A Drug-Drug Interaction Study of the Effect of Rabeprazole, Itraconazole or Fluconazole on the Pharmacokinetics of Vismodegib

A Clinical Drug-Drug Interaction Study to Evaluate the Effect of a Proton Pump Inhibitor, a Combined P-gp/CYP3A4 Inhibitor, and a CYP2C9 Inhibitor on the Pharmacokinetics of Vismodegib

This randomized, open-label, 4-arm, multiple-dose study will evaluate the effect of coadministration of a protein pump inhibitor, an inhibitor of P-glycoprotein and CYP3A4, or an inhibitor of CYP2C9 on the pharmacokinetics of vismodegib in healthy female subjects of non-childbearing potential. Subjects will be randomized to receive multiple oral doses of vismodegib, alone or in combination with multiple oral doses of either rabeprazole, itraconazole or fluconazole. Anticipated time on study treatment is up to 11 days.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteer
• Intervention / Treatment: Drug: vismodegib; Drug: rabeprazole; Drug: itraconazole; Drug: fluconazole

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Daytona Beach, Florida, United States, 32117
  • Texas
    • Dallas, Texas, United States, 75247

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Females of non-childbearing potential
• Body mass index (BMI) 18 to 32 kg/m2, inclusive
• In good health, determined by no clinically significant findings from medical history, physical examination. 12-lead ECG, and vital signs
• Clinical laboratory evaluations, complete blood count and urinalysis within the normal range for the test laboratory, unless not deemed clinically significant by the investigator
• Negative test for drugs of abuse at screening and check-in (including alcohol)
• Negative for hepatitis B, hepatitis C and HIV infection
• Non-childbearing potential is defined as: non-pregnant, non-lactating, and either postmenopausal for at least 1 year or surgically sterile (e.g. bilateral oophorectomy and/or hysterectomy)

Exclusion Criteria:

• Significant history or clinical evidence of any metabolic (including type 1 or 2 diabetes). allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, endocrine, GI (including gastric or duodenal ulcers), Zollinger-Ellison syndrome, Barrett's esophagus, urological, neurological, or psychiatric disorder
• History of inflammatory arthritis
• History of symptomatic hypotension
• History of seizure disorders
• History of bipolar or major depressive disorder
• History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs (appendectomy, hernia repair, and/or cholecystectomy will be allowed)
• History of alcoholism or drug addiction within 1 year prior to check-in
• Use of any tobacco- or nicotine-containing products within 6 months prior to check-in
• Participation in any other investigational study drug or biological agent trial in which receipt of investigational study drug occurred within 5 half-lives or 30 days, whichever is longer, prior to check-in
• Use of PPIs, H2-receptor antagonists, or antacids within 1 month prior to check-in
• History of chronic PPI use (> 30 days of continuous daily dosing) within 6 months of check-in

Study Plan

How is the study designed?

Design Details

• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: A: Vismodegib	Drug: vismodegib; Multiple oral doses
EXPERIMENTAL: B: Rabeprazole + Vismodegib	Drug: vismodegib; Multiple oral doses; Drug: rabeprazole; Multiple oral doses
EXPERIMENTAL: C: Itraconazole + Vismodegib	Drug: vismodegib; Multiple oral doses; Drug: itraconazole; Multiple oral doses
EXPERIMENTAL: D: Fluconazole + Vismodegib	Drug: vismodegib; Multiple oral doses; Drug: fluconazole; Multiple oral doses

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Relative effect of rabeprazole on steady-state pharmacokinetics of vismodegib: Area under the concentration-time curve (AUC)/Steady-state concentration (Css)	up to 12 days
Relative effect of itraconazole on steady-state pharmacokinetics of vismodegib: Area under the concentration-time curve (AUC)/Steady-state concentration (Css)	up to 12 days
Relative effect of fluconazole on the steady-state pharmacokinetics of vismodegib: Area under the concentration-time curve (AUC)/Steady-state concentration (Css)	up to 12 days

Collaborators and Investigators

• Sponsor: Genentech, Inc.

Publications and helpful links

General Publications

• Malhi V, Colburn D, Williams SJ, Hop CE, Dresser MJ, Chandra P, Graham RA. A clinical drug-drug interaction study to evaluate the effect of a proton-pump inhibitor, a combined P-glycoprotein/cytochrome 450 enzyme (CYP)3A4 inhibitor, and a CYP2C9 inhibitor on the pharmacokinetics of vismodegib. Cancer Chemother Pharmacol. 2016 Jul;78(1):41-9. doi: 10.1007/s00280-016-3020-z. Epub 2016 May 6.

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (ACTUAL): May 1, 2013
• Study Completion (ACTUAL): May 1, 2013

Study Registration Dates

• First Submitted: January 17, 2013
• First Submitted That Met QC Criteria: January 17, 2013
• First Posted (ESTIMATE): January 21, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): November 2, 2016
• Last Update Submitted That Met QC Criteria: November 1, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Gastrointestinal Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Anti-Ulcer Agents; Proton Pump Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Rabeprazole; Itraconazole; Fluconazole
• Other Study ID Numbers: GP28465