/ml) 27 9.12 11.4 125.16 (119.83, 130.72) M-II Cmax (ng/ml) 27 116 136 116.73 (108.24, 125.90) AUC(0-tlqc) (ng hr/ml) 27 323 490 151.91 (142.75, 161.66) AUC(0-inf) (ng hr/ml) 27 326 495 151.69 (142.55, 161.42) M-III Cmax (ng/ml) 27 1.39 2.17 156.43 (101.93, 240.07) AUC(0-tlqc) (ng hr/ml) 27 1.80 3.32 184.92 (118.69, 288.10) AUC(0-inf) (ng hr/ml) 16 4.32 5.53 128.21 (114.65, 143.38) M-IV Cmax (ng/ml) 27 11.5 11.2 97.84 (91.98, 104.07) AUC(0-tlqc) (ng hr/ml) 27 62.8 65.0 103.63 (99.11, 108.34) AUC(0-inf) (ng hr/ml) 27 67.5 70.0 103.74 (99.65, 108.01) Source: Table 14.2.1.7. T indicates Test; R, Reference. (a) Mean ratios and CIs expressed as percentages. The results indicate that administration of multiple doses of fluoxetine produces a statistically significant increase in the single-dose exposure to ramelteon and its metabolites, with the exception of M-IV, where the 90% CI for Cmax, AUC(0-tlqc), and AUC(0-inf) were contained within the equivalence range of 80% to 125%.
Page 7 of 1660 Safety Results: Eight of 19 men (42.1%) and 5 of 9 women (55.5%) experienced at least 1 treatment-emergent adverse event during the study. All adverse events were mild in severity. Overall, there were 35 adverse events reported during the study: 5 subjects (5/28; 17.9%) experienced 8 adverse events after a single administration of ramelteon alone; 10 subjects (10/28; 35.7%) experienced 21 adverse events during a 10-day administration of fluoxetine alone; and 5 subjects (5/27; 18.5%) experienced 6 adverse events after a single concurrent administration of ramelteon with fluoxetine The most frequent adverse events occurred in the nervous system disorder class (somnolence, dizziness, tremor, and headache) followed by gastrointestinal disorder class (dyspepsia, nausea, abdominal discomfort, and abdominal pain). There were no deaths or serious adverse events (SAE) during the study. No clinically meaningful changes in vital signs, physical examinations or ECG findings were reported in this study. Two subjects had clinically significant laboratory findings (elevated serum creatinine and abnormal urinalysis on Day 14) reported as adverse events after coadministration of ramelteon with fluoxetine; both were mild in intensity, and possibly related to study medication. All repeat values (obtained approximately 1 week later) were within ranges considered not clinically significant. CONCLUSIONS: Statistically significant increases were noted in peak and total exposures to ramelteon and its metabolites (M-I, M-II, and M-III) in serum after administration of ramelteon with fluoxetine compared to ramelteon alone. The magnitude of these increases (about 50%) in ramelteon exposure was not sufficient to warrant a recommendation to adjust the dose of ramelteon in subjects who are concurrently receiving fluoxetine. The present study results suggest that fluoxetine modestly inhibits the metabolism of ramelteon and its major metabolite, M-II. Under the conditions of this trial, concomitant fluoxetine and ramelteon administration appeared to be safe and well tolerated. Date of Report: