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To Evaluate The Effect Of Ketoconazole, Ritonavir and Erythromycin on the Safety and Pharmacokinetics of Avanafil

Primary Purpose

Erectile Dysfunction

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Ritonavir

Ketoconazole

Erythomycin

Avanafil

About this trial

This is an interventional treatment trial for Erectile Dysfunction

Eligibility Criteria

21 Years - 45 Years (Adult)MaleAccepts Healthy Volunteers

Inclusion Criteria:

Males, 21 to 45 years of age (inclusive).
A body weight of at least 50 kg and a body mass index (BMI) between 21 and 28 kg/m2, inclusive
Medically healthy, with clinically insignificant screening results [e.g., laboratory profiles, medical histories, ECGs, physical exam, etc., in the opinion of the investigator.
Subjects are able to communicate with the investigator, and to understand and comply with all requirements of study participation.
Voluntarily consent to participate in the study
The subject must agree not to donate his sperm during and within 3-months of the completion of the study.
All sexually active male subjects and their female partners of childbearing potential must agree to use adequate contraception methods, for the specified time.

Exclusion Criteria:

A history or presence of significant cardiovascular, neurological, hematological, psychiatric, hepatic, gastrointestinal, pulmonary, endocrine, immunologic or renal disease or other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs or place the subjects at increased risk as determined by the investigator.
Any clinically significant laboratory abnormalities as judged by the investigator.
Systolic blood pressure < 90 or >140 mmHg; diastolic blood pressure < 50 or > 90 mmHg at screening or at check-in on day 1 in treatment period 1.
Positive urine drug test and/or positive breath alcohol test.
Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV) at screening.
Any history or presence of alcoholism or drug or substance abuse.
Allergy to or previous adverse events with PDE5 inhibitors, ketoconazole, ritonavir and/or erythromycin or their constituents.
Use of any prescription or over-the-counter (OTC) medication, including herbal products.
Use of any drugs known to have clinical significance in inhibiting or inducing liver enzymes involved in drug metabolism
Blood donation or significant blood loss.
Any use of tobacco or nicotine products within 6 months.
Any history of celiac diseases, food allergies, and those on vegetarian or other diets incompatible with study objectives.
Any subject who received an investigational drug within 30 days .
Clinical judgment by the investigator that the subject should not participate in the study.

Sites / Locations

Research Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Group 1

Group 2

Group 3

Arm Description

Ketoconazole 400 mg qd for 5 days (Days 2-6) plus a single dose of 50 mg avanafil on Days 1 and 6

Erythromycin 500mg every 12 hours for 5 days (Days 2-6) plus a single dose of 200 mg Avanafil on Days 1 and 6.

Ritonavir 300 mg bid for 1 day (Day 2), 400 mg bid for 1 day (Day 3), 600 mg bid for 5 days (Day 4-8) plus a single dose of 50 mg avanafil on Days 1 and 8

Outcomes

Primary Outcome Measures

Evaluate the safety of avanafil when administered with Ketoconazole, ritonavir, or erythromycin and to assess the effect of co-administration of these drugs on the pharmacokinetics of avanafil

Secondary Outcome Measures

Full Information

NCT ID

NCT00770042

First Posted

October 6, 2008

Last Updated

November 30, 2009

Sponsor

VIVUS LLC

1. Study Identification

Unique Protocol Identification Number

NCT00770042

Brief Title

To Evaluate The Effect Of Ketoconazole, Ritonavir and Erythromycin on the Safety and Pharmacokinetics of Avanafil

Official Title

A Phase I, Single-Centre, Open-Label, Randomized, One-sequence Crossover, Three-Group Study to Evaluate the Effect of Ketoconazole, Ritonavir and Erythromicin on the Safety and Pharmacokinetics of Avanafil (TA-1790) in Healthy Male Subjects

Study Type

Interventional

2. Study Status

Record Verification Date

November 2009

Overall Recruitment Status

Completed

Study Start Date

October 2008 (undefined)

Primary Completion Date

November 2008 (Actual)

Study Completion Date

December 2008 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor

VIVUS LLC

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

This study is being conducted to examine the effect of three CYP3A4 inhibitors (ketoconazole, erythromycin and ritonavir) on the single dose pharmacokinetics of avanafil. Ketoconazole and ritonavir are potent inhibitors of CYP3A4 and erythromycin is a moderate CYP3A4 inhibitor. Any interaction that is observed would be predictive of other inhibitors of CYP3A4.

