Effects of Posaconazole and Voriconazole on the Pharmacokinetics and Pharmacodynamics of Sublingual Buprenorphine
Condition: Pharmacokinetics and Pharmacodynamics of Sublingual Buprenorphine
Study type: Interventional
Phase: Phase 1

Summary: 
      Variability in drug response can be due to either pharmacokinetic or pharmacodynamic factors.
      The reasons why people differ in pharmacokinetics or pharmacodynamics are manifold and
      include, e.g., genetic factors, diseases, age and concomitantly administered drugs. Oxidation
      reactions are dominant in the metabolism of drugs and cytochrome P-450 enzymes (CYP) have
      been recognized as chief contributors. We have previously shown that drug interactions
      mediated by the inhibition of CYP enzymes may be of major clinical significance.

      This study is aimed to examine the possible interactions of low-dose sublingual buprenorphine
      with posaconazole and voriconazole.

      The study will be conducted using a randomized, balanced cross-over design in three phases.

      Twelve male or female adult non-smoking subjects aged 18-40 years with body weights within
      ±15% of the ideal weight for height will be recruited for the study. The subjects will be
      submitted to physical examination, determination of previous or present chronic diseases, and
      comprehensive laboratory testing to ascertain that they are in good health. The subjects will
      fill in a modified Finnish version of the Abuse Questions to assess their vulnerability for
      opioid abuse. Laboratory screening will include CBC (including hemoglobin, hematocrit,
      differential WBC, platelet count), SGOT, SGPT, alkaline phosphatase, BUN and creatinine, and
      for women a pregnancy test. Urine will be screened for glucose, proteins and drugs with
      addiction potential. Blood pressure in sitting position must be within normal limits. Base
      line ECG must be normal.

      The subjects will be given in a randomized, cross-over, balanced manner at intervals of four
      weeks either placebo, vorikonazole or posakonazole. On day 5, the challenge dose of 0.4 or
      0.6 mg of sublingual buprenorphine (Temgesic, Schering-Plough) will be administered at 11.00,
      i.e. 1 h after the last dose of placebo, voriconazole or posaconazole. The dose is 0.6 mg
      after placebo and 0.4 mg after posaconazole and voriconazole. If necessary, naloxone
      (Naloxone B. Braun, Braun) will be given in sufficient doses to counteract the severe adverse
      effects of buprenorphine. For nausea and vomiting, intravenous tropisetron will used, if
      needed.

      On day 4, a forearm vein will be cannulated with a plastic cannula for blood sampling. Timed
      venous blood samples will be drawn before the administration of buprenorphine and 0.5, 1,
      1.5, 2, 3, 4, 5, 6, 8, 10, 12 and 18-20 hours after administration. Another venous cannula
      will be inserted to the opposite forearm for the intravenous administration of naloxone.
      Urine will be collected for 18-20 hours.

      The psychomotor effects of buprenorphine will be assessed with visual analog scales (Bond and
      Lader 1974) and digit symbol substitution test (Stone 1984) at 1-2 hour intervals up to 12
      hours after buprenorphine administration. Visual analogue scales will be used for the
      following items: alert / drowsy, good / poor performance, no / strong drug effect, unpleasant
      /pleasant feeling, no / extreme nausea. For each pharmacodynamic variable, the area under the
      response-time curve will be determined by trapezoidal rule for 12 hours.

      The analgesic effect of buprenorphine will be evaluated using the cold pressor test.
    


Intervention name(s): Placebo; vorikonazole; posakonazole
Intervention type(s): Drug; Drug; Drug
Intervention description(s): The subjects will be given placebo twice a day for 5 days prior to the study; The subject will be given vorikonazole twice a day for 5 days prior to the study. The dose will be 400 mg twice a day on day one ans 200 mg twice a day on days 2-5.; The subjects will be given posaconazole 400 mg twice a day for 5 days prior to the study.
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Buprenorphine; Vorikonazole; Posakonazole; Interactions