To Evaluate The Effect Of Ketoconazole, Ritonavir and Erythromycin on the Safety and Pharmacokinetics of Avanafil
Condition: Erectile Dysfunction
MeSH terms: Erectile Dysfunction
Study type: Interventional
Phase: Phase 1

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
    

Intervention name(s): Ritonavir; Ketoconazole; Erythomycin; Avanafil; Avanafil; Avanafil
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): 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); Ketoconazole 400 mg qd for 5 days (Days 2-6); Erythromycin 500 mg every 12 hours for 5 days (Days 2-6); Avanafil 50 mg on Days 1 and 8; Avanafil 50 mg on Days 1 and 6; Avanafil 200mg Days 1 and 6
Intervention MeSH terms: Ritonavir; Ketoconazole
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment