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TAK-385 Phase I Absorption, Distribution, Metabolism, Excretion and Absolute Bioavailability Study

Phase 1
Completed
Conditions
Healthy Volunteers
Interventions
Drug: [14C]-TAK-385 Oral Solution
Drug: TAK-385 Tablets
Drug: [14C]-TAK-385 Solution for Intravenous Infusion
Registration Number
NCT02252354
Lead Sponsor
Takeda
Brief Summary

The purpose of this 2 part study is to look at how TAK-385 is taken up, broken down and removed from the body when given as a radiolabelled oral solution (by mouth) or as an oral tablet (by mouth) followed by a radiolabelled intravenous (IV) infusion (into the arm vein).

Detailed Description

The study will consist of 2 parts involving up to 12 healthy male participants. In Part 1, up to 6 participants will receive a single 80 mg dose of \[14C\]-TAK-385 administered as an oral solution. In Part 2, up to 6 participants will receive a single oral 80 mg dose of TAK-385 administered as two 40 mg tablets and an 80 μg intravenous (into a vein) dose of \[14C\]-TAK-385 (containing not more than 37.0kBq \[1000 nCi\] 14C).

This single centre study will take place in the United Kingdom.

Recruitment & Eligibility

Status
COMPLETED
Sex
Male
Target Recruitment
12
Inclusion Criteria
  1. Signs a written, informed consent form prior to the initiation of any study procedures.
  2. Is a healthy male, aged 18 to 55; inclusive on Day-1.
  3. Is capable of understanding and complying with protocol requirements.
  4. Weighs at least 50 kg and has a body mass index (BMI) between 18.0 and 35.0 kg/m^2, inclusive at Screening or Day-1.
  5. In the opinion of the investigator, is in good healthy condition on the basis of a pre-study physical examination, medical history, vital signs, electrocardiogram, and the results of blood biochemistry, hematology, and serology test and urinalysis at Screening and Day -1.
  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 90 days after last dose.
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Exclusion Criteria
  1. Has received any investigational compound within 45 days prior to Day -1.
  2. Has received TAK-385 in a previous clinical study.
  3. Has a resting systolic blood pressure ≤90 mmHg or ≥140 mmHg and a resting diastolic blood pressure ≤50 mmHg or ≥90 mmHg in supine position at Screening or Day-1.
  4. QTc (Fridericia's correction) is >450 msec at Screening or at Day -1 as read on the printout of the ECG produced by the electrocardiogram (ECG) equipment and evaluated by the investigator
  5. Has active liver disease or jaundice, or with alanine aminotransferase (ALT),aspartate aminotransferase (AST), or bilirubin (total bilirubin) >1.5 times the upper limit of normal (ULN) in the clinical laboratory tests at VISIT 1 and 2. The participant has positive test results for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti-HCV) or known history of human immunodeficiency virus (HIV) at Screening.
  6. Has a resting pulse and heart rate (as read on ECG) <45 beats per minute (bpm) or >100 bpm at Screening or Day -1.
  7. Has had an acute, clinically significant illness within 30 days prior to Day -1.
  8. Has a history or clinical manifestations of significant metabolic (including diabetes mellitus, hypercholesterolemia, or dyslipidemia), hematologic, pulmonary, cardiovascular,gastrointestinal, neurological, rheumatologic, skin and subcutaneous tissue disorders,infectious, hepatic, renal, urologic, immunologic, psychiatric or mood disorders (including any past history of suicide attempt), or history of lactose intolerance.
  9. Has a family history of bleeding disorders.
  10. Has current or recent (within 6 months) history of gastrointestinal disease that would be expected to influence the absorption of drugs (ie, history of malabsorption,esophageal reflux, peptic ulcer disease, erosive esophagitis, frequent heartburn, or any surgical intervention).
  11. Has irregular defecation patterns (less than one defecation per two days or excessive diarrhea) and/or has a history of changes in bowel habits with daily routine or environment changes.
  12. Radiation exposure, including that from the present study, excluding background radiation but including diagnostic x-rays and other medical exposures, exceeding 5 millisievert (mSv) in the last 12 months or 10 mSv in the last 5 years. No occupationally exposed worker, as defined in the Ionising Radiation Regulations 1999, shall participate in the study
  13. Has a history of abdominal surgery (except laparoscopic cholecystectomy or uncomplicated appendectomy), thoracic or nonperipheral vascular surgery within 6 months prior to Day - 1.
  14. Has a history of cancer, other than basal cell or Stage 1 squamous cell carcinoma of the skin that has not been in remission for at least 5 years prior to Day 1.
  15. Has significant cardiovascular disease including, but not limited to, a history of myocardial infarction, coronary angioplasty or bypass graft, unstable angina pectoris, transient ischemic attacks, clinically significant abnormal ECGs, New York Heart Association (NYHA) Functional Classification III or IV, or documented cerebrovascular accident within 6 months prior to Day -1.
  16. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse (defined as regular or daily consumption of more than 4 alcoholic drinks per day) within 1 year prior to the Screening Visit.
  17. Has used any tobacco (ie, nicotine) products (including but not limited to cigarettes, pipe, cigar, chewing tobacco, nicotine patch, or nicotine gum) within 6 months prior to Day -1 or is unwilling to abstain from these products for the duration of the study or has a positive carbon monoxide test result at Screening or Day -1.
  18. Has taken any medications, supplements or food products as described in the Excluded Medications section. A subject has a positive carbon monoxide test result on Day-1.
  19. Has poor peripheral venous access.
  20. Is unwilling or unable to comply with the protocol or scheduled appointments
  21. Is unable to understand verbal and/or written English.
  22. Is a study site employee, or is an immediate family member (ie, spouse, parent, child, and sibling) of a study site employee, involved in conduct of this study.
  23. Has received or donated more than 400 mL of blood or blood products within the 45 days preceding the beginning of the study or plans to donate blood during the study.
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Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Part 1: [14C]-TAK-385[14C]-TAK-385 Oral Solution\[14C\]-TAK-385 80 mg, solution, orally, once on Day 1.
Part 2: TAK-385 + [14C]-TAK-385 IVTAK-385 TabletsTAK-385 80 mg, tablets, orally, and \[14C\]-TAK-385 80 μg, infusion, intravenous once on Day 1.
Part 2: TAK-385 + [14C]-TAK-385 IV[14C]-TAK-385 Solution for Intravenous InfusionTAK-385 80 mg, tablets, orally, and \[14C\]-TAK-385 80 μg, infusion, intravenous once on Day 1.
Primary Outcome Measures
NameTimeMethod
Part 1: Cmax: Maximum Observed Plasma Concentration for TAK-385Day 1 pre-dose and various time-points (up to 168 hours) post-dose

Maximum observed concentration (Cmax) is the peak concentration of a drug after administration, obtained directly from the concentration-time curve. Plasma concentrations of TAK-385 were measured by high-performance liquid chromatography with tandem mass spectrometry method (LC-MS/MS). Correction of the LC-MS/MS derived concentrations were based upon the specific activity of the administered radiolabelled drug product (\[14C\]-TAK-385).

Part 1: AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for TAK-385Day 1 pre-dose and various time-points (up to 168 hours) post-dose

AUC(0-168) is measure of area under the curve over the dosing interval (tau) (AUC(0-tau\]), where tau is the length of the dosing interval -168 hours in this study). Plasma concentrations of TAK-385 were measured by high-performance liquid chromatography with tandem mass spectrometry method (LC-MS/MS). Correction of the LC-MS/MS derived concentrations were based upon the specific activity of the administered radiolabelled drug product (\[14C\]-TAK-385).

