Pharmacodynamics, Pharmacokinetics, Safety, Tolerability
Conditions
Keywords
MLN3126
Brief summary
The purpose of this study is to evaluate the safety and tolerability of single and multiple oral dosing of MLN3126 in ascending doses in healthy non-Japanese and Japanese participants.
Detailed description
MLN3126 is being tested to find a safe and well-tolerated dose in healthy people and to assess how MLN3126 is processed by the body. In total, approximately 64 participants will be enrolled in the study. This study is composed of 2 parts: Part A healthy non-Japanese participants and Part B healthy Japanese participants. Each part will consist of 4 Cohorts with 8 participants in each Cohort. In each Cohort, 6 participants will receive MLN3126 and 2 participants will receive matched placebo within 30 minutes after the start of a standard breakfast. The starting dose will be 100 mg followed by doses of 300 mg, 800 mg, and a dose to be determined during the study. Progression to the next dose level will only occur if the previous dose level was considered to be safe and well tolerated. This single-center trial will be conducted in the United States. The overall time to participate in this study is up to 20 days. All participants will be contacted by telephone 7 days after the last dose of study drug for a follow-up assessment. Due to toxicology findings from a long-term animal study, Takeda made the decision to terminate this study. No clinically significant safety and/or tolerability issues have been observed or reported in participants exposed to MLN3126.
Interventions
DRUGMLN3126
MLN3126 tablets
DRUGMLN3126 Matched Placebo
MLN3126 placebo-matching tablets
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
Part A (Healthy non-Japanese participants): 1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements. 2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures, including requesting that a participant fast for any laboratory evaluations. 3. Is a male or female adult, 18 to 55 years of age, inclusive, at the time of informed consent and study drug dosing. 4. Is a healthy adult male or female participant as evidenced by their medical history, complete physical examination, vital signs, electrocardiogram (ECG), and safety laboratory evaluations. 5. Weighs at least 45 kg and has a body mass index (BMI) between 18 and 30 kg/m\^2 inclusive at Screening. 6. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 12 weeks after last dose. 7. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to routinely use adequate contraception from signing of informed consent throughout the duration of the study to their next postconfinement menstruation. In addition, participants must be advised not to donate ova during this period. Part B (Healthy Japanese participants): 1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements. 2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures, including requesting that a participant fast for any laboratory evaluations. 3. Is a male or female adult, 20 to 55 years of age, inclusive, at the time of informed consent and study drug dosing, is of Japanese descent (born to Japanese parents and grandparents and has lived outside Japan for less than 15 years), and maintains a Japanese diet and lifestyle. 4. Is a healthy adult male or female participant as evidenced by their medical history, complete physical examination, vital signs, ECG, and safety laboratory evaluations. 5. Weighs at least 45 kg and has a BMI between 18 and 28 kg/m\^2 inclusive at Screening. 6. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 12 weeks after the last dose. 7. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to routinely use adequate contraception from signing of informed consent throughout the duration of the study to their next postconfinement menstruation. In addition, participants must be advised not to donate ova during this period.
Exclusion criteria
Part A (Healthy non-Japanese participants) and Part B (Healthy Japanese participants): 1. Has received any investigational compound within 30 days or 5 half-lives of the investigational compound, whichever is longer, prior to the first dose of study medication. 2. Has received MLN3126 in a previous clinical study. 3. Is an immediate family member, study site employee, or in a dependant relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress. 4. Has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal (GI), or endocrine disease or allergic skin rash or other abnormality which may impact the ability of the participant to participate or potentially confound the study results. 5. Has a known hypersensitivity to any component of the formulation of MLN3126. 6. Has a positive urine drug result for drugs of abuse at Screening or Check-in (Day -1). 7. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse (defined as 4 or more alcoholic beverages per day) within 1 year prior to the Screening Visit or is unwilling to agree to abstain from alcohol and drugs throughout the study. 8. Has taken any excluded medication, supplements, or food products listed in the Excluded Medications and Dietary Products section of the protocol. 9. If female, the participant is pregnant or lactating or intending to become pregnant before or during the study, including the timeframe to the participant's next post-confinement menstruation after participating in this study. 10. If male, the participant intends to donate sperm during the course of this study or for 12 weeks thereafter. 11. Has current or recent (within 6 months) GI disease that would be expected to influence the absorption of drugs (ie, a history of malabsorption, any surgical intervention known to impact absorption \[eg, bariatric surgery or bowel resection\], esophageal reflux, peptic ulcer disease, erosive esophagitis, or frequent \[more than once per week\] occurrence of heartburn). 12. Has Gilbert's syndrome or bilirubin level 1.2x the upper limits of normal (ULN). 13. Has a history of cancer, except basal cell carcinoma, that has been in remission for at least 5 years prior to Day 1. 14. Has a positive test result for hepatitis B surface antigen (HBsAg) or antibody to hepatitis C virus (anti-HCV) at Screening or a known history of human immunodeficiency virus infection. 