A Study to Evaluate the Pharmacokinetics of BAL8728 After a Single Dose of Pyridinylmethyl-14C-Labeled Isavuconazonium Sulfate in Healthy Male Subjects

Overview

The purpose of this study is to evaluate the pharmacokinetics of 14C-labeled cleavage product (BAL8728), in particular the routes of excretion and extent ot metabolism of the cleavage product following administration of a single intravenous dose of pyridinylmethyl-14C-labeled prodrug isavuconazonium sulfate (BAL8557). In addition, identify the metabolic profile of BAL8728 in human plasma, urine and/or feces after a single intravenous dose of pyridinylmethyl-14C-labeled BAL8557 and evaluate the pharmacokinetics of BAL8728 and BAL4815. Safety and tolerability after a single intravenous dose of pyridinylmethyl-14C-labeled isavuconazonium sulfate will also be evaluated.

Full Title of Study: “A Phase 1 Open-Label Mass Balance Study to Evaluate the Pharmacokinetics of BAL8728 After A Single Intravenous Dose of 14C-Labeled Isavuconazonium Sulfate in Healthy Male Subjects”

Study Type

  • Study Type: Interventional
  • Study Design
    • Intervention Model: Single Group Assignment
    • Masking: None (Open Label)
  • Study Primary Completion Date: April 2013

Interventions

  • Drug: Pyridinylmethyl-14C-labeled isavuconazonium sulfate
    • Intravenous

Arms, Groups and Cohorts

  • Experimental: Pyridinylmethyl-14C-labeled isavuconazonium sulfate
    • single dose

Clinical Trial Outcome Measures

Primary Measures

  • Radioactivity in whole blood and in plasma: Area under the concentration-time curve (AUC) from time of dosing to infinity (AUCinf)
    • Time Frame: 20 time points up to Day 4. If Day 4 is not the end of the study, samples will be drawn once a day up to Day 9
  • Radioactivity in whole blood and in plasma: AUC from time of dosing to the last quantifiable concentration (AUClast)
    • Time Frame: 20 time points up to Day 4. If Day 4 is not the end of the study, samples will be drawn once a day up to Day 9
  • Radioactivity in whole blood and in plasma: Maximum concentration (Cmax)
    • Time Frame: 20 time points up to Day 4. If Day 4 is not the end of the study, samples will be drawn once a day up to Day 9
  • Radioactivity in whole blood and in plasma: Time to Attain Cmax (tmax)
    • Time Frame: 20 time points up to Day 4. If Day 4 is not the end of the study, samples will be drawn once a day up to Day 9
  • Radioactivity in whole blood and in plasma: Apparent terminal elimination half-life (t1/2)
    • Time Frame: 20 time points up to Day 4. If Day 4 is not the end of the study, samples will be drawn once a day up to Day 9
  • Radioactivity in emesis (if applicable)
    • Time Frame: After study drug administration up to Day 9
  • Radioactivity ratio blood/plasma
    • Time Frame: Day 1
  • Percent of dose and cumulative percent of dose of radioactivity recovered in urine
    • Time Frame: 7 time intervals up to Day 4. If Day 4 is not the end of the study, sample collection will continue in 24 hour intervals until discharge up to Day 9
  • Percent of dose and cumulative percent dose of radioactivity recovered in feces
    • Time Frame: 4 time intervals up to Day 4. If Day 4 is not the end of the study, sample collection will continue in 24 hour intervals until discharge up to Day 9
  • Pharmacokinetics of BAL8728 (cleavage product) in plasma: AUCinf
    • Time Frame: 20 time points up to Day 4. If Day 4 is not the end of the study, samples will be drawn once a day up to Day 9
  • Pharmacokinetics of BAL8728 (cleavage product) in plasma: AUClast
    • Time Frame: 20 time points up to Day 4. If Day 4 is not the end of the study, samples will be drawn once a day up to Day 9
  • Pharmacokinetics of BAL8728 (cleavage product) in plasma: Cmax
    • Time Frame: 20 time points up to Day 4. If Day 4 is not the end of the study, samples will be drawn once a day up to Day 9
  • Pharmacokinetics of BAL8728 (cleavage product) in plasma: tmax
    • Time Frame: 20 time points up to Day 4. If Day 4 is not the end of the study, samples will be drawn once a day up to Day 9
  • Pharmacokinetics of BAL8728 (cleavage product) in plasma: total body clearance after intravenous dosing (CLtot)
    • Time Frame: 20 time points up to Day 4. If Day 4 is not the end of the study, samples will be drawn once a day up to Day 9
  • Pharmacokinetics of BAL8728 (cleavage product) in plasma: volume of distribution during terminal phase after intravenous dosing (Vz)
    • Time Frame: 20 time points up to Day 4. If Day 4 is not the end of the study, samples will be drawn once a day up to Day 9
  • Pharmacokinetics of BAL8728 (cleavage product) in plasma: t 1/2
    • Time Frame: 20 time points up to Day 4. If Day 4 is not the end of the study, samples will be drawn once a day up to Day 9
  • Pharmacokinetics of BAL8728 (cleavage product) in urine: amount excreted (Ae)
    • Time Frame: 7 time intervals up to Day 4. If Day 4 is not the end of the study, sample collection will continue in 24 hour intervals until discharge up to Day 9
  • Pharmacokinetics of BAL8728 (cleavage product) in urine: percent of unchanged drug excreted into the urine (Ae%)
    • Time Frame: 7 time intervals up to Day 4. If Day 4 is not the end of the study, sample collection will continue in 24 hour intervals until discharge up to Day 9
  • Pharmacokinetics of BAL8728 (cleavage product) in urine: renal clearance (CLr)
    • Time Frame: 7 time intervals up to Day 4. If Day 4 is not the end of the study, sample collection will continue in 24 hour intervals until discharge up to Day 9
  • Pharmacokinetics of BAL4815 (isavuconazole) in plasma: AUClast
    • Time Frame: 20 time points up to Day 4. If Day 4 is not the end of the study, samples will be drawn once a day up to Day 9
  • Pharmacokinetics of BAL4815 (isavuconazole) in plasma: Cmax
    • Time Frame: 20 time points up to Day 4. If Day 4 is not the end of the study, samples will be drawn once a day up to Day 9
  • Pharmacokinetics of BAL4815 (isavuconazole) in plasma: tmax
    • Time Frame: 20 time points up to Day 4. If Day 4 is not the end of the study, samples will be drawn once a day up to Day 9

