Drug Interaction Study of Multiple Doses of Isavuconazole and Single Dose of Dextromethorphan in Healthy Adult Subjects

Overview

The purpose of this study is to assess the effect of multiple doses of isavuconazole on the pharmacokinetics of a single dose of dextromethorphan in healthy adult subjects.

Full Title of Study: “A Phase 1, Open-Label, Sequential Study of the Effect of Multiple Doses of Isavuconazole on the Pharmacokinetics of a Single Dose of Dextromethorphan in Healthy Adult Subjects”

Study Type

  • Study Type: Interventional
  • Study Design
    • Intervention Model: Single Group Assignment
    • Masking: None (Open Label)
  • Study Primary Completion Date: May 2012

Detailed Description

Subjects will check-in on Day -1 and remain confined to the clinical unit until Day 13. On the morning of Day 1, subjects will receive a single dose of dextromethorphan. On Days 6 and 7, subjects will receive isavuconazole three times daily (TID) administered approximately 8 hours apart. On Day 8 through 12, subjects will receive isavuconazole once daily (QD). On Day 10, subjects will receive a single dose of dextromethorphan. A follow-up visit will be scheduled on Day 21 (± 2 days).

Interventions

  • Drug: Isavuconazole
    • oral
  • Drug: dextromethorphan
    • oral

Arms, Groups and Cohorts

  • Experimental: Isavuconazole and dextromethorphan
    • Dextromethorphan on Day 1and Day 10, Isavuconazole three times per day (TID) on Days 6 and 7, and once daily (QD) on Days 8 thru 12.

Clinical Trial Outcome Measures

Primary Measures

  • Pharmacokinetic (PK) profile for dextromethorphan (in plasma): AUCinf, Cmax , AUClast
    • Time Frame: Pre-dose on Days 1 and 10, and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 48 and 72 hours post-dose
    • Area under the concentration-time curve (AUC) from time 0 extrapolated to infinity (AUCinf), maximum concentration (Cmax), and AUC from time of dosing to the last quantifiable concentration (AUClast).

Secondary Measures

  • PK profile for dextromethorphan (in plasma): t1/2, tmax, CL/F, and Vz/F
    • Time Frame: Pre-dose on Days 1 and 10, and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 48 and 72 hours post-dose
    • Apparent terminal elimination half-life (t1/2), time to attain Cmax (tmax), apparent body clearance after oral dosing (CL/F), and apparent volume of distribution (Vz/F)
  • PK profile for dextrorphan (in plasma): AUClast, AUCinf, Cmax, tmax, t1/2
    • Time Frame: Pre-dose on Days 1 and 10, and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 48 and 72 hours post-dose
  • PK Isavuconazole (in plasma): trough concentration (Ctrough)
    • Time Frame: Pre-dose on Days 8 and 12 and at 24 (Day 13) hours post-dose
  • PK profile for Isavuconazole (in plasma): AUCtau, Cmax, and tmax
    • Time Frame: Day 9 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12,16, 20 hours post-dose and Day 10 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, and 24 (Day 11) hours post-dose
    • AUC during time interval between consecutive dosing (AUCtau)
  • Safety assessed by recording of adverse events, clinical laboratory evaluation, electrocardiograms (ECGs) and vital signs
    • Time Frame: Day 1 through Day 13

Participating in This Clinical Trial

Inclusion Criteria

  • The subject has a body weight of at least 45.0 kg and has a body mass index (BMI) of 18.0 to 32.0 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 as determined by the investigator, including a QTcF of 430 msec or less for male or 450 msec or less for female subjects
  • The subject's clinical laboratory test results at Screening and Day -1 are within normal limits unless the investigator considers the abnormality to be not clinically significant. Results for aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be ≤ upper limit of normal, and total bilirubin must be ≤ 1.5 mg/dL
  • The female subject agrees to sexual abstinence, or is surgically sterile, postmenopausal (defined as at least 2 years at Screening without menses), or using a medically acceptable double barrier method (e.g. spermicide and diaphragm, or spermicide and condom) to prevent pregnancy and agrees to continue using this method from Screening until 3 weeks after the follow-up visit at the end of the study; and is not lactating or pregnant as documented by negative pregnancy tests at Screening and Day -1
  • The male subject agrees to sexual abstinence, is surgically sterile, or is using a medically acceptable method to prevent pregnancy and agrees to continue using this method from Screening until 3 weeks after the follow-up visit at the end of the study

Exclusion Criteria

  • The subject has any clinically significant (as judged by the Investigator) disease history of the following systems: pulmonary, gastrointestinal, cardiovascular (including a history of clinically significant arrhythmia or clinically significant conduction delays on ECG), hepatic, neurological, psychiatric, renal, genitourinary, endocrine, metabolic, dermatologic, immunologic, hematologic, or malignancy excluding non melanoma skin cancer
  • The subject has a history of unexplained syncope, cardiac arrest, unexplained cardiac arrhythmia or torsade de pointes, structural heart disease, or family history of Long QT syndrome (suggested by sudden death of a close relative at a young age due to possible or probable cardiac causes)
  • The subject has/had a symptomatic, viral, bacterial (including upper respiratory infection), or fungal (non-cutaneous) infection within 1 week prior to clinic check in on Day -1
  • The subject has received a vaccination within the last 30 days prior to study drug administration or plans to receive any vaccinations during the study or within 2 weeks after the last dose of study drug
  • The subject has a positive result for hepatitis C antibodies or hepatitis B surface antigen at Screening or is known to be positive for human immunodeficiency virus (HIV)
  • The subject has a known or suspected allergy to any of the components of the trial products including dextromethorphan or the azole class of compounds, or a history of multiple and/or severe allergies to drugs or foods (as judged by the investigator), or a history of severe anaphylactic reactions
  • The subject has smoked (any use of tobacco or nicotine containing products) within 6 months prior to Screening
  • The subject has had treatment with prescription drugs or complementary and alternative medicines within 14 days prior to Day -1, or over-the-counter medications within 1 week prior to Day -1, with the exception of occasional use of acetaminophen up to 2 g/day
  • The subject has received an experimental agent within 30 days or 5 half-lives, whichever is longer, prior to Day -1
  • 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 has donated plasma within 7 days prior to clinic check-in on Day -1
  • The subject has taken part in strenuous exercise within 3 days prior to study drug administration
  • The subject anticipates an inability to abstain from caffeine or alcohol use for 48 hours prior to clinical check-in on Day -1 and throughout the duration of the study; or from grapefruit, Seville oranges, star fruit, or any products containing these items from 72 hours prior to clinic check-in on Day -1 and throughout the duration of the study
  • The subject has a recent history (within the last 2 years) of drug or alcohol abuse, as defined by the investigator, or a positive drug and/or alcohol screen at Screening or Day -1

Gender Eligibility: All

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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