Effects of Voriconazole on the Pharmacokinetics and Pharmacodynamics of Oral Buprenorphine: A Two-phase Cross-over Study in Healthy Subjects
Condition: Healthy
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 (Guengerich 1992). We have previously shown that drug
      interactions mediated by the inhibition of CYP enzymes may be of major clinical significance
      (Olkkola et al. 1993; Olkkola et al. 1994; Varhe et al. 1994; Olkkola et al. 1999; Palkama et
      al. 1999; Jokinen et al. 2000).

      Buprenorphine undergoes extensive first-pass metabolism and has low oral bioavailability of
      15 % (Cone et al. 1984). Bioavailability following sublingual administration of buprenorphine
      is higher, 50-60 % (Nath et al. 1999). After high sublingual doses of buprenorphine (8-24
      mg), peak plasma concentrations are reached in 1 hour (McAleer et al. 2003, Ciraulo et al.
      2006) and after low sublingual doses (0.4 mg) they are reached in approximately 3 h
      (Billingham 1981). Approximately two-thirds of a buprenorphine dose is excreted unchanged,
      and the rest is metabolized in the liver and intestinal wall. N-dealkylation of buprenorphine
      mainly via CYP3A but also CYP2C8 yields norbuprenorphine, and glucuronidation yields
      buprenorphine-3-glucuronide (Cone et al. 984). Norbuprenorphine is excreted in the urine
      after subsequent conjugation. 80-90 % of buprenorphine is excreted by the biliary system and
      enterohepatic circulation (Brewster et al. 1984)

      Although few interaction studies of high-dose buprenorphine and antiretrovirals have been
      conducted (McCance-Katz EF et al. 2007), the effect of CYP3A inhibitors on the
      pharmacokinetics of low-dose buprenorphine is unknown. Because the use of buprenorphine in
      pain management is increasing after the introduction of transdermal buprenorphin patches to
      the market, it is clinically relevant to study and quantify possible interactions of
      buprenorphine with inhibitors of its CYP3A-mediated metabolism such as voriconazole.

      This study is aimed to examine the possible interactions of oral buprenorphine with
      voriconazole.

      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 (Michna et al. 2004) 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.

      Placebo and voriconazole should always be ingested with food, except the first dose on day 5.

      On day 5, the challenge dose of 0.2 or 3.6. mg of oral buprenorphine (Temgesic,
      Schering-Plough) will be administered at 11.00, i.e. 1 h after the last dose of placebo or
      voriconazole. The dose is 3.6 mg after placebo and 0.2 mg after 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.

      The volunteers will fast at least 8 h before the administration of buprenorphine and they
      will have a standard meal 4 h and 8 h afterwards. Ingestion of alcohol, coffee, tea, cola,
      energydrinks and grapefruit juice is not allowed during the test days, nor is smoking
      permitted.

      The interval between the study phases will be four weeks.
    


Intervention name(s): Placebo; Vorikonazole
Intervention type(s): 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.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: Buprenorphine; Vorikonazole; Interactions; Pharmacokinetics; Pharmacodynamics; Voriconazole