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2.0 SYNOPSIS Name of Sponsor: Takeda Global Research & Development (TGRD) Centre (Europe) Ltd. Name of Finished Product: TAK-491 (also known as azilsartan medoxomil), chlorthalidone, and TAK-491CLD (fixed dose combination tablet of azilsartan medoxomil and chlorthalidone) Investigator: Steve Warrington, MA, MD, FRCP, FFPM Publications Based on the Study: None. Study Period: 20 July 2010 to 14 September 2010 Study Address: Hammersmith Medicines Research (HMR) London NW10 7EW, United Kingdom Phase of Development: Phase 1 OBJECTIVES: Primary: To assess the relative bioavailability of chlorthalidone and TAK-491 (as the active moiety TAK-536) in the TGRD fixed-dose-combination (FDC) tablet containing TAK-491 and chlorthalidone to that of an European Union (EU)- approved tablet formulation of chlorthalidone and the TAK-491 monotherapy tablet, under development, in healthy adult subjects administered these agents as a single oral dose. Secondary: To evaluate the safety and tolerability of single doses of the proposed commercial FDC and coadministered TAK-491 and chlorthalidone tablets in healthy adult subjects. METHODS: This was a phase 1, single-center, open-label, randomized, single-dose, 2-period crossover study. Forty-eight healthy adult subjects between the ages of 18 and 55 years, inclusive, received 1 single dose of each study medication (one TAK-491CLD 80 mg/25 mg FDC tablet and coadministered TAK-491 80 mg + chlorthalidone 25 mg tablets) in a randomized, crossover fashion; consecutive treatments were separated by 14 days. Subjects were discharged from the clinic on Day 6 of Period 1 and returned to the clinic 8 days later (Day -1 of Period 2). Follow-up phone calls were made approximately 9 days after Study Exit (Day 15 [±2 days] of Period 2). In each period, serial blood samples were collected over 72 hours postdose for the analysis of TAK-536 (the active moiety of TAK-491) and over 120 hours postdose for the analysis of chlorthalidone. Number of Subjects (Planned and Analyzed): Planned: 48 subjects. Enrolled: 48 subjects. Completed: 48 subjects. Analyzed: Pharmacokinetics 48 subjects; Safety 48 subjects. Diagnosis and Main Criteria for Inclusion/Exclusion: Primary inclusion criteria were: male or female subjects aged 18 to 55 years, inclusive; screening body mass index between 18 and 32 kg/m 2, inclusive; capability of protocol compliance; willingness to sign the informed consent prior to undergoing any study-related procedures; clinical laboratory evaluation within the reference range for the testing laboratory; and use of adequate contraception throughout the study for female subjects.
Primary exclusion criteria were: known hypersensitivities to any component of the TAK-491 formulation, other angiotensin II inhibitors or related compounds, chlorthalidone, thiazide-type diuretics, or sulfonamide-related compounds: use of any investigational compounds within 30 days of Check-in; use of TAK-491 and/or chlorthalidone in a clinical trial or as a therapeutic agent; pregnancy; presence of significant clinical comorbidities; history of drug abuse; use of excluded medications; evidence of gastrointestinal disease that might have impacted drug absorption; history of cancer; use of nicotine-containing products within 28 days of Check-in; abnormal clinically significant ECG, abnormal clinically significant laboratory values, including evidence of liver toxicity; blood pressure outside normal range; hypo- or hyperkalaemia; and haemoglobin < 12 g/dl. Test Product, Dose and Mode of Administration, Lot Number: Drug Dose Form Route Lot No. TAK-491CLD FDC TAK-491CLD 80 mg/25 mg FDC tablet Tablet Oral Z657N052 Duration of Study: The entire study duration, from Screening through the follow-up phone call, may have been up to approximately 8 weeks. Each subject received 1 single dose of each study medication (one TAK-491CLD 80 mg/25 mg FDC tablet and coadministered TAK-491 80 mg + chlorthalidone 25 mg tablets) in a randomized, crossover fashion on Day 1 of each period; doses were separated by 14 days. Reference Therapy, Dose and Mode of Administration, Lot Number: Drug Dose Form Route Lot No. TAK-491 80 mg Tablet Oral Z624D174 Chlorthalidone 25 mg Tablet Oral 100201 Criteria for Evaluation: Pharmacokinetics: Since TAK-491 is rapidly and completely converted to TAK-536, the focus of the pharmacokinetic evaluation was on TAK-536. The pharmacokinetic parameters of TAK-536 and chlorthalidone were determined from the concentration-time data for all evaluable subjects. The following parameters were calculated from plasma concentration values using noncompartmental methods: area under the concentration-time curve from time 0 to the time of last quantifiable concentration (AUC(0-tlqc)), area under the concentration-time curve from time 0 extrapolated to infinity (AUC(0-inf)), maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax), terminal elimination rate constant (λz), and terminal elimination half-life (T1/2). Safety: Safety variables included adverse event monitoring, clinical laboratory test results (hematology, serum chemistry, and urinalysis), vital sign measurements, 12-lead electrocardiogram (ECG) results, and physical examination findings. Statistical Methods: Pharmacokinetic Analyses: Relative bioavailability was assessed using an analysis of variance (ANOVA) model comparing the TAK-491CLD FDC tablet to coadminstration of individual tablets of TAK-491 and chlorthalidone. The analysis was performed on log (natural logarithms) transformed values of AUC(0-tlqc), AUC(0-inf), and Cmax, with fixed effects of sequence, period, treatment, and subjects nested within sequence. The ratios and their 90% confidence intervals (CIs) for the test treatment (TAK-491CLD FDC tablet) central values relative to the reference treatment (coadministration of individual TAK-491 and chlorthalidone tablets) central values were obtained. The ratios were calculated by taking
the antilog of the difference of the least squares (LS) means on a log scale. The 90% CIs for the ratios were obtained by taking the antilog of the 90% CIs for the difference between the LS means on a log scale. Safety Analysis: Adverse events, vital sign measurements, and 12-lead ECG parameters were summarized with descriptive statistics. Abnormal laboratory values, as well as those meeting the predefined criteria for markedly abnormal values, for hematology and chemistry tests and urinalyses were listed by individual subject. Vital sign and ECG measurements that met the predefined criteria for very low or very high values were also listed. SUMMARY OF RESULTS Subject Disposition: A total of 48 subjects (mean age of 29.4 years), including 31 men and 17 women, were enrolled in the study. All of the subjects completed treatment. Pharmacokinetic Results: The median Tmax values of TAK-536 and chlorthalidone were approximately 0.5 hr and 1 hr earlier, respectively, after administration of the TAK-491CLD FDC tablet compared to coadministration of the monotherapy tablets. The mean Cmax, AUC(0-tlqc), and AUC(0-inf) values of TAK-536 were lower after the administration of the TAK-491CLD FDC tablet when compared to the reference treatment, coadministration of the monotherapy tablets; the decreases were within approximately 10%. The mean Cmax, AUC(0-tlqc), and AUC(0-inf) values of chlorthalidone were greater after administration of the TAK-491CLD FDC tablet when compared to the coadministration of the monotherapy tablets; the increase in arithmetic mean values was approximately 10% for AUC but was much higher (237 ng/ml vs 177 ng/ml) for Cmax. The mean T1/2 values for both TAK-536 and chlorthalidone were similar for both treatments (FDC tablet and individual tablets). Summary of Pharmacokinetic Parameters Analyte TAK-491CLD 80 mg/25 mg FDC Tablet (Test) TAK-491 80 mg + Chlorthalidone 25 mg Individual Tablets (Reference) Parameter n (a) Mean (%CV) n (a) Mean (%CV) TAK-536 AUC(0-tlqc) (ng hr/ml) 48 37637 (28) 48 41266 (27) AUC(0-inf) (ng hr/ml) 47 38060 (28) 48 41691 (27) Cmax (ng/ml) 48 4085 (27) 48 4557 (31) T1/2 (hr) 47 11.4 (13) 48 11.2 (15) Tmax (hr) (b) 48 2.53 (1.00, 5.15) 48 3.00 (0.98, 5.00) Chlorthalidone AUC(0-tlqc) (ng hr/ml) 48 3575 (22) 48 3224 (19) AUC(0-inf) (ng hr/ml) 45 4059 (22) 43 3680 (18) Cmax (ng/ml) 48 264 (34) 48 177 (27) T1/2 (hr) 45 41.9 (19) 43 42.1 (18) Tmax (hr) (b) 48 1.00 (1.00, 4.03) 48 2.00 (1.00, 4.17) CV=coefficient of variation. (a) n for AUC(0-inf) and T1/2 was lower due to exclusion of subjects who had a regression line that was a poor fit (Rsq<0.8) to the terminal elimination phase or who had >20% extrapolation between AUC(0-tlqc) and AUC(0-inf). (b) Median (minimum, maximum) for Tmax.
