Japanese Healthy Adult Males
Conditions
Brief summary
The purpose of this study is to evaluate the effect of repeated-dose administration of itraconazole on the pharmacokinetics of TAK-272, as well as the effect of repeated-dose administration of TAK-272 on the pharmacokinetics of digoxin or midazolam in healthy Japanese adult males.
Detailed description
In Cohort 1, the effect of repeated-dose administration of itraconazole on the pharmacokinetics of TAK-272 was evaluated by comparing between participants receiving TAK-272 alone and those receiving TAK-272 in combination with itraconazole. In Cohort 2, the effect of repeated-dose administration of TAK-272 on the pharmacokinetics of digoxin or midazolam was evaluated by comparing between participants receiving digoxin or midazolam alone and those receiving either of the drugs in combination with TAK-272.
Interventions
DRUGTAK-272
TAK-272 tablet.
DRUGDigoxin
Digoxin tablet.
DRUGItraconazole
Itraconazole oral solution
DRUGMidazolam
Midazolam syrup.
Sponsors
Takeda
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
20 Years to 35 Years
Healthy volunteers
Yes
Inclusion criteria
1. Is capable of understanding and complying with protocol requirements. 2. Who can sign and date the informed consent form before the initiation of the study procedure. 3. Healthy Japanese adult male volunteer. 4. Is of 20 to 35 years of age at the time of informed consent 5. Weighs 50 kilogram (kg) or more with a body mass index (BMI) of 18.5 to less than 25.0 kilogram per square meter (kg/m\^2) at the screening test. 6. Male participant who was nonsterilized and sexually active with a female partner of childbearing potential had to agree to use adequate contraception from signing of informed consent throughout the duration of the study and for 12 weeks after the completion of the study.
Exclusion criteria
1. Who was administered any investigational product within 16 weeks (112 days) prior to the initial drug administration. 2. Who has received TAK-272 in previous. 3. Employees of the study site, their family members, those who are in a dependency relationship with employees of the study site involved in the conduct of the study (example, spouse, parents, children, brothers and sisters), or those who might be coerced to consent to participate in the study. 4. Who has poorly controlled, clinically significant abnormalities of the nervous system, cardiovascular system, lungs, liver, kidneys, metabolism, gastrointestinal system, urinary system, endocrinological system or other organs or systems, and which may possibly affect study participation or study results. 5. Who has a history of serious hepatic disease. 6. Who has atrioventricular block or sinoatrial block. 7. Has digitalis intoxication. 8. Has acute narrow-angle glaucoma. 9. Has myasthenia gravis. 10. Has hypersensitivity to TAK-272 or any other renin inhibitors. 11. Has hypersensitivity to itraconazole, digoxin, digitalis preparation, or midazolam. 12. Has allergy to cherries. 13. Has a positive to urine test for drug abuse at the screening. 14. Has a history of drug abuse (defined as illegal drug use) or alcohol addiction within 1 year prior to the screening visit, and those who are not willing to give up alcohol or drugs during the study period. 15. Who needs to use prohibited concomitant drugs, vitamins, or foods listed in the table of prohibited concomitant drugs and foods, and the participant who has used any of them during the period prohibiting the concomitant use. 16. Male participants who plans to donate sperm during the study period or up to 12 weeks after the end of the study. 