NCT01466803

Effects of Voriconazole on the Pharmacokinetics and Pharmacodynamics of Oral Buprenorphine: A Two-phase Cross-over Study in Healthy Subjects

Completed Phase 1 Last updated 27 April 2013

What this trial tests

Phase 1 trial testing Placebo in Healthy in 12 participants. Completed in 1 December 2011.

Timeline

1 October 2011

Primary endpoint
1 December 2011

1 December 2011

Quick facts

Lead sponsor	Turku University Hospital
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	crossover
Masking	single
Primary purpose	basic science
Enrollment	12
Start date	1 October 2011
Primary completion	1 December 2011
Estimated completion	1 December 2011
Sites	1 location across Finland

Drugs / interventions tested

• Placebo
• Vorikonazole — full drug profile →

Conditions studied

• Healthy — all drugs for Healthy →

Sponsor

Turku University Hospital

Who can join

Adults 18 to 40, any sex, with Healthy. Healthy volunteers can join.

What's being measured

Primary outcomes are the specific endpoints the trial is designed to prove or disprove.

• Concentration of buprenorphine and its metabolites in plasma and urine Concentration of buprenorphine and its metabolites in plasma and urine
  Time frame: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 and 20 hours after administration of buprenorphine

Sponsor's own description

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

Publications & conference data

No peer-reviewed publications indexed yet for this trial. Completed trials usually publish results within 12-18 months.