Part 1: Terminal Phase Elimination Half-Life (t1/2z) in Plasma and Whole Blood Radioactivity for [14C]-TAK-385Day 1 pre-dose and various time-points (up to 288 hours) post-dose

Terminal phase elimination half-life (t1/2z) is the time required for half of the drug to be eliminated from the blood. Radioactivity corresponds to NMT 4.7 MBq (127 mCi). It was calculated as disintegration per minute per mL (DPM/mL). Total \[14C\]-TAK-385 determination of plasma and whole blood samples was determined by AMS method.

Part 1: Overall Cumulative Percent Recovery of Total Dosed Radioactivity in Urine and FecesDay 1 pre-dose and various time-points (up to Day 288) post-dose

Overall cumulative percent of radioactive dose recovered in urine and feces is the total radioactivity excreted in urine and feces divided by the amount of total radioactivity dosed for each participant. Total \[14-C\] determination of urine and feces samples were determined by Liquid Scintillation Counting (LSC).

Part 2: Tmax : Time to Reach the Maximum Plasma Radioactivity Concentration (Cmax) for [14C]-TAK-385Day 1 pre-dose and various time-points (up to 168 hours) post-dose

Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax. Radioactivity corresponds to NMT 37.0 kilobecquerel (kBq) (1000 nanocurie \[nCi\]). Total radioactivity and \[14C\]-TAK-385 determination of plasma samples was determined by AMS.

Part 2: Cmax: Maximum Observed Plasma Radioactivity Concentration for [14C]-TAK-385Day 1 pre-dose and various time-points (up to 168hours) post-dose

Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Radioactivity corresponds to NMT 37.0 kBq (1000 nCi).Total radioactivity and \[14C\]-TAK-385 determination of plasma samples was determined by AMS.

Part 2: Cmax: Maximum Observed Plasma Radioactivity Concentration for TAK-385Day 1 pre-dose and various time-points (up to 168 hours) post-dose

Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.

Part 2: Terminal Phase Elimination Half-Life (t1/2z) in Plasma for TAK-385Day 1 pre-dose and various time-points (up to 168 hours) post-dose

Terminal phase elimination half-life (t1/2z) is the time required for half of the drug to be eliminated from the blood.

Part 1: Cmax: Maximum Observed Plasma and Whole Blood Radioactivity Concentration for [14C]-TAK-385Day 1 pre-dose and various time-points (up to 288 hours) post-dose

Maximum observed concentration (Cmax) is the peak concentration of a drug after administration, obtained directly from the concentration-time curve. Radioactivity corresponds to NMT 4.7 MBq (127 mCi). Cmax was measured in nanogram equivalent per milliliter (ng eq/mL) and was calculated as disintegration per minute per mL (DPM/mL). Total \[14C\]-TAK-385 determination of plasma and whole blood samples was determined by AMS method.

Part 1: AUC(0-inf): Area Under the Plasma and Whole Blood Radioactivity Concentration-time Curve From Time 0 to Infinity for [14C]-TAK-385Day 1 pre-dose and various time-points (up to 288 hours) post-dose

AUC(0-inf) is measure of area under the curve from time 0 to infinity. Radioactivity corresponds to NMT 4.7 MBq (127 mCi). AUC(0-inf) was measured in nanogram equivalent\*hour per milliliter (ng eq\*hr/mL) and was calculated as disintegration per minute per mL (DPM/mL). Total \[14C\]-TAK-385 determination of plasma and whole blood samples was determined by AMS method.

Part 1: AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-385Day 1 pre-dose and various time-points (up to 168 hours) post-dose

AUC(0-inf) is area under the concentration-time curve from time 0 to infinity. Plasma concentrations of TAK-385 were measured by high-performance liquid chromatography with tandem mass spectrometry method (LC-MS/MS). Correction of the LC-MS/MS derived concentrations were based upon the specific activity of the administered radiolabelled drug product (\[14C\]-TAK-385) .