17. Who currently has cardiovascular, central nervous, hepatic, or hematopoietic disease, renal insufficiency, metabolic or endocrinological disorder, serious allergy, asthma, hypoxemia, hypertension, convulsions, or allergic rash. 18. Has a disease history, examination findings, or clinical test findings related to safety that reasonably suggest a disease for which TAK 272 or related renin inhibitors in the same class, itraconazole, digoxin, or midazolam is contraindicated or a disease that may affect the study conduct (which includes, for example, peptic ulcer disease, convulsive disorder, and arrhythmia). 19. Who currently has or recently had (within the past 6 months) gastrointestinal disease that may affect drug absorption (malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis, frequent \[at least once a week\] heartburn, surgical intervension \[e.g., cholecystectomy\]). 20. Has past history of cancer. 21. Who is positive for any of the following at screening: hepatitis B virus surface antigen (HBs), antibody against hepatitis C virus (HCV), human immunodeficiency virus (HIV) antigen, anti-HIV antibody, or serological tests for syphilis. 22. The participant with difficulty having blood collected from a peripheral vein. 23. Who has donated 200 milliliter (mL) or more whole blood within the 4 weeks (28 days) or 400 mL or more whole blood within the 12 weeks (84 days) before starting the study drug administration. 24. Who has donated a total of 800 mL or more of whole blood within the 52 weeks (364 days) before the day of starting the study drug administration. 25. Who has donated blood components within the 2 weeks (14 days) before starting the study drug administration. 26. Who shows clinically significant abnormalities in electrocardiogram at screening or before the study drug administration. 27. Who shows laboratory test abnormalities suggestive of a clinically significant primary disease or who shows abnormal values in any of the following parameters at screening or before the study drug administration: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) exceeding 1.5 times the upper limit of the normal range. 28. Who is unlikely to comply with the study protocol or is ineligible for the study for any other reason, as considered by the investigator or sub investigator. 29. Who had systolic blood pressure under 80 millimeter of mercury(mmHg) at Screening, pretreatment examination, and before the start of study drug administration, and who had suspected hypotension with 2 or more of the following symptoms and findings through physical examinations: dizziness postural, facial pallor, cold sweat.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Digoxin in Cohort 2 | Day 1 and Day 7: pre-dose and at multiple time-points (upto 48 hours) postdose; Day 1 for Cohort 2: Digoxin and Day 7 for Cohort 2: Digoxin + TAK-272 | — |
| Urinary Excretion Ratio of Digoxin From 0 to 48 Hours Postdose in Cohort 2 | Day 1 and Day 7: pre-dose and at multiple time-points (upto 48 hours) postdose; Day 1 for Cohort 2: Digoxin and Day 7 for Cohort 2: Digoxin + TAK-272 | — |
| Cmax: Maximum Observed Plasma Concentration for Midazolam and 1'Hydroxymidazolam in Cohort 2 | Day 1 and Day 7: pre-dose and at multiple time-points (upto 24 hours) postdose; Day 1 for Cohort 2: Midazolam and Day 7 for Cohort 2: Midazolam + TAK-272 | — |
| Cmax: Maximum Observed Plasma Concentration for TAK 272F and TAK 272-Metabolite (M-I) in Cohort 1 | Day 1 and Day 10: pre-dose and at multiple time-points (upto 72 hours) postdose; Day 1 for Cohort 1: TAK-272 and Day 10 for Cohort 1: TAK-272 + Itraconazole | — |
| AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK 272F and TAK 272-M-I in Cohort 1 | Day 1 and Day 10: pre-dose and at multiple time-points (upto 72 hours) postdose; Day 1 for Cohort 1: TAK-272 and Day 10 for Cohort 1: TAK-272 + Itraconazole | — |
| AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK 272F and TAK 272-M-I in Cohort 1 | Day 1 and Day 10: pre-dose and at multiple time-points (upto 72 hours) postdose; Day 1 for Cohort 1: TAK-272 and Day 10 for Cohort 1: TAK-272 + Itraconazole | — |
| Cumulative Urinary Excretion Ratio of TAK 272F and TAK 272-M-I From 0 to 72 Hours Postdose in Cohort 1 | Day 1 and Day 10: pre-dose and at multiple time-points (upto 72 hours) postdose; Day 1 for Cohort 1: TAK-272 and Day 10 for Cohort 1: TAK-272 + Itraconazole | — |
| Cmax: Maximum Observed Plasma Concentration for Digoxin in Cohort 2 | Day 1 and Day 7: pre-dose and at multiple time-points (upto 48 hours) postdose; Day 1 for Cohort 2: Digoxin and Day 7 for Cohort 2: Digoxin + TAK-272 | — |
| AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Digoxin in Cohort 2 | Day 1 and Day 7: pre-dose and at multiple time-points (upto 48 hours) postdose; Day 1 for Cohort 2: Digoxin and Day 7 for Cohort 2: Digoxin + TAK-272 | — |
| AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Midazolam and 1'Hydroxymidazolam in Cohort 2 | Day 1 and Day 7: pre-dose and at multiple time-points (upto 24 hours) postdose; Day 1 for Cohort 2: Midazolam and Day 7 for Cohort 2: Midazolam + TAK-272 | — |
| AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Midazolam and 1'Hydroxymidazolam in Cohort 2 | Day 1 and Day 7: pre-dose and at multiple time-points (upto 24 hours) postdose; Day 1 for Cohort 2: Midazolam and Day 7 for Cohort 2: Midazolam + TAK-272 | — |
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | Cohort 1: Baseline up to Day 19; Cohort 2: Baseline up to Day 15 | — |
| Number of Participants With TEAEs Related to Vital Signs | Cohort 1: Baseline up to Day 19; Cohort 2: Baseline up to Day 15 | — |
| Number of Participants With TEAEs Related to Body Weight | Cohort 1: Baseline up to Day 19; Cohort 2: Baseline up to Day 15 | — |
| Number of Participants Who Had Clinically Significant Changes From Baseline in 12-lead Electrocardiograms | Cohort 1: Baseline up to Day 19; Cohort 2: Baseline up to Day 15 | Number of participants who had ECG findings changed from within normal limit or abnormal, clinically significant to abnormal and clinically significant after study drug administration. |
| Number of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Chemistry, Hematology or Urinalysis | Cohort 1: Baseline up to Day 19; Cohort 2: Baseline up to Day 15 | — |
| Number of Participants With Clinically Significant Change From Baseline in Continuous Pulse Oximetry (SpO2) in Cohort 2 | Cohort 2: Baseline up to Day 15 | — |
Countries
Japan
Participant flow
Recruitment details
Participants took part in the study at 1 investigative site in Japan from 25-February-2015 to 16-April-2015.
Pre-assignment details
Healthy Japanese adult male participants were enrolled to receive TAK-272 and itraconazole in cohort 1 or TAK-272 and digoxin/midazolam in cohort 2.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: TAK-272 + Itraconazole TAK-272 40 milligram (mg), tablet, orally, once on Day 1 and 10, followed by Itraconazole 200 mg, solution, orally, twice on Day 4, further followed by Itraconazole 200 mg, solution, orally, once from Day 5 to 12. | 15 |
| Cohort 2: Midazolam + Digoxin + TAK-272 Midazolam 2 mg, syrup, and Digoxin 0.25 mg, tablet, orally, once on Day 1 and 7, followed by TAK-272 80 mg, tablet, orally, once on Day 3 to 8. | 18 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 1: TAK-272 + Itraconazole | Cohort 2: Midazolam + Digoxin + TAK-272 | Total |