15. Has used nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days prior to Check-in (Day -1). Cotinine test is positive at Screening or Check-in (Day -1). 16. Has poor peripheral venous access. 17. Has donated or lost 450 mL or more of his or her blood volume (including plasmapheresis) or had a transfusion of any blood product within 45 days prior to Day 1. 18. Has a Screening or Check-in (Day -1) abnormal (clinically significant) electrocardiogram (ECG). Entry of any participant with an abnormal (not clinically significant) ECG must be approved, and documented by signature by the principal investigator. 19. Has a QT interval with Fridericia correction method (QTcF) \> 430 milliseconds (ms) for men or \> 450 ms for women or a PR outside the range of 120 to 210 ms confirmed upon repeat testing within a maximum of 30 minutes, at the Screening Visit or Check-in (Day -1). 20. Has abnormal Screening or Check-in (Day -1) laboratory values that suggest a clinically significant underlying disease or participant with the following laboratory abnormalities: Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \> 1.5 ULN.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | Baseline up to 7 days after last dose of study drug (Day 22) | A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. |
| Percentage of Participants Who Meet the Markedly Abnormal Criteria for Electrocardiogram Measurements at Least Once Post Dose | Baseline up to 7 days after last dose of study drug (Day 22) | A standard 12-lead ECG was performed. The percentage of participants with markedly abnormal electrocardiogram (ECG) findings during the study. |
| Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post Dose | Baseline up to 7 days after last dose of study drug (Day 22) | The percentage of participants with any markedly abnormal, according to Takeda criteria, standard safety laboratory values, including hematology, serum chemistry, and urinalysis, during the treatment period. |
| Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post Dose | Baseline up to 7 days after last dose of study drug (Day 22) | The percentage of participants who meet markedly abnormal criteria designated by Takeda Global Research and Development Center, Inc. (TGRD). Criteria for markedly abnormal vital signs included body temperature, systolic blood pressure, diastolic blood pressure and pulse rate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC(0-96): Area Under the Plasma Concentration-time Curve From Time 0 to 96 Hours Post Dose for MLN3126 and Its Metabolite | Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose | M-I is the inactive metabolite of MLN3126. |
| AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN3126 and Its Metabolite | Days 1 and 15: predose and at multiple timepoints (up to 96 hours) post-dose | M-I is the inactive metabolite of MLN3126. |
| CL/F: Apparent Oral Clearance of MLN3126 and Its Metabolite After Multiple Dosing (at Steady State) | Day 1: predose and at multiple timepoints (up to 96 hours) post-dose | M-I is the inactive metabolite of MLN3126. |
| Terminal Phase Elimination Half-life (T1/2) for MLN3126 and Its Metabolite | Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose | M-I is the inactive metabolite of MLN3126. |
| Cav: Average Plasma Concentration for MLN3126 and Its Metabolite on Day 1 | Day 1: pre-dose and at multiple timepoints (up to 96 hours) post-dose | M-I is the inactive metabolite of MLN3126. |
| Cavss: Average Plasma Concentration for MLN3126 and Its Metabolite at Steady State on Day 15 | Day 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose | M-I is the inactive metabolite of MLN3126. |
| Cmax: Maximum Plasma Concentration for MLN3126 and Its Metabolite | Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose | M-I is the inactive metabolite of MLN3126. |
| Cmax Ratio: Ratio of Maximum Plasma Concentration Between MLN3126 and Its Metabolite | Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose | M-I is the inactive metabolite of MLN3126. |
| Ratio of AUC(0-tau): Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Between MLN3126 and Its Metabolite | Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose | M-I is the inactive metabolite of MLN3126. |
| Ae (0-4): Amount of MLN3126 and Its Metabolite Excreted in Urine From 0 to 4 Hours Post Dose | Days 1 and 15: pre-dose and at multiple timepoints (up to 4 hours) post-dose | M-I is the inactive metabolite of MLN3126. |
| Fe (0-4): Fraction of Dose of MLN3126 and Its Metabolite Excreted Unchanged in Urine From 0 to 4 Hours Post Dose | Days 1 and 15: pre-dose and at multiple timepoints (up to 4 hours) post-dose | M-I is the inactive metabolite of MLN3126. |
| CLr: Renal Clearance of MLN3126 and Its Metabolite | Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose | CLr is the volume of plasma from which the drug is completely removed by the kidney in a given amount of time, calculated as the amount of drug excreted in the urine divided by the area under the plasma concentration-time curve, expressed in liter per hour (L/hr). M-I is the inactive metabolite of MLN3126. |
| Rac AUC(0-96): Accumulation Ratio of AUC(0-96) for MLN3126 and Its Metabolite | Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose | M-I is the inactive metabolite of MLN3126. |
| Tmax- Time to Reach the Cmax for MLN3126 and Its Metabolite | Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose | M-I is the inactive metabolite of MLN3126. |
| AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau for MLN3126 and Its Metabolite | Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose | M-I is the inactive metabolite of MLN3126. |
| AUC (0-last): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN3126 and Its Metabolite | Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose | M-I is the inactive metabolite of MLN3126. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at single site in the United States from 04 August 2014 to 09 December 2014.
Pre-assignment details
Part A was performed on non-Japanese participants and Part B was performed on Japanese participants. Planned doses of MLN3126 800 mg to be decided (TBD) dose for Part A, and MLN3126 300 mg, 800 mg, and TBD dose for Part 2 were not administered due to early termination of the study.
