TMC125-TiDP2-C187: A Phase I, Open-label Trial to Investigate the Pharmacokinetic Interaction Between TMC125 and Two Antifungal Agents (Fluconazole and Voriconazole), All at Steady-state in Healthy Subjects.
Condition: HIV; AIDS; Fungal Infection
MeSH terms: Mycoses
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a Phase I, open-label, 3-period crossover trial to investigate the pharmacokinetic
      interaction (process by which a drug is absorbed, distributed, metabolised and eliminated by
      the body) between TMC125 and fluconazole, and between TMC125 and voriconazole.
    

Detailed description: 
      In this Phase I, open-label, 3-period crossover trial the potential pharmacokinetic
      interaction between TMC125 and fluconazole and between TMC125 and voriconazole will be
      investigated. Fluconazole and voriconazole are triazole antifungal agents.

      Fluconazole and voriconazole are inhibitors of CYP isoenzymes 2C19, 2C9 and CYP3A4.
      Fluconazole is metabolized by the liver to a small extent. Approximately 80% of the
      administered fluconazole dose appears in the urine in unchanged form. Voriconazole is
      metabolized by CYP2C19, 2C9 and 3A4. TMC125 is also metabolized by CYP3A, 2C9 and 2C19.
      Because of the effect of fluconazole and voriconazole on the metabolic pathways relevant for
      TMC125 metabolism, concomitant administration of TMC125 and fluconazole or voriconazole might
      increase TMC125 pharmacokinetics. Because of the effect of TMC125 on the metabolic pathways
      relevant for voriconazole metabolism, concomitant administration of TMC125 and voriconazole
      might also modify voriconazole pharmacokinetics. Since the elimination of fluconazole is
      mainly via the kidneys, an effect of TMC125 on fluconazole pharmacokinetics is not expected.
      The current trial aims to assess the 2-way pharmacokinetic interaction between TMC125 and
      fluconazole, and between TMC125 and voriconazole, to provide dosing recommendations for
      combined use in the treatment of HIV infected patients.In this trial the pharmacokinetic
      interaction between TMC125 and fluconazole, and between TMC125 and voriconazole, all at
      steady-state will be investigated in 18 healthy subjects. During the first two sessions, each
      subject will receive 2 treatments (Treatments A and B) in a randomized way. In Treatment A,
      200 mg TMC125 twice a day. will be administered from Day 1 to Day 7 with an additional
      morning dose on Day 8. In Treatment B, 200 mg fluconazole once a day in the morning will be
      administered from Day 1 to Day 16, co-administered with 200 mg TMC125 twice a day from Day 9
      to Day 16.

      These sessions are followed by a third session, Treatment C, in which 400 mg voriconazole
      twice a day will be administered on Day 1 and 200 mg voriconazole twice a day will be
      administered from Day 2 to Day 15, with an additional morning dose on Day 16. From Day 9 to
      Day 15, 200 mg TMC125 twice a day will be co-administered, with an additional morning dose on
      Day 16. All TMC125 and fluconazole intakes will be under fed conditions, within 10 minutes
      after a meal. Voriconazole will be administered 1.5 hour before a meal. Between subsequent
      treatment sessions, there will be a washout period of at least 2 weeks. Full pharmacokinetic
      profiles will be determined for one dosing interval (12 hours) for TMC125 on Day 8 of
      Treatment A and on Day 16 of Treatments B and C. For fluconazole, full pharmacokinetic
      profiles will be determined for one dosing interval (24 hours) on Days 8 and 16 of Treatment
      B. For voriconazole, full pharmacokinetic profiles will be determined for one dosing interval
      (12 hours) on Days 8 and 16 of Treatment C. Safety and tolerability will be monitored
      continuously throughout the trial. Treatment A: 200 mg TMC125 twice daily, orally from Day 1
      to 7 and a morning dose on Day 8. Treatment B: 200 mg fluconazole once daily, orally from Day
      1 to 16, co-administered with 200 mg TMC125 twice daily from Day 9 to 16. Treatment C: 400 mg
      voriconazole twice daily, orally on Day 1 and 200 mg voriconazole twice daily will be
      administered from Day 2 to 15, with a morning dose on Day 16. From Day 9 to 15, 200 mg TMC125
      twice daily will be co-administered, with a morning dose on Day 16.
    

Intervention name(s): TMC125
Intervention type(s): Drug
Intervention MeSH terms: Etravirine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: TMC125-C187; TMC125-TiDP2-C187; HIV; AIDS; Fungal Infection; Pharmacokinetics