Detailed Description

Rationale: Erectile dysfunction (ED) is the persistent or recurrent inability to attain and maintain penile erection sufficient to permit satisfactory sexual performance. The current first-line treatment for ED consists of oral therapy with phosphodiesterase type 5 (PDE5) inhibitors. These drugs prevents the hydrolysis of cyclic guanosine monophosphate (cGMP), resulting in increased levels of cGMP and decreased Ca+2 concentrations in the smooth muscle cells of the erectile tissues, smooth muscle relaxation and increased blood flow into the penis. The drugs are extensively metabolized in human liver microsomes, and involve the cytochrome P450, CYP2C subfamily and CYP3A4. This enzyme system is readily inhibited by many drugs. When enzymes that metabolize PDE5 inhibitors are inhibited, there may be increased plasma concentrations of the drugs and possible increases in or prolongation of therapeutic and/or adverse effects. Avanafil is a potent and highly specific PDE5 inhibitor that is rapidly absorbed from the gastrointestinal tract and that has a relatively short half-life (0.55-1.2 hours). The formation of the main metabolites of avanafil is catalyzed by CYP3A4. It is possible that the pharmacokinetics of avanafil may be modified by drugs that block the cytochrome P450 enzyme pathways, resulting in significant changes in its pharmacokinetic (PK), efficacy and adverse event profiles. This study is being conducted to examine the effect of three CYP3A4 inhibitors (ketoconazole, erythromycin and ritonavir) on the single dose pharmacokinetics of avanafil. Ketoconazole and ritonavir are potent inhibitors of CYP3A4 and erythromycin is a moderate CYP3A4 inhibitor. Any interaction that is observed would be predictive of other inhibitors of CYP3A4

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Erectile Dysfunction

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

44 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Group 1

Arm Type

Experimental

Arm Description

Ketoconazole 400 mg qd for 5 days (Days 2-6) plus a single dose of 50 mg avanafil on Days 1 and 6

Arm Title

Group 2

Arm Type

Experimental

Arm Description

Erythromycin 500mg every 12 hours for 5 days (Days 2-6) plus a single dose of 200 mg Avanafil on Days 1 and 6.

Arm Title

Group 3

Arm Type

Experimental

Arm Description

Ritonavir 300 mg bid for 1 day (Day 2), 400 mg bid for 1 day (Day 3), 600 mg bid for 5 days (Day 4-8) plus a single dose of 50 mg avanafil on Days 1 and 8

Intervention Type

Drug

Intervention Name(s)

Ritonavir

Intervention Description

Ritonavir 300 mg bid for 1 day (Day 2), 400 mg bid for 1 day (Day 3), 600 mg bid for 5 days (Day 4-8)

Intervention Type

Drug

Intervention Name(s)

Ketoconazole

Intervention Description

Ketoconazole 400 mg qd for 5 days (Days 2-6)

Intervention Type

Drug

Intervention Name(s)

Erythomycin

Intervention Description

Erythromycin 500 mg every 12 hours for 5 days (Days 2-6)

Intervention Type

Drug

Intervention Name(s)

Avanafil

Intervention Description

Avanafil 50 mg on Days 1 and 8

Intervention Type

Drug

Intervention Name(s)

Avanafil

Intervention Description

Avanafil 50 mg on Days 1 and 6

Intervention Type

Drug

Intervention Name(s)

Avanafil

Intervention Description

Avanafil 200mg Days 1 and 6

Primary Outcome Measure Information:

Title

Evaluate the safety of avanafil when administered with Ketoconazole, ritonavir, or erythromycin and to assess the effect of co-administration of these drugs on the pharmacokinetics of avanafil

Time Frame

9 days

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

21 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Males, 21 to 45 years of age (inclusive). A body weight of at least 50 kg and a body mass index (BMI) between 21 and 28 kg/m2, inclusive Medically healthy, with clinically insignificant screening results [e.g., laboratory profiles, medical histories, ECGs, physical exam, etc., in the opinion of the investigator. Subjects are able to communicate with the investigator, and to understand and comply with all requirements of study participation. Voluntarily consent to participate in the study The subject must agree not to donate his sperm during and within 3-months of the completion of the study. All sexually active male subjects and their female partners of childbearing potential must agree to use adequate contraception methods, for the specified time. Exclusion Criteria: A history or presence of significant cardiovascular, neurological, hematological, psychiatric, hepatic, gastrointestinal, pulmonary, endocrine, immunologic or renal disease or other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs or place the subjects at increased risk as determined by the investigator. Any clinically significant laboratory abnormalities as judged by the investigator. Systolic blood pressure < 90 or >140 mmHg; diastolic blood pressure < 50 or > 90 mmHg at screening or at check-in on day 1 in treatment period 1. Positive urine drug test and/or positive breath alcohol test. Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV) at screening. Any history or presence of alcoholism or drug or substance abuse. Allergy to or previous adverse events with PDE5 inhibitors, ketoconazole, ritonavir and/or erythromycin or their constituents. Use of any prescription or over-the-counter (OTC) medication, including herbal products. Use of any drugs known to have clinical significance in inhibiting or inducing liver enzymes involved in drug metabolism Blood donation or significant blood loss. Any use of tobacco or nicotine products within 6 months. Any history of celiac diseases, food allergies, and those on vegetarian or other diets incompatible with study objectives. Any subject who received an investigational drug within 30 days . Clinical judgment by the investigator that the subject should not participate in the study.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Shiyin Yee, PhD

Organizational Affiliation

VIVUS LLC

Official's Role

Study Director

Facility Information:

Facility Name

Research Site

City

Lincoln

State/Province

Nebraska

ZIP/Postal Code

68502

Country

United States

12. IPD Sharing Statement

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To Evaluate The Effect Of Ketoconazole, Ritonavir and Erythromycin on the Safety and Pharmacokinetics of Avanafil

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