Participants by arm
| Arm | Count |
|---|---|
| Part A: Placebo MLN3126 placebo-matching tablet, orally, once on Day 1 of the single dosing period, followed by 1 week washout period, further followed by MLN3126 placebo-matching tablets, orally, once daily from Day 9 up to Day 15 of the 7 day multiple dosing period. | 3 |
| Part A: MLN3126 100 mg MLN3126 100 mg, tablet, orally, once on Day 1 of the single dosing period, followed by 1 week washout period, further followed by MLN3126 100 mg, tablets, orally, once daily from Day 9 up to Day 15 of the 7 day multiple dosing period. | 6 |
| Part A: MLN3126 300 mg MLN3126 300 mg, tablet, orally, once on Day 1 of the single dosing period, followed by 1 week washout period, further followed by MLN3126 300 mg, tablets, orally, once daily from Day 9 up to Day 15 of the 7 day multiple dosing period. | 6 |
| Part B: Placebo MLN3126 placebo-matching tablet, orally, once on Day 1 of the single dosing period, followed by 1 week washout period, further followed by MLN3126 placebo-matching tablets, orally, once daily from Day 9 up to Day 15 of the 7 day multiple dosing period. | 2 |
| Part B: MLN3126 100 mg MLN3126 100 mg, tablet, orally, once on Day 1 of the single dosing period, followed by 1 week washout period, further followed by MLN3126 100 mg, tablets, orally, once daily from Day 9 up to Day 15 of the 7 day multiple dosing period. | 6 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Part A: Placebo | Part B: MLN3126 100 mg | Part A: MLN3126 100 mg | Part B: Placebo | Part A: MLN3126 300 mg |
|---|---|---|---|---|---|---|
| Age, Continuous | 39.7 years STANDARD_DEVIATION 10.5 | 36.7 years STANDARD_DEVIATION 7.77 | 41.0 years STANDARD_DEVIATION 12.47 | 38.8 years STANDARD_DEVIATION 12.91 | 52.5 years STANDARD_DEVIATION 0.71 | 36.3 years STANDARD_DEVIATION 7.12 |
| Alcohol Classification Current Drinker | 14 participants | 2 participants | 6 participants | 1 participants | 2 participants | 3 participants |
| Alcohol Classification Ex-Drinker | 2 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Alcohol Classification Never Drunk | 7 participants | 1 participants | 0 participants | 4 participants | 0 participants | 2 participants |
| Body Mass Index | 26.27 kilogram per square meter STANDARD_DEVIATION 2.531 | 27.13 kilogram per square meter STANDARD_DEVIATION 3.616 | 23.94 kilogram per square meter STANDARD_DEVIATION 1.559 | 27.36 kilogram per square meter STANDARD_DEVIATION 2.08 | 25.77 kilogram per square meter STANDARD_DEVIATION 0.564 | 27.25 kilogram per square meter STANDARD_DEVIATION 2.547 |
| Female Reproductive Status Female of Childbearing Potential | 6 participants | 2 participants | 2 participants | 1 participants | 0 participants | 1 participants |
| Female Reproductive Status Postmenopausal | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Female Reproductive Status Surgically Sterile | 1 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants |
| Height | 169.5 centimeter STANDARD_DEVIATION 10.76 | 173.3 centimeter STANDARD_DEVIATION 4.93 | 163.2 centimeter STANDARD_DEVIATION 9.33 | 173.0 centimeter STANDARD_DEVIATION 14.71 | 170.0 centimeter STANDARD_DEVIATION 5.66 | 170.3 centimeter STANDARD_DEVIATION 10.84 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 9 participants | 0 participants | 6 participants | 1 participants | 2 participants | 0 participants |
| Race/Ethnicity, Customized Black or African American | 7 participants | 2 participants | 0 participants | 3 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 6 participants | 1 participants | 0 participants | 1 participants | 0 participants | 4 participants |
| Race/Ethnicity, Customized Non Hispanic or Latino | 17 participants | 2 participants | 6 participants | 5 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized White | 6 participants | 1 participants | 0 participants | 2 participants | 0 participants | 3 participants |
| Region of Enrollment United States | 23 participants | 3 participants | 6 participants | 6 participants | 2 participants | 6 participants |
| Sex: Female, Male Female | 8 Participants | 2 Participants | 3 Participants | 2 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 15 Participants | 1 Participants | 3 Participants | 4 Participants | 2 Participants | 5 Participants |
| Smoking Classification Ex-Smoker | 7 participants | 1 participants | 2 participants | 1 participants | 1 participants | 2 participants |
| Smoking Classification Never Smoked | 16 participants | 2 participants | 4 participants | 5 participants | 1 participants | 4 participants |
| Weight | 76.12 kilogram STANDARD_DEVIATION 14.004 | 81.70 kilogram STANDARD_DEVIATION 13.023 | 64.15 kilogram STANDARD_DEVIATION 10.227 | 82.50 kilogram STANDARD_DEVIATION 15.92 | 74.45 kilogram STANDARD_DEVIATION 3.323 | 79.50 kilogram STANDARD_DEVIATION 13.435 |
| Xanthine/Caffeine History Consumer | 7 participants | 0 participants | 4 participants | 2 participants | 1 participants | 0 participants |
| Xanthine/Caffeine History Non-Consumer | 16 participants | 3 participants | 2 participants | 4 participants | 1 participants | 6 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 3 | 1 / 6 | 1 / 6 | 0 / 2 | 2 / 6 |
| serious Total, serious adverse events | 0 / 3 | 0 / 6 | 0 / 6 | 0 / 2 | 0 / 6 |
Outcome results
Primary
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
Time frame: Baseline up to 7 days after last dose of study drug (Day 22)
Population: Safety analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Placebo | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 1 participants |
| Part A: MLN3126 100 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 1 participants |
| Part A: MLN3126 300 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 1 participants |
| Part B: Placebo | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 0 participants |
| Part B: MLN3126 100 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 2 participants |
Primary
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Electrocardiogram Measurements at Least Once Post Dose
A standard 12-lead ECG was performed. The percentage of participants with markedly abnormal electrocardiogram (ECG) findings during the study.