Part 1: Time to Reach the Maximum Plasma and Whole Blood Radioactivity Concentration (Cmax) for [14C]-TAK-385Day 1 pre-dose and various time-points (up to 288 hours) post-dose

Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax. Radioactivity corresponds to no more than (NMT) 4.7 millibecquerel (MBq) (127 microcurie \[mCi\]). Cmax was calculated as disintegration per minute per mL (DPM/mL). Total \[14C\]-TAK-385 determination of plasma and whole blood samples was determined by accelerator mass spectrometry (AMS) method.

Part 1: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-385Day 1 pre-dose and various time-points (up to 168 hours) post-dose

Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax. Plasma concentrations of TAK-385 were measured by high-performance liquid chromatography with tandem mass spectrometry method (LC-MS/MS). Correction of the LC-MS/MS derived concentrations were based upon the specific activity of the administered radiolabelled drug product (\[14C\]-TAK-385).

Part 1: AUC(0-168): Area Under the Plasma and Whole Blood Radioactivity Concentration-Time Curve From Time 0 to 168 Hours Postdose for [14C]-TAK-385Day 1 pre-dose and various time-points (up to 288 hours) post-dose

AUC(0-168) is measure of area under the curve over the dosing interval (tau),where tau is the length of the dosing interval: 168 hours in this study (AUC(0-168\]). Radioactivity corresponds to NMT 4.7 MBq (127 mCi). It was calculated as disintegration per minute per mL (DPM/mL). Total \[14C\]-TAK-385 determination of plasma and whole blood samples was determined by AMS method.

Part 1: Terminal Phase Elimination Half-Life (t1/2z) in Plasma for TAK-385Day 1 pre-dose and various time-points (up to 168 hours) post-dose

Terminal phase elimination half-life (t1/2z) is the time required for half of the drug to be eliminated from the blood. Plasma concentrations of TAK-385 were measured by high-performance liquid chromatography with tandem mass spectrometry method (LC-MS/MS). Correction of the LC-MS/MS derived concentrations were based upon the specific activity of the administered radiolabelled drug product (\[14C\]-TAK-385).

Part 2: Tmax : Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-385Day 1 pre-dose and various time-points (up to 168 hours) post-dose

Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.

Part 2: AUC(0-168): Area Under the Plasma Radioactivity Concentration-Time Curve From Time 0 to 168 Hours Postdose for [14C]-TAK-385Day 1 pre-dose and various time-points (up to 168 hours) post-dose

AUC(0-168) is measure of area under the curve over the dosing interval (tau), where tau is the length of the dosing interval :168 hours in this study (AUC(0-tau\]). AUC(0-168) was corrected according to Hamilton Pool result.Radioactivity corresponds to NMT 37.0 kBq (1000 nCi).Total radioactivity and \[14C\]-TAK-385 determination of plasma samples was determined by AMS.

Part 2: AUC(0-inf): Area Under the Plasma Radioactivity Concentration-time Curve From Time 0 to Infinity for [14C]-TAK-385Day 1 pre-dose and various sampling time-points (up to 168 hours) post-dose

AUC(0-inf) is measure of area under the curve from time 0 to Infinity. Radioactivity corresponds to NMT 37.0 kBq (1000 nCi).AUC(0-inf) was corrected according to Hamilton Pool result.Total radioactivity and \[14C\]-TAK-385 determination of plasma samples was determined by AMS.

Part 2: AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for TAK-385Day 1 pre-dose and various time-points (up to 168 hours) post-dose

AUC(0-168) is measure of area under the curve over the dosing interval (tau),where tau is the length of the dosing interval: 168 hours in this study (AUC(0-tau\]). AUC was corrected using the Hamilton Pool Data to get an AUC for TAK-385.

