Ignite Creation Date:
2024-05-05 @ 11:59 PM
Last Modification Date:
2024-10-26 @ 10:43 AM
Study NCT ID:
NCT01466803
Status:
COMPLETED
Last Update Posted:
2013-04-30
First Post:
2011-11-03
Brief Title:
Effects of Voriconazole on the Pharmacokinetics and Pharmacodynamics of Oral Buprenorphine A Two-phase Cross-over Study in Healthy Subjects
Sponsor:
Turku University Hospital
Organization:
Turku University Hospital
Study Overview
Official Title:
Effects of Voriconazole on the Pharmacokinetics and Pharmacodynamics of Oral Buprenorphine A Two-phase Cross-over Study in Healthy Subjects
Status:
COMPLETED
Status Verified Date:
2013-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 eg 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 04 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 02 or 36 mg of oral buprenorphine Temgesic Schering-Plough will be administered at 1100 ie 1 h after the last dose of placebo or voriconazole The dose is 36 mg after placebo and 02 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
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 04 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 02 or 36 mg of oral buprenorphine Temgesic Schering-Plough will be administered at 1100 ie 1 h after the last dose of placebo or voriconazole The dose is 36 mg after placebo and 02 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
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None