Time frame: Baseline up to 7 days after last dose of study drug (Day 22)
Population: Safety analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Placebo | Percentage of Participants Who Meet the Markedly Abnormal Criteria for Electrocardiogram Measurements at Least Once Post Dose | 0 percentage of participants |
| Part A: MLN3126 100 mg | Percentage of Participants Who Meet the Markedly Abnormal Criteria for Electrocardiogram Measurements at Least Once Post Dose | 0 percentage of participants |
| Part A: MLN3126 300 mg | Percentage of Participants Who Meet the Markedly Abnormal Criteria for Electrocardiogram Measurements at Least Once Post Dose | 0 percentage of participants |
| Part B: Placebo | Percentage of Participants Who Meet the Markedly Abnormal Criteria for Electrocardiogram Measurements at Least Once Post Dose | 0 percentage of participants |
| Part B: MLN3126 100 mg | Percentage of Participants Who Meet the Markedly Abnormal Criteria for Electrocardiogram Measurements at Least Once Post Dose | 0 percentage of participants |
Primary
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post Dose
The percentage of participants with any markedly abnormal, according to Takeda criteria, standard safety laboratory values, including hematology, serum chemistry, and urinalysis, during the treatment period.
Time frame: Baseline up to 7 days after last dose of study drug (Day 22)
Population: Safety analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Placebo | Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post Dose | 0 percentage of participants |
| Part A: MLN3126 100 mg | Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post Dose | 0 percentage of participants |
| Part A: MLN3126 300 mg | Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post Dose | 0 percentage of participants |
| Part B: Placebo | Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post Dose | 0 percentage of participants |
| Part B: MLN3126 100 mg | Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post Dose | 0 percentage of participants |
Primary
Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post Dose
The percentage of participants who meet markedly abnormal criteria designated by Takeda Global Research and Development Center, Inc. (TGRD). Criteria for markedly abnormal vital signs included body temperature, systolic blood pressure, diastolic blood pressure and pulse rate.
Time frame: Baseline up to 7 days after last dose of study drug (Day 22)
Population: Safety analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Placebo | Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post Dose | 3 percentage of participants |
| Part A: MLN3126 100 mg | Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post Dose | 2 percentage of participants |
| Part A: MLN3126 300 mg | Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post Dose | 6 percentage of participants |
| Part B: Placebo | Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post Dose | 0 percentage of participants |
| Part B: MLN3126 100 mg | Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post Dose | 8 percentage of participants |
Secondary
Ae (0-4): Amount of MLN3126 and Its Metabolite Excreted in Urine From 0 to 4 Hours Post Dose
M-I is the inactive metabolite of MLN3126.
Time frame: Days 1 and 15: pre-dose and at multiple timepoints (up to 4 hours) post-dose
Population: Data is not reported because the study was terminated early at Cohorts 2A and 1B, yielding limited data for only 2 dose levels of MLN3126 in non-Japanese participants and one dose level in Japanese participants. Therefore the analyses to determine urine PK parameters was not performed.
Secondary
AUC(0-96): Area Under the Plasma Concentration-time Curve From Time 0 to 96 Hours Post Dose for MLN3126 and Its Metabolite
M-I is the inactive metabolite of MLN3126.
Time frame: Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose
Population: The PK analysis set included all participants who received the study drug and had at least 1 measurable plasma concentration for either MLN3126 or its M-I metabolite.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | AUC(0-96): Area Under the Plasma Concentration-time Curve From Time 0 to 96 Hours Post Dose for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 28827.86 ng*hr/mL | Standard Deviation 4652.165 |
| Part A: Placebo | AUC(0-96): Area Under the Plasma Concentration-time Curve From Time 0 to 96 Hours Post Dose for MLN3126 and Its Metabolite | Day 15 (MLN3126) ((n=6, 6, 5) | 19240.50 ng*hr/mL | Standard Deviation 4032.308 |
| Part A: Placebo | AUC(0-96): Area Under the Plasma Concentration-time Curve From Time 0 to 96 Hours Post Dose for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 2478.39 ng*hr/mL | Standard Deviation 1296.387 |
| Part A: Placebo | AUC(0-96): Area Under the Plasma Concentration-time Curve From Time 0 to 96 Hours Post Dose for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 2042.91 ng*hr/mL | Standard Deviation 995.133 |
| Part A: MLN3126 100 mg | AUC(0-96): Area Under the Plasma Concentration-time Curve From Time 0 to 96 Hours Post Dose for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 2413.78 ng*hr/mL | Standard Deviation 935.159 |
| Part A: MLN3126 100 mg | AUC(0-96): Area Under the Plasma Concentration-time Curve From Time 0 to 96 Hours Post Dose for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 55971.02 ng*hr/mL | Standard Deviation 14936.843 |
| Part A: MLN3126 100 mg | AUC(0-96): Area Under the Plasma Concentration-time Curve From Time 0 to 96 Hours Post Dose for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 3726.75 ng*hr/mL | Standard Deviation 1616.928 |
| Part A: MLN3126 100 mg | AUC(0-96): Area Under the Plasma Concentration-time Curve From Time 0 to 96 Hours Post Dose for MLN3126 and Its Metabolite | Day 15 (MLN3126) ((n=6, 6, 5) | 33136.80 ng*hr/mL | Standard Deviation 7352.169 |
| Part A: MLN3126 300 mg | AUC(0-96): Area Under the Plasma Concentration-time Curve From Time 0 to 96 Hours Post Dose for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 2010.24 ng*hr/mL | Standard Deviation 993.327 |
| Part A: MLN3126 300 mg | AUC(0-96): Area Under the Plasma Concentration-time Curve From Time 0 to 96 Hours Post Dose for MLN3126 and Its Metabolite | Day 15 (MLN3126) ((n=6, 6, 5) | 22929.63 ng*hr/mL | Standard Deviation 6521.723 |
| Part A: MLN3126 300 mg | AUC(0-96): Area Under the Plasma Concentration-time Curve From Time 0 to 96 Hours Post Dose for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 2051.37 ng*hr/mL | Standard Deviation 885.185 |
| Part A: MLN3126 300 mg | AUC(0-96): Area Under the Plasma Concentration-time Curve From Time 0 to 96 Hours Post Dose for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 35900.38 ng*hr/mL | Standard Deviation 8806.878 |
Secondary
AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN3126 and Its Metabolite
M-I is the inactive metabolite of MLN3126.