|---|---|---|---|
| Age, Continuous | 26.8 years STANDARD_DEVIATION 4.11 | 25.3 years STANDARD_DEVIATION 4.44 | 26.0 years STANDARD_DEVIATION 4.3 |
| Alcohol Classification Does not drink | 5 participants | 11 participants | 16 participants |
| Alcohol Classification Drinks a few days per month | 5 participants | 5 participants | 10 participants |
| Alcohol Classification Drinks a few days per week | 5 participants | 2 participants | 7 participants |
| Caffeine Classification Caffeine consumption | 7 participants | 6 participants | 13 participants |
| Caffeine Classification No caffeine consumption | 8 participants | 12 participants | 20 participants |
| Sex/Gender, Customized Male | 15 participants | 18 participants | 33 participants |
| Smoking Classification Current smoker | 1 participants | 1 participants | 2 participants |
| Smoking Classification Ex-smoker | 2 participants | 5 participants | 7 participants |
| Smoking Classification Never smoked | 12 participants | 12 participants | 24 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 16 | 7 / 18 |
| serious Total, serious adverse events | 0 / 16 | 0 / 18 |
Outcome results
Primary
AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Digoxin in Cohort 2
Time frame: Day 1 and Day 7: pre-dose and at multiple time-points (upto 48 hours) postdose; Day 1 for Cohort 2: Digoxin and Day 7 for Cohort 2: Digoxin + TAK-272
Population: The pharmacokinetic analysis set was defined as the set of participants treated with the study drug that had no significant protocol deviation, satisfied the minimum protocol provisions, and could be evaluated for pharmacokinetics.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: TAK-272 | AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Digoxin in Cohort 2 | 15.49 ng*hr/mL | Standard Deviation 4.4007 |
| Cohort 1: TAK-272 + Itraconazole | AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Digoxin in Cohort 2 | 15.79 ng*hr/mL | Standard Deviation 4.2495 |
90% CI: [0.919, 1.131]
Primary
AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Midazolam and 1'Hydroxymidazolam in Cohort 2
Time frame: Day 1 and Day 7: pre-dose and at multiple time-points (upto 24 hours) postdose; Day 1 for Cohort 2: Midazolam and Day 7 for Cohort 2: Midazolam + TAK-272
Population: The pharmacokinetic analysis set was defined as the set of participants treated with the study drug that had no significant protocol deviation, satisfied the minimum protocol provisions, and could be evaluated for pharmacokinetics.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: TAK-272 | AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Midazolam and 1'Hydroxymidazolam in Cohort 2 | Midazolam | 27.11 ng*hr/mL | Standard Deviation 11.362 |
| Cohort 1: TAK-272 | AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Midazolam and 1'Hydroxymidazolam in Cohort 2 | 1'hydroxymidazolam | 13.00 ng*hr/mL | Standard Deviation 4.0705 |
| Cohort 1: TAK-272 + Itraconazole | AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Midazolam and 1'Hydroxymidazolam in Cohort 2 | Midazolam | 38.55 ng*hr/mL | Standard Deviation 18.588 |
| Cohort 1: TAK-272 + Itraconazole | AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Midazolam and 1'Hydroxymidazolam in Cohort 2 | 1'hydroxymidazolam | 14.06 ng*hr/mL | Standard Deviation 4.5131 |
Comparison: Analysis for Midazolam90% CI: [1.29, 1.568]
Comparison: Analysis for 1'Hydroxymidazolam90% CI: [1.008, 1.16]
Primary
AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK 272F and TAK 272-M-I in Cohort 1
Time frame: Day 1 and Day 10: pre-dose and at multiple time-points (upto 72 hours) postdose; Day 1 for Cohort 1: TAK-272 and Day 10 for Cohort 1: TAK-272 + Itraconazole
Population: The pharmacokinetic analysis set was defined as the set of participants treated with the study drug that had no significant protocol deviation, satisfied the minimum protocol provisions, and could be evaluated for pharmacokinetics.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: TAK-272 | AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK 272F and TAK 272-M-I in Cohort 1 | TAK 272 | 1861 nanogram hours per milliliter (ng*hr/mL) | Standard Deviation 731.14 |
| Cohort 1: TAK-272 | AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK 272F and TAK 272-M-I in Cohort 1 | TAK 272-M-I | 46.53 nanogram hours per milliliter (ng*hr/mL) | Standard Deviation 19.347 |
| Cohort 1: TAK-272 + Itraconazole | AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK 272F and TAK 272-M-I in Cohort 1 | TAK 272 | 9098 nanogram hours per milliliter (ng*hr/mL) | Standard Deviation 2809.8 |
| Cohort 1: TAK-272 + Itraconazole | AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK 272F and TAK 272-M-I in Cohort 1 | TAK 272-M-I | 9.373 nanogram hours per milliliter (ng*hr/mL) | Standard Deviation 8.9682 |
Comparison: Analysis for TAK 272F90% CI: [4.137, 5.777]
Primary
AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Digoxin in Cohort 2
Time frame: Day 1 and Day 7: pre-dose and at multiple time-points (upto 48 hours) postdose; Day 1 for Cohort 2: Digoxin and Day 7 for Cohort 2: Digoxin + TAK-272
Population: The pharmacokinetic analysis set was defined as the set of participants treated with the study drug that had no significant protocol deviation, satisfied the minimum protocol provisions, and could be evaluated for pharmacokinetics.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: TAK-272 | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Digoxin in Cohort 2 | 9.191 ng*hr/mL | Standard Deviation 2.615 |
| Cohort 1: TAK-272 + Itraconazole | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Digoxin in Cohort 2 | 10.61 ng*hr/mL | Standard Deviation 2.6705 |
90% CI: [1.035, 1.289]
Primary
AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Midazolam and 1'Hydroxymidazolam in Cohort 2
Time frame: Day 1 and Day 7: pre-dose and at multiple time-points (upto 24 hours) postdose; Day 1 for Cohort 2: Midazolam and Day 7 for Cohort 2: Midazolam + TAK-272
Population: The pharmacokinetic analysis set was defined as the set of participants treated with the study drug that had no significant protocol deviation, satisfied the minimum protocol provisions, and could be evaluated for pharmacokinetics.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: TAK-272 | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Midazolam and 1'Hydroxymidazolam in Cohort 2 | Midazolam | 26.77 ng*hr/mL | Standard Deviation 11.343 |
| Cohort 1: TAK-272 | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Midazolam and 1'Hydroxymidazolam in Cohort 2 | 1'hydroxymidazolam | 12.49 ng*hr/mL | Standard Deviation 3.7079 |
| Cohort 1: TAK-272 + Itraconazole | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Midazolam and 1'Hydroxymidazolam in Cohort 2 | Midazolam | 38.16 ng*hr/mL | Standard Deviation 18.205 |
| Cohort 1: TAK-272 + Itraconazole | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Midazolam and 1'Hydroxymidazolam in Cohort 2 | 1'hydroxymidazolam | 13.25 ng*hr/mL | Standard Deviation 3.3695 |
Comparison: Analysis for Midazolam90% CI: [1.291, 1.574]
Comparison: Analysis for 1'Hydroxymidazolam90% CI: [0.986, 1.143]
Primary
AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK 272F and TAK 272-M-I in Cohort 1
Time frame: Day 1 and Day 10: pre-dose and at multiple time-points (upto 72 hours) postdose; Day 1 for Cohort 1: TAK-272 and Day 10 for Cohort 1: TAK-272 + Itraconazole
Population: The pharmacokinetic analysis set was defined as the set of participants treated with the study drug that had no significant protocol deviation, satisfied the minimum protocol provisions, and could be evaluated for pharmacokinetics.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: TAK-272 | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK 272F and TAK 272-M-I in Cohort 1 | TAK 272 | 1842 ng*hr/mL | Standard Deviation 728.15 |
| Cohort 1: TAK-272 | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK 272F and TAK 272-M-I in Cohort 1 | TAK 272-M-I | 38.34 ng*hr/mL | Standard Deviation 16.944 |
| Cohort 1: TAK-272 + Itraconazole | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK 272F and TAK 272-M-I in Cohort 1 | TAK 272 | 8659 ng*hr/mL | Standard Deviation 2596.7 |
| Cohort 1: TAK-272 + Itraconazole | AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK 272F and TAK 272-M-I in Cohort 1 | TAK 272-M-I | 0.9092 ng*hr/mL | Standard Deviation 1.59 |
Comparison: Analysis for TAK 272F90% CI: [3.969, 5.569]
Comparison: Analysis for TAK 272-M-I90% CI: [0.012, 0.045]
Primary
Cmax: Maximum Observed Plasma Concentration for Digoxin in Cohort 2
Time frame: Day 1 and Day 7: pre-dose and at multiple time-points (upto 48 hours) postdose; Day 1 for Cohort 2: Digoxin and Day 7 for Cohort 2: Digoxin + TAK-272
Population: The pharmacokinetic analysis set was defined as the set of participants treated with the study drug that had no significant protocol deviation, satisfied the minimum protocol provisions, and could be evaluated for pharmacokinetics.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: TAK-272 | Cmax: Maximum Observed Plasma Concentration for Digoxin in Cohort 2 | 1.212 ng/mL | Standard Deviation 0.58104 |
| Cohort 1: TAK-272 + Itraconazole | Cmax: Maximum Observed Plasma Concentration for Digoxin in Cohort 2 | 1.635 ng/mL | Standard Deviation 0.70089 |
90% CI: [1.117, 1.628]
Primary
Cmax: Maximum Observed Plasma Concentration for Midazolam and 1'Hydroxymidazolam in Cohort 2
Time frame: Day 1 and Day 7: pre-dose and at multiple time-points (upto 24 hours) postdose; Day 1 for Cohort 2: Midazolam and Day 7 for Cohort 2: Midazolam + TAK-272
Population: The pharmacokinetic analysis set was defined as the set of participants treated with the study drug that had no significant protocol deviation, satisfied the minimum protocol provisions, and could be evaluated for pharmacokinetics.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: TAK-272 | Cmax: Maximum Observed Plasma Concentration for Midazolam and 1'Hydroxymidazolam in Cohort 2 | Midazolam | 10.02 ng/mL | Standard Deviation 3.6198 |
| Cohort 1: TAK-272 | Cmax: Maximum Observed Plasma Concentration for Midazolam and 1'Hydroxymidazolam in Cohort 2 | 1'hydroxymidazolam | 4.813 ng/mL | Standard Deviation 1.809 |
| Cohort 1: TAK-272 + Itraconazole | Cmax: Maximum Observed Plasma Concentration for Midazolam and 1'Hydroxymidazolam in Cohort 2 | Midazolam | 12.37 ng/mL | Standard Deviation 5.0127 |
| Cohort 1: TAK-272 + Itraconazole | Cmax: Maximum Observed Plasma Concentration for Midazolam and 1'Hydroxymidazolam in Cohort 2 | 1'hydroxymidazolam | 4.270 ng/mL | Standard Deviation 1.1195 |
Comparison: Analysis for Midazolam90% CI: [1.1, 1.387]
Comparison: Analysis for 1'Hydroxymidazolam90% CI: [0.781, 1.008]
