NCT00770042

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

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

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 44 (actual)
• Sponsor: VIVUS LLC · Industry
• Sex: Male
• Age: 21 Years – 45 Years
• Healthy volunteers: Accepted

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

Conditions

• Erectile Dysfunction

Interventions

Type	Name	Description
DRUG	Ritonavir	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)
DRUG	Ketoconazole	Ketoconazole 400 mg qd for 5 days (Days 2-6)
DRUG	Erythomycin	Erythromycin 500 mg every 12 hours for 5 days (Days 2-6)
DRUG	Avanafil	Avanafil 50 mg on Days 1 and 8
DRUG	Avanafil	Avanafil 50 mg on Days 1 and 6
DRUG	Avanafil	Avanafil 200mg Days 1 and 6

Timeline

• Start date: 2008-10-01
• Primary completion: 2008-11-01
• Completion: 2008-12-01
• First posted: 2008-10-09
• Last updated: 2009-12-02

Locations

1 site across 1 country: United States