Time frame: Days 1 and 15: predose and at multiple timepoints (up to 96 hours) post-dose
Population: The PK analysis set included all participants who received the study drug and had at least 1 measurable plasma concentration for either MLN3126 or its M-I metabolite.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 29005.04 ng*hr/mL | Standard Deviation 4679.572 |
| Part A: Placebo | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 19328.57 ng*hr/mL | Standard Deviation 4036.507 |
| Part A: Placebo | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 2499.49 ng*hr/mL | Standard Deviation 1304.091 |
| Part A: Placebo | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 2068.13 ng*hr/mL | Standard Deviation 1008.064 |
| Part A: MLN3126 100 mg | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 2437.78 ng*hr/mL | Standard Deviation 949.142 |
| Part A: MLN3126 100 mg | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 56338.09 ng*hr/mL | Standard Deviation 15089.327 |
| Part A: MLN3126 100 mg | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 3747.82 ng*hr/mL | Standard Deviation 1631.659 |
| Part A: MLN3126 100 mg | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 33250.14 ng*hr/mL | Standard Deviation 7370.421 |
| Part A: MLN3126 300 mg | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 2031.41 ng*hr/mL | Standard Deviation 997.685 |
| Part A: MLN3126 300 mg | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 23046.44 ng*hr/mL | Standard Deviation 6603.581 |
| Part A: MLN3126 300 mg | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 2065.18 ng*hr/mL | Standard Deviation 892.563 |
| Part A: MLN3126 300 mg | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 36073.07 ng*hr/mL | Standard Deviation 8916.201 |
Secondary
AUC (0-last): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN3126 and Its Metabolite
M-I is the inactive metabolite of MLN3126.
Time frame: Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose
Population: The PK analysis set included all participants who received the study drug and had at least 1 measurable plasma concentration for either MLN3126 or its M-I metabolite.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | AUC (0-last): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 28827.86 ng*hr/mL | Standard Deviation 4652.165 |
| Part A: Placebo | AUC (0-last): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 19240.50 ng*hr/mL | Standard Deviation 4032.308 |
| Part A: Placebo | AUC (0-last): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 2467.13 ng*hr/mL | Standard Deviation 1308.583 |
| Part A: Placebo | AUC (0-last): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 2017.37 ng*hr/mL | Standard Deviation 989.383 |
| Part A: MLN3126 100 mg | AUC (0-last): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 2392.01 ng*hr/mL | Standard Deviation 930.338 |
| Part A: MLN3126 100 mg | AUC (0-last): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 55970.97 ng*hr/mL | Standard Deviation 14936.883 |
| Part A: MLN3126 100 mg | AUC (0-last): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 3713.57 ng*hr/mL | Standard Deviation 1628.713 |
| Part A: MLN3126 100 mg | AUC (0-last): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 33136.84 ng*hr/mL | Standard Deviation 7352.192 |
| Part A: MLN3126 300 mg | AUC (0-last): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 1989.59 ng*hr/mL | Standard Deviation 1005.862 |
| Part A: MLN3126 300 mg | AUC (0-last): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 22929.63 ng*hr/mL | Standard Deviation 6521.723 |
| Part A: MLN3126 300 mg | AUC (0-last): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 2025.77 ng*hr/mL | Standard Deviation 888.467 |
| Part A: MLN3126 300 mg | AUC (0-last): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 35900.38 ng*hr/mL | Standard Deviation 8806.878 |
Secondary
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau for MLN3126 and Its Metabolite
M-I is the inactive metabolite of MLN3126.
Time frame: Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose
Population: The PK analysis set included all participants who received the study drug and had at least 1 measurable plasma concentration for either MLN3126 or its M-I metabolite.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 21429.42 nanogram*hour per milliliter (ng*hr/mL | Standard Deviation 3241.902 |
| Part A: Placebo | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 15748.80 nanogram*hour per milliliter (ng*hr/mL | Standard Deviation 3632.489 |
| Part A: Placebo | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 2027.06 nanogram*hour per milliliter (ng*hr/mL | Standard Deviation 1038.274 |
| Part A: Placebo | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 1698.10 nanogram*hour per milliliter (ng*hr/mL | Standard Deviation 857.178 |
| Part A: MLN3126 100 mg | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 1920.06 nanogram*hour per milliliter (ng*hr/mL | Standard Deviation 689.354 |
| Part A: MLN3126 100 mg | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 41451.93 nanogram*hour per milliliter (ng*hr/mL | Standard Deviation 10339.782 |
| Part A: MLN3126 100 mg | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 2935.78 nanogram*hour per milliliter (ng*hr/mL | Standard Deviation 1180.471 |
| Part A: MLN3126 100 mg | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 26353.06 nanogram*hour per milliliter (ng*hr/mL | Standard Deviation 5626.212 |
| Part A: MLN3126 300 mg | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 1634.08 nanogram*hour per milliliter (ng*hr/mL | Standard Deviation 849.8 |
| Part A: MLN3126 300 mg | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 18166.90 nanogram*hour per milliliter (ng*hr/mL | Standard Deviation 4516.041 |
| Part A: MLN3126 300 mg | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 1721.86 nanogram*hour per milliliter (ng*hr/mL | Standard Deviation 768.842 |
| Part A: MLN3126 300 mg | AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 27344.25 nanogram*hour per milliliter (ng*hr/mL | Standard Deviation 6318.106 |
Secondary
Cav: Average Plasma Concentration for MLN3126 and Its Metabolite on Day 1
M-I is the inactive metabolite of MLN3126.