Secondary Measures

  • Metabolic profile of BAL8728 and possible metabolites in plasma, urine, and feces
    • Time Frame: Up to 3 days (72 hours) after dosing

Participating in This Clinical Trial

Inclusion Criteria

  • The subject has a body weight of at least 45 kg and a body mass index of 18 to 32 kg/m2, inclusive.
  • The subject's 12-lead electrocardiogram (ECG) is normal at Screening and Day -1; or, if abnormal, the abnormality is not clinically significant. The ECG for the subject has a QTcF of at least 360 but not more than 430 msec.

Exclusion Criteria

  • The subject has any clinically significant disease history of the following systems: pulmonary, gastrointestinal, cardiovascular (including a history of clinically significant arrhythmia), hepatic, neurological, psychiatric, renal, genitourinary, endocrine, metabolic, dermatologic, immunologic, hematologic, or malignancy excluding non melanoma skin cancer.
  • The subject has a positive test for hepatitis B surface antigen or hepatitis C antibodies at Screening or is known to be positive for human immunodeficiency virus.
  • The subject has a known or suspected allergy to any of the azole class of compounds, or a history of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reactions.
  • The subject has used tobacco or nicotine containing products in the last 6 months prior to Day -1.
  • The subject has had treatment with prescription drugs, over-the-counter medication, or complementary and alternative medicines within 14 days prior to Day -1, with the exception of occasional use of acetaminophen up to 2 g/day.
  • The subject has participated in any interventional clinical study or has received any investigational agent within 28 days or 5 half-lives, whichever is longer, prior to Screening.
  • The subject has had any significant blood loss, donated one unit (450 mL) of blood or more, or received a transfusion of any blood or blood products within 60 days or donated plasma within 7 days prior to clinic admission on Day -1.

Gender Eligibility: Male

Minimum Age: 18 Years

Maximum Age: 55 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Astellas Pharma Global Development, Inc.
  • Collaborator
    • Basilea Pharmaceutica International Ltd
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Medical Director, Study Director, Astellas Pharma Global Development

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