Relative Bioavailability Analysis With the exception of Cmax of chlorthalidone, the 90% CIs for the ratios of the AUC and Cmax central values for both analytes were within the 0.80 to 1.25 range. The point estimate of the ratio indicated a 45% increase in chlorathalidone Cmax for the FDC tablet relative to the monotherapy tablets. Analyte Point Estimate for Ratio 90% Confidence Interval Parameter n (Test/Reference) (a) for Ratio (a) TAK-536 AUC(0-tlqc) (ng hr/ml) 48 0.9064 (0.8643, 0.9506) AUC(0-inf) (ng hr/ml) 47 0.9042 (0.8615, 0.9490) Cmax (ng/ml) 48 0.9019 (0.8465, 0.9610) Chlorthalidone AUC(0-tlqc) (ng hr/ml) 48 1.1019 (1.0661, 1.1388) AUC(0-inf) (ng hr/ml) 43 1.0936 (1.0582, 1.1301) Cmax (ng/ml) 48 1.4489 (1.3236, 1.5862) (a) The point estimates for the ratios of the central values and their 90% CIs were obtained by taking the anti-log of the results obtained on the natural logarithm-transformed data, as described in Statistical Methods in this synopsis. Safety Results: The pattern and incidence of adverse events following both treatments were comparable. Adverse events reported for more than 2 subjects consisted of: headache (8 subjects), dizziness (4 subjects), and nausea (3 subjects) following administration of the TAK-491CLD FDC formulation; and headache (4 subjects), dizziness (4 subjects), presyncope (3 subjects), and nausea (3 subjects) following coadministration of the individual tablets. Forty percent of the subjects experienced only mild adverse events, 35% of the subjects experienced at least 1 moderate adverse event, and none of the subjects experienced a severe adverse event. In addition, 46% of the subjects experienced at least 1 adverse event that was considered to be related to study medication. No adverse events causing death or withdrawal, or serious adverse events, occurred during the study. Treatment-emergent dizziness, postural dizziness, or presyncope were reported for 6 subjects following administration of TAK-491CLD and for 7 subjects following coadministration of TAK-491 and chlorthalidone. Dizziness and postural dizziness tended to be moderate in severity and presyncope tended to be mild in severity; all of these events were considered to be related to the study medication. There were no clinically meaningful treatment-related findings observed in the mean vital sign data, or individual clinical laboratory values or ECG data. As expected, both treatments were associated with a decrease in mean blood pressure. CONCLUSIONS:! TAK-536 derived from the TAK-491CLD FDC tablet met all of the bioequivalence criteria (90% CI for the ratios of the central Cmax and AUC values within 0.80 to 1.25) when compared to the TAK-491 monotherapy tablet.! Chlorthalidone derived from the TAK-491CLD FDC tablet met the bioequivalence criteria for AUC(0-tlqc) and AUC(0-inf) when compared with the EU-approved chlorthalidone tablet; however, the point estimate for Cmax was approximately 45% higher following administration of the FDC tablet relative to the EU-approved chlorthalidone tablet and the upper 90% CI for its ratio was greater than 1.25.! Single-dose administration of TAK-491CLD (80 mg/25 mg) and single-dose coadministration of TAK-491 80 mg with chlorthalidone 25 mg were well tolerated in this study. Date of Report: 02 June 2011