Time frame: Day 1: pre-dose and at multiple timepoints (up to 96 hours) post-dose
Population: The PK analysis set included all participants who received the study drug and had at least 1 measurable plasma concentration for either MLN3126 or its M-I metabolite.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Cav: Average Plasma Concentration for MLN3126 and Its Metabolite on Day 1 | MLN3126 | 892.89 ng/mL | Standard Deviation 135.079 |
| Part A: Placebo | Cav: Average Plasma Concentration for MLN3126 and Its Metabolite on Day 1 | M-I | 84.46 ng/mL | Standard Deviation 43.261 |
| Part A: MLN3126 100 mg | Cav: Average Plasma Concentration for MLN3126 and Its Metabolite on Day 1 | MLN3126 | 1727.16 ng/mL | Standard Deviation 430.824 |
| Part A: MLN3126 100 mg | Cav: Average Plasma Concentration for MLN3126 and Its Metabolite on Day 1 | M-I | 122.32 ng/mL | Standard Deviation 49.186 |
| Part A: MLN3126 300 mg | Cav: Average Plasma Concentration for MLN3126 and Its Metabolite on Day 1 | MLN3126 | 1139.34 ng/mL | Standard Deviation 263.254 |
| Part A: MLN3126 300 mg | Cav: Average Plasma Concentration for MLN3126 and Its Metabolite on Day 1 | M-I | 71.74 ng/mL | Standard Deviation 32.035 |
Secondary
Cavss: Average Plasma Concentration for MLN3126 and Its Metabolite at Steady State on Day 15
M-I is the inactive metabolite of MLN3126.
Time frame: Day 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose
Population: The PK analysis set included all participants who received the study drug and had at least 1 measurable plasma concentration for either MLN3126 or its M-I metabolite.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Cavss: Average Plasma Concentration for MLN3126 and Its Metabolite at Steady State on Day 15 | MLN3126 | 656.20 ng/mL | Standard Deviation 151.354 |
| Part A: Placebo | Cavss: Average Plasma Concentration for MLN3126 and Its Metabolite at Steady State on Day 15 | M-I | 70.75 ng/mL | Standard Deviation 35.716 |
| Part A: MLN3126 100 mg | Cavss: Average Plasma Concentration for MLN3126 and Its Metabolite at Steady State on Day 15 | MLN3126 | 1098.04 ng/mL | Standard Deviation 234.426 |
| Part A: MLN3126 100 mg | Cavss: Average Plasma Concentration for MLN3126 and Its Metabolite at Steady State on Day 15 | M-I | 80.00 ng/mL | Standard Deviation 28.723 |
| Part A: MLN3126 300 mg | Cavss: Average Plasma Concentration for MLN3126 and Its Metabolite at Steady State on Day 15 | MLN3126 | 756.95 ng/mL | Standard Deviation 188.168 |
| Part A: MLN3126 300 mg | Cavss: Average Plasma Concentration for MLN3126 and Its Metabolite at Steady State on Day 15 | M-I | 68.09 ng/mL | Standard Deviation 35.408 |
Secondary
CL/F: Apparent Oral Clearance of MLN3126 and Its Metabolite After Multiple Dosing (at Steady State)
M-I is the inactive metabolite of MLN3126.
Time frame: Day 1: predose and at multiple timepoints (up to 96 hours) post-dose
Population: The PK analysis set included all participants who received the study drug and had at least 1 measurable plasma concentration for either MLN3126 or its M-I metabolite.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | CL/F: Apparent Oral Clearance of MLN3126 and Its Metabolite After Multiple Dosing (at Steady State) | MLN3126 | 4.76 liter per hour (L/hr) | Standard Deviation 0.74 |
| Part A: Placebo | CL/F: Apparent Oral Clearance of MLN3126 and Its Metabolite After Multiple Dosing (at Steady State) | M-I | NA liter per hour (L/hr) | — |
| Part A: MLN3126 100 mg | CL/F: Apparent Oral Clearance of MLN3126 and Its Metabolite After Multiple Dosing (at Steady State) | MLN3126 | 7.64 liter per hour (L/hr) | Standard Deviation 1.989 |
| Part A: MLN3126 100 mg | CL/F: Apparent Oral Clearance of MLN3126 and Its Metabolite After Multiple Dosing (at Steady State) | M-I | NA liter per hour (L/hr) | — |
| Part A: MLN3126 300 mg | CL/F: Apparent Oral Clearance of MLN3126 and Its Metabolite After Multiple Dosing (at Steady State) | MLN3126 | 3.87 liter per hour (L/hr) | Standard Deviation 1.132 |
| Part A: MLN3126 300 mg | CL/F: Apparent Oral Clearance of MLN3126 and Its Metabolite After Multiple Dosing (at Steady State) | M-I | NA liter per hour (L/hr) | — |
Secondary
CLr: Renal Clearance of MLN3126 and Its Metabolite
CLr is the volume of plasma from which the drug is completely removed by the kidney in a given amount of time, calculated as the amount of drug excreted in the urine divided by the area under the plasma concentration-time curve, expressed in liter per hour (L/hr). M-I is the inactive metabolite of MLN3126.
Time frame: Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose
Population: Data is not reported because the study was terminated early at Cohorts 2A and 1B, yielding limited data for only 2 dose levels of MLN3126 in non-Japanese participants and one dose level in Japanese participants. Therefore the analyses to determine urine PK parameters was not performed.
Secondary
Cmax: Maximum Plasma Concentration for MLN3126 and Its Metabolite
M-I is the inactive metabolite of MLN3126.
