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A Study to Evaluate Effect of Itraconazole on the Pharmacokinetics of Cobimetinib in Healthy Participants

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ClinicalTrials.gov Identifier: NCT01929876
Recruitment Status : Completed
First Posted : August 28, 2013
Results First Posted : August 4, 2016
Last Update Posted : August 4, 2016
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.

Brief Summary:
This open-label, 2-period, fixed sequence, drug interaction study will investigate the effect of co-administration of itraconazole on the pharmacokinetics of cobimetinib in healthy participants. Participants will receive multiple repeating doses of cobimetinib and itraconazole.

Condition or disease Intervention/treatment Phase
Healthy Participants Drug: Cobimetinib Drug: Itraconazole Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Official Title: A Phase 1, Open-Label Study to Evaluate the Effect of Itraconazole on the Pharmacokinetics of Cobimetinib in Healthy Subjects
Study Start Date : July 2013
Actual Primary Completion Date : October 2013
Actual Study Completion Date : October 2013

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cobimetinib + Itraconazole Drug: Cobimetinib
10 milligram (mg) (2* 5 mg capsules) will be administered orally on Day 1 of Period 1 and Day 4 of Period 2
Other Name: GDC-0973

Drug: Itraconazole
200 mg oral solution will be administered once daily from Day 1 to Day 14 of Period 2




Primary Outcome Measures :
  1. Maximum Observed Plasma Concentration (Cmax) of Cobimetinib With and Without Itraconazole [ Time Frame: Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 ]
    Maximum observed plasma concentration of cobimetinib with and without itraconazole was assessed using a model independent approach.

  2. Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - Inf)] of Cobimetinib With and Without Itraconazole [ Time Frame: Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 ]
    AUC (0 - inf) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf) of cobimetinib with and without itraconazole, assessed using a model independent approach.


Secondary Outcome Measures :
  1. Time to Reach Maximum Observed Plasma Concentration (Tmax) of Cobimetinib With and Without Itraconazole [ Time Frame: Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 ]
    Time to reach maximum observed plasma concentration of cobimetinib with and without itraconazole was assessed using a model independent approach.

  2. Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of Cobimetinib With and Without Itraconazole [ Time Frame: Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 ]
    AUC (0-t) = Area under the plasma concentration versus time curve from time zero (predose) to time of last quantifiable concentration (0-t) of cobimetinib with and without itraconazole was assessed. It was calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations using a model independent approach.

  3. Plasma Half-Life (t1/2) of Cobimetinib With and Without Itraconazole [ Time Frame: Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 ]
    Plasma half-life is the time measured for the plasma concentration to decrease by one half.

  4. Apparent Clearance (CL/F) of Cobimetinib With and Without Itraconazole [ Time Frame: Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 ]
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated using a model independent approach.

  5. Apparent Volume of Distribution (Vz/F) of Cobimetinib With and Without Itraconazole [ Time Frame: Period 1: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192 hours postdose on Day 1; Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction of drug absorbed.

  6. Cmax of Itraconazole and Hydroxy-Itraconazole [ Time Frame: Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 ]
    Maximum observed plasma concentration of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach.

  7. Tmax of Itraconazole and Hydroxy-Itraconazole [ Time Frame: Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 192, 240 hours post cobimetinib dose on Day 4 ]
    Time to reach maximum observed plasma concentration of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach.

  8. Area Under the Curve From Time Zero to 24 Hours [AUC (0-24)] of Itraconazole and Hydroxy-Itraconazole [ Time Frame: Period 2: Predose (0 hour), 0.5, 1, 2, 4, 6, 8, 12, 24 hours post cobimetinib dose on Day 4 ]
    AUC (0-24) = Area under the plasma concentration versus time curve from time zero (predose) to 24 hours postdose (0-24) of itraconazole and its metabolite hydroxy-itraconazole was assessed using a model independent approach.



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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy adult participants
  • Within body mass index (BMI) range 18.5 to 32 kilogram per meter square (kg/m^2), inclusive
  • Creatine phosphokinase levels below 2.5 times the upper limit of normal (ULN) and if elevated, not clinically significant
  • Liver function tests for aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase below 2 times the ULN; bilirubin below 1.5 times the ULN; and all liver function test elevations not clinically significant
  • In good health, determined by no clinically significant findings from medical history, 12-lead electrocardiogram (ECG), and vital signs
  • Clinical laboratory evaluations within the reference range for the test laboratory, unless deemed not clinically significant by the Investigator
  • Negative test for selected drugs of abuse at screening and at each check-in
  • Negative hepatitis panel (including hepatitis B surface antigen [HBsAg] and anti-hepatitis C virus [HCV]) and negative human immunodeficiency virus (HIV) antibody screens
  • Females non-pregnant or non-lactating
  • Males and females (of child-bearing potential) to use two forms of adequate contraception

Exclusion Criteria:

  • Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, or psychiatric disorder
  • History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator
  • History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs; except that appendectomy, hernia repair, and/or cholecystectomy will be allowed
  • History of diabetes mellitus and/or elevated fasting glucose at baseline
  • History or presence of an abnormal ECG, which in the Investigator's opinion, is clinically significant
  • History of alcoholism or drug addiction within 1 year prior to study start
  • Use of any tobacco- or nicotine-containing products (within 6 months prior to study start and during the entire study
  • Participation in any other investigational study or biologic agent trial in which receipt of an investigational study drug occurred within 5 half-lives or 30 days, whichever is longer, or exposure to any biological therapy or investigational biological agent within 90 days prior to study entry and during the entire study from study start to study completion, inclusive

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01929876


Locations
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United States, Texas
Dallas, Texas, United States, 75247
Sponsors and Collaborators
Genentech, Inc.
Investigators
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Study Director: Clinical Trials Genentech, Inc.

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Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT01929876     History of Changes
Other Study ID Numbers: GP28620
First Posted: August 28, 2013    Key Record Dates
Results First Posted: August 4, 2016
Last Update Posted: August 4, 2016
Last Verified: June 2016
Additional relevant MeSH terms:
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Itraconazole
Hydroxyitraconazole
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP3A Inhibitors