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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy Adult Volunteers; Pharmacokinetics of Isavuconazole; Pharmacokinetics of Dextromethorphan
• Intervention / Treatment: Drug: Isavuconazole; Drug: dextromethorphan

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).

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21225
      • Parexel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Isavuconazole; oral; Other Names: ASP9766; BAL4815; Drug: dextromethorphan; oral; Other Names: DXM

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic (PK) profile for dextromethorphan (in plasma): AUCinf, Cmax , AUClast	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).	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK profile for dextromethorphan (in plasma): t1/2, tmax, CL/F, and Vz/F	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)	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 profile for dextrorphan (in plasma): AUClast, AUCinf, Cmax, tmax, t1/2		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)		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	AUC during time interval between consecutive dosing (AUCtau)	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
Safety assessed by recording of adverse events, clinical laboratory evaluation, electrocardiograms (ECGs) and vital signs		Day 1 through Day 13

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.
• Collaborators: Basilea Pharmaceutica International Ltd

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): May 1, 2012
• Study Completion (Actual): May 1, 2012

Study Registration Dates

• First Submitted: July 23, 2012
• First Submitted That Met QC Criteria: July 25, 2012
• First Posted (Estimate): July 27, 2012

Study Record Updates

• Last Update Posted (Estimate): February 23, 2015
• Last Update Submitted That Met QC Criteria: February 20, 2015
• Last Verified: February 1, 2015

More Information

Terms related to this study

• Keywords: Healthy Volunteers; Isavuconazole; dextromethorphan; BAL4815; DXM; dextrorphan
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Respiratory System Agents; Antifungal Agents; Antitussive Agents; Dextromethorphan; Isavuconazole
• Other Study ID Numbers: 9766-CL-0042