Time frame: Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose
Population: The pharmacokinetic (PK) analysis set included all participants who received the study drug and had at least 1 measurable plasma concentration for either MLN3126 or its M-I metabolite.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Cmax: Maximum Plasma Concentration for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 2053.33 nanogram per milliliter (ng/mL) | Standard Deviation 420.983 |
| Part A: Placebo | Cmax: Maximum Plasma Concentration for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 1845.00 nanogram per milliliter (ng/mL) | Standard Deviation 617.665 |
| Part A: Placebo | Cmax: Maximum Plasma Concentration for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 167.00 nanogram per milliliter (ng/mL) | Standard Deviation 73.645 |
| Part A: Placebo | Cmax: Maximum Plasma Concentration for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 149.57 nanogram per milliliter (ng/mL) | Standard Deviation 79.078 |
| Part A: MLN3126 100 mg | Cmax: Maximum Plasma Concentration for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 176.58 nanogram per milliliter (ng/mL) | Standard Deviation 55.561 |
| Part A: MLN3126 100 mg | Cmax: Maximum Plasma Concentration for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 3220.00 nanogram per milliliter (ng/mL) | Standard Deviation 730.479 |
| Part A: MLN3126 100 mg | Cmax: Maximum Plasma Concentration for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 225.77 nanogram per milliliter (ng/mL) | Standard Deviation 74.661 |
| Part A: MLN3126 100 mg | Cmax: Maximum Plasma Concentration for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 3088.33 nanogram per milliliter (ng/mL) | Standard Deviation 721.565 |
| Part A: MLN3126 300 mg | Cmax: Maximum Plasma Concentration for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 149.12 nanogram per milliliter (ng/mL) | Standard Deviation 80.138 |
| Part A: MLN3126 300 mg | Cmax: Maximum Plasma Concentration for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 2200.00 nanogram per milliliter (ng/mL) | Standard Deviation 541.618 |
| Part A: MLN3126 300 mg | Cmax: Maximum Plasma Concentration for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 157.60 nanogram per milliliter (ng/mL) | Standard Deviation 83.847 |
| Part A: MLN3126 300 mg | Cmax: Maximum Plasma Concentration for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 2526.67 nanogram per milliliter (ng/mL) | Standard Deviation 702.244 |
Secondary
Cmax Ratio: Ratio of Maximum Plasma Concentration Between MLN3126 and Its Metabolite
M-I is the inactive metabolite of MLN3126.
Time frame: Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose
Population: The PK analysis set included all participants who received the study drug and had at least 1 measurable plasma concentration for either MLN3126 or its M-I metabolite.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Cmax Ratio: Ratio of Maximum Plasma Concentration Between MLN3126 and Its Metabolite | Day 1 | 0.0781 ratio | Standard Deviation 0.02078 |
| Part A: Placebo | Cmax Ratio: Ratio of Maximum Plasma Concentration Between MLN3126 and Its Metabolite | Day 15 | 0.0774 ratio | Standard Deviation 0.02228 |
| Part A: MLN3126 100 mg | Cmax Ratio: Ratio of Maximum Plasma Concentration Between MLN3126 and Its Metabolite | Day 1 | 0.0732 ratio | Standard Deviation 0.02842 |
| Part A: MLN3126 100 mg | Cmax Ratio: Ratio of Maximum Plasma Concentration Between MLN3126 and Its Metabolite | Day 15 | 0.0578 ratio | Standard Deviation 0.0189 |
| Part A: MLN3126 300 mg | Cmax Ratio: Ratio of Maximum Plasma Concentration Between MLN3126 and Its Metabolite | Day 1 | 0.0595 ratio | Standard Deviation 0.01627 |
| Part A: MLN3126 300 mg | Cmax Ratio: Ratio of Maximum Plasma Concentration Between MLN3126 and Its Metabolite | Day 15 | 0.0663 ratio | Standard Deviation 0.02617 |
Secondary
Fe (0-4): Fraction of Dose of MLN3126 and Its Metabolite Excreted Unchanged in Urine From 0 to 4 Hours Post Dose
M-I is the inactive metabolite of MLN3126.
Time frame: Days 1 and 15: pre-dose and at multiple timepoints (up to 4 hours) post-dose
Population: Data is not reported because the study was terminated early at Cohorts 2A and 1B, yielding limited data for only 2 dose levels of MLN3126 in non-Japanese participants and one dose level in Japanese participants. Therefore the analyses to determine urine PK parameters was not performed.
Secondary
Rac AUC(0-96): Accumulation Ratio of AUC(0-96) for MLN3126 and Its Metabolite
M-I is the inactive metabolite of MLN3126.
Time frame: Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose
Population: The PK analysis set included all participants who received the study drug and had at least 1 measurable plasma concentration for either MLN3126 or its M-I metabolite.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Rac AUC(0-96): Accumulation Ratio of AUC(0-96) for MLN3126 and Its Metabolite | MLN3126 | 0.66572 ratio | Standard Deviation 0.084399 |
| Part A: Placebo | Rac AUC(0-96): Accumulation Ratio of AUC(0-96) for MLN3126 and Its Metabolite | M-I | 0.84423 ratio | Standard Deviation 0.113307 |
| Part A: MLN3126 100 mg | Rac AUC(0-96): Accumulation Ratio of AUC(0-96) for MLN3126 and Its Metabolite | MLN3126 | 0.60172 ratio | Standard Deviation 0.082195 |
| Part A: MLN3126 100 mg | Rac AUC(0-96): Accumulation Ratio of AUC(0-96) for MLN3126 and Its Metabolite | M-I | 0.65535 ratio | Standard Deviation 0.100968 |
| Part A: MLN3126 300 mg | Rac AUC(0-96): Accumulation Ratio of AUC(0-96) for MLN3126 and Its Metabolite | MLN3126 | 0.64024 ratio | Standard Deviation 0.077509 |
| Part A: MLN3126 300 mg | Rac AUC(0-96): Accumulation Ratio of AUC(0-96) for MLN3126 and Its Metabolite | M-I | 0.89068 ratio | Standard Deviation 0.090814 |
Secondary
Ratio of AUC(0-tau): Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Between MLN3126 and Its Metabolite
M-I is the inactive metabolite of MLN3126.