Part 2: Absolute Bioavailability for the Oral Tablet FormulationDay 1 pre-dose and various time-points (up to 168 hours) post-dose

Absolute bioavailability, defined as the fraction or percentage of the unchanged, orally administered dose that is systemically available, relative to the total dose administered intravenously. AUC was corrected using the Hamilton Pool Data to get an AUC for TAK-385

Part 1: Excretion of TAK-385 and Its Metabolites in Human Feces as Percent Radioactivity0 to 191 hours post-dose

Amount of total \[14\]C, TAK-385, metabolite A, B, and C, and others excreted from feces, calculated as percentage of recovered radioactivity, are reported. Others were calculated by subtraction of the sum of the values for TAK-385, Metabolite-A, Metabolite-B, and Metabolite-C from the value of the total radioactivity (total \[14\]C).Radioactivity corresponds to NMT 4.7 MBq (127 mCi).

Part 1: Excretion of TAK-385 and Its Metabolites in Human Urine as Percent Radioactivity0 to 144 hours post-dose

Amount of total \[14\]C, TAK-385, metabolite A, B, and C, and others excreted from urine, calculated as percentage of recovered radioactivity, are reported. Others were calculated by subtraction of the sum of the values for TAK-385, Metabolite-A, Metabolite-B, and Metabolite-C from the value of the total radioactivity (total \[14\]C).Radioactivity corresponds to NMT 4.7 MBq (127 mCi).

Part 1: [14]C Distribution Profile From TAK-385 and Metabolites A, B, and C in Plasma Pools at Hour 4 Post-doseHour 4 post-dose

Percentage of \[14\]C as measured from TAK-385, metabolite A and B, and metabolite C in the plasma pools were calculated as the percentage of dose administered.

Part 1: [14]C Distribution Profile From TAK-385 and Metabolites A, B, and C in Plasma Pools at Hour 8 Post-doseHour 8 post-dose

Percentage of \[14\]C as measured from TAK-385, metabolite A and B, and metabolite C in the plasma pools were calculated as the percentage of dose administered.

Part 2: AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-385Day 1 pre-dose and various time-points (up to 288 hours) post-dose

AUC(0-inf) is measure of area under the curve from time 0 to Infinity.

Part 1: [14]C Distribution Profile From TAK-385 and Metabolites A, B, and C in Plasma Pools at Hour 12 Post-doseHour 12 post-dose

Percentage of \[14\]C as measured from TAK-385, metabolite A and B, and metabolite C in the plasma pools were calculated as the percentage of dose administered.

Part 2: Terminal Phase Elimination Half-Life (t1/2z) in Plasma Radioactivity for [14C]-TAK-385Day 1 pre-dose and various time-points (up to 168 hours) post-dose

Terminal phase elimination half-life (t1/2z) is the time required for half of the drug to be eliminated from the blood. Radioactivity corresponds to NMT 37.0 kBq (1000 nCi).Total radioactivity and \[14C\]-TAK-385 determination of plasma samples was determined by AMS.

Part 1: Excretion of TAK-385 and Its Metabolites in Human Urine as Percentage of Dose0 to 144 hours post-dose

Amount of total \[14\]C, TAK-385, metabolite A, B, and C, and others excreted from urine, calculated as percentage of dose. Others were calculated by subtraction of the sum of the values for TAK-385, Metabolite-A, Metabolite-B, and Metabolite-C from the value of the total \[14\]C.

Part 1: [14]C Distribution Profile From TAK-385 and Metabolites A, B, and C in Plasma Pools at Hour 1 Post-doseHour 1 post-dose

Percentage of \[14\]C as measured from TAK-385, metabolite A and B, and metabolite C in the plasma pools were calculated as the percentage of dose administered.

Part 1: [14]C Distribution Profile From TAK-385 and Metabolites A, B, and C in Plasma Pools at Hour 36 Post-doseHour 36 post-dose

Percentage of \[14\]C as measured from TAK-385, metabolite A and B, and metabolite C in the plasma pools were calculated as the percentage of dose administered.

Part 1: [14]C Distribution Profile From TAK-385 and Metabolites A, B, and C in Plasma Pools at Hour 48 Post-doseHour 48 post-dose

Percentage of \[14\]C as measured from TAK-385, metabolite A and B, and metabolite C in the plasma pools were calculated as the percentage of dose administered.

