A Drug-Drug Interaction Study Between Danoprevir/Low-Dose Ritonavir and Cyclosporine in Healthy Volunteers

A Drug-Drug Interaction Study Between Danoprevir/Low-dose Ritonavir and Cyclosporine, a Potent Inhibitor of OATP, in Healthy Subjects

This single-dose, randomized, open-label, 2-sequence, 3-period study will evaluate the effect of cyclosporine on the pharmacokinetics of ritonavir-boosted danoprevir (DNV/r) in healthy volunteers. Subjects will be randomized to one of two treatment sequences to receive a single oral dose of DNV/r or cyclosporine. In treatment period 3, subjects will receive a single oral dose of DNV/r plus cyclosporine. Anticipated time on study is 33 days.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteer
• Intervention / Treatment: Drug: cyclosporine; Drug: danoprevir; Drug: ritonavir

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Lenexa, Kansas, United States, 66219

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female healthy volunteers, 18 to 45 years of age inclusive
• Body mass index (BMI) 18.0 to 32.0 kg/m2
• Weight >/= 50 kg
• Healthy status defined by absence of evidence of any active or chronic disease following detailed medical and surgical history and a complete physical examination
• Nonsmoker
• Females of childbearing potential and males and their female partner(s) of childbearing potential must agree to use 2 forms of contraception, 1 of which must be a barrier method, during the study and for 90 days after the last drug administration (acceptable barrier forms are condom and diaphragm, acceptable non-barrier forms of contraception for this study are non-hormonal intrauterine device and/or spermicide)

Exclusion Criteria:

• Pregnant or lactating females
• Positive results for drugs of abuse in the urine at screening or prior to admission to the clinical site during any study period
• Positive for hepatitis B, hepatitis C or HIV infection
• Current smokers or subjects who have discontinued smoking less than 6 months prior to the first dose of study medication
• Use of hormonal contraceptives (birth control pills, patches or injectable, implantable devices) within 30 days before the first dose of study medication
• Routine chronic use of more than 2 g acetaminophen daily
• Use of any investigational drug or device within 30 days of screening (6 months for biologic therapies) or 5 half-lives of the investigational drug, whichever is longer
• History of clinically significant disease or disorder
• History of clinically significant drug-related allergy (such as anaphylaxis) or hepatotoxicity
• History (within 3 months of screening) of alcohol consumption exceeding 2 standard drinks per day on average (1 standard drink = 10 grams of alcohol)

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: cyclosporine	Drug: cyclosporine; Single oral dose
Experimental: DNV/r+cyclosporine	Drug: cyclosporine; Single oral dose; Drug: danoprevir; Single oral dose; Drug: ritonavir; Single oral dose
Active Comparator: danoprevir+ritonavir	Drug: danoprevir; Single oral dose; Drug: ritonavir; Single oral dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Effect of single dose of cyclosporine on pharmacokinetics of ritonavir-boosted danoprevir: maximum plasma concentration (Cmax)/area under the concentration-time curve (AUC)	16 time points up to 96 hours

Secondary Outcome Measures

Outcome Measure	Time Frame
Effect of single dose of ritonavir-boosted danoprevir on pharmacokinetics of cyclosporine	16 time points up to 96 hours
Safety: Incidence of adverse events	approximately 50 days

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Brennan BJ, Moreira SA, Morcos PN, Navarro MT, Asthappan J, Goelzer P, Weigl P, Smith PF. Pharmacokinetics of a three-way drug interaction between danoprevir, ritonavir and the organic anion transporting polypeptide (OATP) inhibitor ciclosporin. Clin Pharmacokinet. 2013 Sep;52(9):805-13. doi: 10.1007/s40262-013-0077-2.

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Actual): February 1, 2012
• Study Completion (Actual): February 1, 2012

Study Registration Dates

• First Submitted: January 16, 2012
• First Submitted That Met QC Criteria: January 18, 2012
• First Posted (Estimate): January 23, 2012

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; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Protease Inhibitors; Dermatologic Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Antifungal Agents; HIV Protease Inhibitors; Viral Protease Inhibitors; Calcineurin Inhibitors; Ritonavir; Cyclosporine; Cyclosporins
• Other Study ID Numbers: NP27947