Primary
Cmax: Maximum Observed Plasma Concentration for TAK 272F and TAK 272-Metabolite (M-I) in Cohort 1
Time frame: Day 1 and Day 10: pre-dose and at multiple time-points (upto 72 hours) postdose; Day 1 for Cohort 1: TAK-272 and Day 10 for Cohort 1: TAK-272 + Itraconazole
Population: The pharmacokinetic analysis set was defined as the set of participants treated with the study drug that had no significant protocol deviation, satisfied the minimum protocol provisions, and could be evaluated for pharmacokinetics.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: TAK-272 | Cmax: Maximum Observed Plasma Concentration for TAK 272F and TAK 272-Metabolite (M-I) in Cohort 1 | TAK 272 | 387.8 nanogram per milliliter (ng/mL) | Standard Deviation 286.18 |
| Cohort 1: TAK-272 | Cmax: Maximum Observed Plasma Concentration for TAK 272F and TAK 272-Metabolite (M-I) in Cohort 1 | TAK 272-M-I | 10.02 nanogram per milliliter (ng/mL) | Standard Deviation 7.1545 |
| Cohort 1: TAK-272 + Itraconazole | Cmax: Maximum Observed Plasma Concentration for TAK 272F and TAK 272-Metabolite (M-I) in Cohort 1 | TAK 272 | 780.3 nanogram per milliliter (ng/mL) | Standard Deviation 258.45 |
| Cohort 1: TAK-272 + Itraconazole | Cmax: Maximum Observed Plasma Concentration for TAK 272F and TAK 272-Metabolite (M-I) in Cohort 1 | TAK 272-M-I | 0.9550 nanogram per milliliter (ng/mL) | Standard Deviation 0.55302 |
Comparison: Analysis for TAK 272F90% CI: [1.632, 2.481]
Comparison: Analysis for TAK 272-M-I90% CI: [0.064, 0.123]
Primary
Cumulative Urinary Excretion Ratio of TAK 272F and TAK 272-M-I From 0 to 72 Hours Postdose in Cohort 1
Time frame: Day 1 and Day 10: pre-dose and at multiple time-points (upto 72 hours) postdose; Day 1 for Cohort 1: TAK-272 and Day 10 for Cohort 1: TAK-272 + Itraconazole
Population: The pharmacokinetic analysis set was defined as the set of participants treated with the study drug that had no significant protocol deviation, satisfied the minimum protocol provisions, and could be evaluated for pharmacokinetics.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: TAK-272 | Cumulative Urinary Excretion Ratio of TAK 272F and TAK 272-M-I From 0 to 72 Hours Postdose in Cohort 1 | TAK 272 | 11.523 percentage of dose | Standard Deviation 2.6615 |
| Cohort 1: TAK-272 | Cumulative Urinary Excretion Ratio of TAK 272F and TAK 272-M-I From 0 to 72 Hours Postdose in Cohort 1 | TAK 272-M-I | 0.556 percentage of dose | Standard Deviation 0.1534 |
| Cohort 1: TAK-272 + Itraconazole | Cumulative Urinary Excretion Ratio of TAK 272F and TAK 272-M-I From 0 to 72 Hours Postdose in Cohort 1 | TAK 272 | 37.803 percentage of dose | Standard Deviation 5.4878 |
| Cohort 1: TAK-272 + Itraconazole | Cumulative Urinary Excretion Ratio of TAK 272F and TAK 272-M-I From 0 to 72 Hours Postdose in Cohort 1 | TAK 272-M-I | 0.071 percentage of dose | Standard Deviation 0.0467 |
Primary
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
Time frame: Cohort 1: Baseline up to Day 19; Cohort 2: Baseline up to Day 15
Population: The safety analysis set was defined as all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: TAK-272 | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 10 participants |
| Cohort 1: TAK-272 + Itraconazole | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 7 participants |
Primary
Number of Participants Who Had Clinically Significant Changes From Baseline in 12-lead Electrocardiograms
Number of participants who had ECG findings changed from within normal limit or abnormal, clinically significant to abnormal and clinically significant after study drug administration.