Part 1: [14]C Distribution Profile From TAK-385 and Metabolites A, B, and C in Plasma Pools at Hour 72 Post-doseHour 72 post-dose

Percentage of \[14\]C as measured from TAK-385, metabolite A and B, and metabolite C in the plasma pools were calculated as the percentage of dose administered.

Part 1: [14]C Distribution Profile From TAK-385 and Metabolites A, B, and C in Plasma Pools at Hour 2 Post-doseHour 2 post-dose

Percentage of \[14\]C as measured from TAK-385, metabolite A and B, and metabolite C in the plasma pools were calculated as the percentage of dose administered.

Part 1: [14]C Distribution Profile From TAK-385 and Metabolites A, B, and C in Plasma Pools at Hour 24 Post-doseHour 24 post-dose

Percentage of \[14\]C as measured from TAK-385, metabolite A and B, and metabolite C in the plasma pools were calculated as the percentage of dose administered.

Part 1: Excretion of TAK-385 and Its Metabolites in Human Feces as Percentage of Dose0 to 191 hours post-dose

Amount of total \[14\]C, TAK-385, metabolite A, B, and C, and others excreted from feces, calculated as percentage of dose. Others were calculated by subtraction of the sum of the values for TAK-385, Metabolite-A, Metabolite-B, and Metabolite-C from the value of the total \[14\]C.

Secondary Outcome Measures
NameTimeMethod
Part 2: Apparent Oral Clearance (CL/F) for TAK-385Day 1 pre-dose and various time-points (up to 168 hours) post-dose

CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided by AUC expressed in liters/hour (L/hr).CL which was calculated by correcting the \[14C\]TAK-385 AUC, following the intravenous dose with the hamilton pool result to get a true CL (L/h).

Part 2: Overall Cumulative Percent Recovery of Total Dosed Radioactivity in Urine and FecesDay 1 pre-dose and various time-points (up to 72 hours) post-dose for urine; Day 1 pre-dose and various time-points (up to 48 hours) post-dose

Overall cumulative percent of radioactive dose recovered in urine and feces is the total radioactivity excreted in urine and feces divided by the amount of total radioactivity dosed for each participant.

Part 2: Clearance (CL) for [14C]-TAK-385Day 1 pre-dose and various time-points (up to 168 hours) post-dose

CL is clearance of the drug from the plasma, calculated as the drug dose divided by AUC expressed in L/hr. CL is a quantitative measure of the rate at which a drug substance is removed from the body. Radioactivity corresponds to NMT 37.0 kBq (1000 nCi).

Part 1: Apparent Oral Clearance (CL/F) for TAK-385Day 1 pre-dose and various time-points (up to 168 hours) post-dose

CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided by AUC expressed in liters/hour (L/hr). CL which was calculated by correcting the \[14C\]TAK-385 AUC, following the intravenous dose with the hamilton pool result to get a true CL (L/h). Plasma concentrations of TAK-385 were measured by high-performance liquid chromatography with tandem mass spectrometry method (LC-MS/MS). Correction of the LC-MS/MS derived concentrations were based upon the specific activity of the administered radiolabelled drug product.

Part 1: Volume of Distribution (Vz/F) for TAK-385Day 1 pre-dose and various time-points (up to 168 hours) post-dose

Vz/F is the distribution of a drug between plasma and the rest of the body following oral administration, calculated as CL/F divided by the terminal elimination rate constant (λz). Plasma concentrations of TAK-385 were measured by high-performance liquid chromatography with tandem mass spectrometry method (LC-MS/MS). Correction of the LC-MS/MS derived concentrations were based upon the specific activity of the administered radiolabelled drug product.

Part 2: Volume of Distribution (Vz/F) for TAK-385Day 1 pre-dose and various time-points (up to 168 hours) post-dose

Vz/F is the distribution of a drug between plasma and the rest of the body following oral administration, calculated as CL/F divided by the terminal elimination rate constant (λz).

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