Time frame: Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose
Population: The PK analysis set included all participants who received the study drug and had at least 1 measurable plasma concentration for either MLN3126 or its M-I metabolite.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Ratio of AUC(0-tau): Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Between MLN3126 and Its Metabolite | Day 1 | 0.0909 ratio | Standard Deviation 0.0362 |
| Part A: Placebo | Ratio of AUC(0-tau): Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Between MLN3126 and Its Metabolite | Day 15 | 0.1055 ratio | Standard Deviation 0.04173 |
| Part A: MLN3126 100 mg | Ratio of AUC(0-tau): Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Between MLN3126 and Its Metabolite | Day 1 | 0.0722 ratio | Standard Deviation 0.02894 |
| Part A: MLN3126 100 mg | Ratio of AUC(0-tau): Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Between MLN3126 and Its Metabolite | Day 15 | 0.0727 ratio | Standard Deviation 0.02549 |
| Part A: MLN3126 300 mg | Ratio of AUC(0-tau): Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Between MLN3126 and Its Metabolite | Day 1 | 0.0621 ratio | Standard Deviation 0.01972 |
| Part A: MLN3126 300 mg | Ratio of AUC(0-tau): Ratio of Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Between MLN3126 and Its Metabolite | Day 15 | 0.0898 ratio | Standard Deviation 0.04073 |
Secondary
Terminal Phase Elimination Half-life (T1/2) for MLN3126 and Its Metabolite
M-I is the inactive metabolite of MLN3126.
Time frame: Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose
Population: The PK analysis set included all participants who received the study drug and had at least 1 measurable plasma concentration for either MLN3126 or its M-I metabolite.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Terminal Phase Elimination Half-life (T1/2) for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 14.901 hours | Standard Deviation 2.7546 |
| Part A: Placebo | Terminal Phase Elimination Half-life (T1/2) for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 12.901 hours | Standard Deviation 0.9029 |
| Part A: Placebo | Terminal Phase Elimination Half-life (T1/2) for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 16.644 hours | Standard Deviation 3.2368 |
| Part A: Placebo | Terminal Phase Elimination Half-life (T1/2) for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 13.459 hours | Standard Deviation 0.5482 |
| Part A: MLN3126 100 mg | Terminal Phase Elimination Half-life (T1/2) for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 13.131 hours | Standard Deviation 2.9209 |
| Part A: MLN3126 100 mg | Terminal Phase Elimination Half-life (T1/2) for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 12.308 hours | Standard Deviation 0.9315 |
| Part A: MLN3126 100 mg | Terminal Phase Elimination Half-life (T1/2) for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 13.717 hours | Standard Deviation 0.9151 |
| Part A: MLN3126 100 mg | Terminal Phase Elimination Half-life (T1/2) for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 13.724 hours | Standard Deviation 2.0905 |
| Part A: MLN3126 300 mg | Terminal Phase Elimination Half-life (T1/2) for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 15.086 hours | Standard Deviation 3.2709 |
| Part A: MLN3126 300 mg | Terminal Phase Elimination Half-life (T1/2) for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 12.830 hours | Standard Deviation 1.9144 |
| Part A: MLN3126 300 mg | Terminal Phase Elimination Half-life (T1/2) for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 12.727 hours | Standard Deviation 1.0056 |
| Part A: MLN3126 300 mg | Terminal Phase Elimination Half-life (T1/2) for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 13.374 hours | Standard Deviation 4.6494 |
Secondary
Tmax- Time to Reach the Cmax for MLN3126 and Its Metabolite
M-I is the inactive metabolite of MLN3126.
Time frame: Days 1 and 15: pre-dose and at multiple timepoints (up to 96 hours) post-dose
Population: The PK analysis set included all participants who received the study drug and had at least 1 measurable plasma concentration for either MLN3126 or its M-I metabolite.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: Placebo | Tmax- Time to Reach the Cmax for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 4.00 hours |
| Part A: Placebo | Tmax- Time to Reach the Cmax for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 5.00 hours |
| Part A: Placebo | Tmax- Time to Reach the Cmax for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 6.00 hours |
| Part A: Placebo | Tmax- Time to Reach the Cmax for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 4.00 hours |
| Part A: MLN3126 100 mg | Tmax- Time to Reach the Cmax for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 4.00 hours |
| Part A: MLN3126 100 mg | Tmax- Time to Reach the Cmax for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 4.00 hours |
| Part A: MLN3126 100 mg | Tmax- Time to Reach the Cmax for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 6.00 hours |
| Part A: MLN3126 100 mg | Tmax- Time to Reach the Cmax for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 4.00 hours |
| Part A: MLN3126 300 mg | Tmax- Time to Reach the Cmax for MLN3126 and Its Metabolite | Day 1 (M-I) (n=6, 6, 6) | 6.00 hours |
| Part A: MLN3126 300 mg | Tmax- Time to Reach the Cmax for MLN3126 and Its Metabolite | Day 1 (MLN3126) (n=6, 6, 6) | 4.00 hours |
| Part A: MLN3126 300 mg | Tmax- Time to Reach the Cmax for MLN3126 and Its Metabolite | Day 15 (MLN3126) (n=6, 6, 5) | 4.00 hours |
| Part A: MLN3126 300 mg | Tmax- Time to Reach the Cmax for MLN3126 and Its Metabolite | Day 15 (M-I) (n=6, 6, 5) | 4.00 hours |