Time frame: Cohort 1: Baseline up to Day 19; Cohort 2: Baseline up to Day 15
Population: The safety analysis set was defined as all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: TAK-272 | Number of Participants Who Had Clinically Significant Changes From Baseline in 12-lead Electrocardiograms | 0 participants |
| Cohort 1: TAK-272 + Itraconazole | Number of Participants Who Had Clinically Significant Changes From Baseline in 12-lead Electrocardiograms | 0 participants |
Primary
Number of Participants With Clinically Significant Change From Baseline in Continuous Pulse Oximetry (SpO2) in Cohort 2
Time frame: Cohort 2: Baseline up to Day 15
Population: The safety analysis set was defined as all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: TAK-272 | Number of Participants With Clinically Significant Change From Baseline in Continuous Pulse Oximetry (SpO2) in Cohort 2 | 0 participants |
Primary
Number of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Chemistry, Hematology or Urinalysis
Time frame: Cohort 1: Baseline up to Day 19; Cohort 2: Baseline up to Day 15
Population: The safety analysis set was defined as all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: TAK-272 | Number of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Chemistry, Hematology or Urinalysis | Alanine aminotransferase increased | 2 participants |
| Cohort 1: TAK-272 | Number of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Chemistry, Hematology or Urinalysis | Blood triglycerides increased | 0 participants |
| Cohort 1: TAK-272 | Number of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Chemistry, Hematology or Urinalysis | Blood creatine phosphokinase increased | 1 participants |
| Cohort 1: TAK-272 | Number of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Chemistry, Hematology or Urinalysis | Urine ketone body present | 0 participants |
| Cohort 1: TAK-272 + Itraconazole | Number of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Chemistry, Hematology or Urinalysis | Blood creatine phosphokinase increased | 0 participants |
| Cohort 1: TAK-272 + Itraconazole | Number of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Chemistry, Hematology or Urinalysis | Alanine aminotransferase increased | 1 participants |
| Cohort 1: TAK-272 + Itraconazole | Number of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Chemistry, Hematology or Urinalysis | Urine ketone body present | 1 participants |
| Cohort 1: TAK-272 + Itraconazole | Number of Participants With TEAEs Categorized Into Investigations System Organ Class (SOC) Related to Chemistry, Hematology or Urinalysis | Blood triglycerides increased | 1 participants |
Primary
Number of Participants With TEAEs Related to Body Weight
Time frame: Cohort 1: Baseline up to Day 19; Cohort 2: Baseline up to Day 15
Population: The safety analysis set was defined as all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: TAK-272 | Number of Participants With TEAEs Related to Body Weight | 0 participants |
| Cohort 1: TAK-272 + Itraconazole | Number of Participants With TEAEs Related to Body Weight | 0 participants |
Primary
Number of Participants With TEAEs Related to Vital Signs
Time frame: Cohort 1: Baseline up to Day 19; Cohort 2: Baseline up to Day 15
Population: The safety analysis set was defined as all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: TAK-272 | Number of Participants With TEAEs Related to Vital Signs | Heart rate increased | 0 participants |
| Cohort 1: TAK-272 | Number of Participants With TEAEs Related to Vital Signs | Blood pressure decreased | 1 participants |
| Cohort 1: TAK-272 | Number of Participants With TEAEs Related to Vital Signs | Hypotension | 2 participants |
| Cohort 1: TAK-272 + Itraconazole | Number of Participants With TEAEs Related to Vital Signs | Blood pressure decreased | 0 participants |
| Cohort 1: TAK-272 + Itraconazole | Number of Participants With TEAEs Related to Vital Signs | Hypotension | 0 participants |
| Cohort 1: TAK-272 + Itraconazole | Number of Participants With TEAEs Related to Vital Signs | Heart rate increased | 1 participants |
Primary
Urinary Excretion Ratio of Digoxin From 0 to 48 Hours Postdose in Cohort 2
Time frame: Day 1 and Day 7: pre-dose and at multiple time-points (upto 48 hours) postdose; Day 1 for Cohort 2: Digoxin and Day 7 for Cohort 2: Digoxin + TAK-272
Population: The pharmacokinetic analysis set was defined as the set of participants treated with the study drug that had no significant protocol deviation, satisfied the minimum protocol provisions, and could be evaluated for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: TAK-272 | Urinary Excretion Ratio of Digoxin From 0 to 48 Hours Postdose in Cohort 2 | 31.391 percentage of dose | Standard Deviation 8.4376 |
| Cohort 1: TAK-272 + Itraconazole | Urinary Excretion Ratio of Digoxin From 0 to 48 Hours Postdose in Cohort 2 | 35.983 percentage of dose | Standard Deviation 7.7691 |