Buprenorphine Accumulation and Description of Its Metabolites During Co-Medication of Buprenorphine Transdermal System (BTDS) and Ketoconazole

A Single Center, Randomized, Double-Blind, Crossover Study to Assess Buprenorphine Accumulation and Description of Its Metabolites During Co-Medication of BTDS and Ketoconazole, Used As a CYP3A4 Inhibitor, in Healthy Subjects

The purpose of this study is to assess the pharmacokinetics of buprenorphine and its metabolites in the presence and absence of ketoconazole.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Buprenorphine transdermal patch; Drug: Ketoconazole tablet; Drug: Placebo to match ketoconazole tablet

Detailed Description

To assess the pharmacokinetics of buprenorphine and its metabolites (nor-buprenorphine, buprenorphine 3 glucuronide and nor-buprenorphine glucuronide) in the presence and absence of ketoconazole.

Safety evaluation of BTDS and ketoconazole in healthy subjects.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Louisiana
    • New Orleans, Louisiana, United States, 70119
      • Clinical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 54 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria Include:

• Males and females aged 18 to 54 years.
• Demonstrate CYP 3A4 inhibition by ketoconazole with the erythromycin breath test (EBT) probe during the screening period.
• Female subjects who are surgically sterile or at least two years postmenopausal.
• Have a body weight ranging from 60 to 100 kilograms (kg), and are within 15% of optimum for height and body frame, as determined from parameters of the Metropolitan Life Index.
• Agree not to use any medication, including over-the-counter (OTC) medications, vitamins, mineral or herbal supplements, during the course of the study and for at least 7 days prior to the start of the study.
• Generally in good health as evidenced by lack of significant abnormal finding(s) in medical history, physical examination, clinical laboratory tests, vital signs, and electrocardiogram (ECG).
• Willing to follow dietary restrictions, including abstention from grapefruit, herbal dietary supplements especially those containing St. John's Wort, and caffeine containing products.
• Willing to refrain from strenuous exercise or contact sports during the study

Exclusion Criteria Include:

• Any history of hypersensitivity to buprenorphine, any excipient of BTDS, ketoconazole, or other opioids, psychotropic or hypnotic drugs.
• Any medical or surgical conditions that might interfere with transdermal drug absorption (eg skin lesions at site of application), gastrointestinal drug absorption (eg, delayed gastric emptying, malabsorption syndromes), distribution (eg, obesity), metabolism, or excretion (eg, hepatitis, glomerulonephritis).
• Any history of significant active medical illness such as:
• History or presence of liver disease or injury as indicated by increase of aspartate transaminase (AST) or alanine transaminase (ALT) or bilirubin above the normal levels
• History or presence of renal insufficiency as indicated by abnormal creatinine or blood urea nitrogen (BUN) or abnormal urinary constituent (eg, albumin).
• Any other clinically significant laboratory abnormalities.
• At risk of transmitting infection via blood samples such as:
• producing a positive human immunodeficiency virus (HIV) test at screening or having participated in a high risk activity for contracting HIV
• producing a positive Hepatitis B surface antigen test at screening
• producing a positive Hepatitis C antibody test at screening.
• Any personal or family history of prolonged QT interval or disorders of cardiac rhythm, including heartbeat below 45, unless agreed upon by sponsor.
• Females who are breastfeeding.
• Females with a positive serum or urine pregnancy test at screening or prior to dosing, respectively.

Other protocol-specific exclusion/inclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Sequence A; BTDS 10 with ketoconazole 200 mg tablets twice daily in period 1 and BTDS 10 with ketoconazole placebo tablets twice daily in period 2.	Drug: Buprenorphine transdermal patch; Buprenorphine 10 mcg/hour patch applied transdermally for 7-day wear.; Other Names: Butrans™; Drug: Ketoconazole tablet; Ketoconazole 200 mg tablets taken orally twice daily.; Drug: Placebo to match ketoconazole tablet; Placebo to match ketoconazole 200 mg tablets taken orally twice daily.
EXPERIMENTAL: Sequence B; BTDS 10 with ketoconazole placebo tablets twice daily in period 1 and BTDS 10 with ketoconazole 200 mg twice daily in period 2.	Drug: Buprenorphine transdermal patch; Buprenorphine 10 mcg/hour patch applied transdermally for 7-day wear.; Other Names: Butrans™; Drug: Ketoconazole tablet; Ketoconazole 200 mg tablets taken orally twice daily.; Drug: Placebo to match ketoconazole tablet; Placebo to match ketoconazole 200 mg tablets taken orally twice daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUCt of Buprenorphine With and Without Ketoconazole.	AUCt (area under the plasma concentration-time curve from hour 0 to the last measurable plasma concentration) of buprenorphine transdermal patch 10 with and without ketoconazole 200 mg oral twice daily. Period 1, subjects wore BTDS 10 patch between days 3 and 10 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 1 and 11. Washout period of 4 to 18 days. Period 2, subjects wore BTDS 10 patch between days 19 and 26 and took ketoconazole (200 mg orally twice daily) or Ketoconazole placebo (orally twice daily) between days 17 and 27.	BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25
AUCinf of Buprenorphine With and Without Ketoconazole.	AUCinf (the area under the plasma-concentration time course profile from time 0 [dosing] to infinity) of buprenorphine transdermal patch 10 with and without ketoconazole 200 mg oral twice daily. Period 1, subjects wore BTDS 10 patch between days 3 and 10 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 1 and 11. Washout period of 4 to 18 days. Period 2, subjects wore BTDS 10 patch between days 19 and 26 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 17 and 27.	BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25
Cmax of Buprenorphine With and Without Ketoconazole.	Cmax (maximum observed plasma concentration) of buprenorphine transdermal patch 10 with and without ketoconazole 200 mg oral tablets twice daily, Period 1, subjects wore BTDS 10 patch between days 3 and 10 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 1 and 11. Washout period of 4 to 18 days. Period 2, subjects wore BTDS 10 patch between days 19 and 26 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 17 and 27.	BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25
AUCt of Nor-buprenorphine With and Without Ketoconazole	For nor-buprenorphine pharmacokinetic metric, AUCt (area under the plasma concentration-time curve from hour 0 to the last measurable plasma concentration). Period 1, subjects wore BTDS 10 patch between days 3 and 10 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 1 and 11. Washout period of 4 to 18 days. Period 2, subjects wore BTDS 10 patch between days 19 and 26 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 17 and 27.	BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25
AUCinf of Nor-buprenorphine With and Without Ketoconazole	For nor-buprenorphine pharmacokinetic metric, AUCinf (the area under the plasma-concentration time course profile from time 0 [dosing] to infinity). Period 1, subjects wore BTDS 10 patch between days 3 and 10 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 1 and 11. Washout period of 4 to 18 days. Period 2, subjects wore BTDS 10 patch between days 19 and 26 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 17 and 27.	BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25
Cmax of Nor-buprenorphine With and Without Ketoconazole	For nor-buprenorphine pharmacokinetic metric, Cmax (maximum observed plasma concentration), log transformed data were analyzed. Period 1, subjects wore BTDS 10 patch between days 3 and 10 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 1 and 11. Washout period of 4 to 18 days. Period 2, subjects wore BTDS 10 patch between days 19 and 26 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 17 and 27.	BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25
AUCt of Nor-buprenorphine Glucuronide With and Without Ketoconazole	For nor-buprenorphine glucuronide pharmacokinetic metrics, AUCt (area under the plasma concentration-time curve from hour 0 to the last measurable plasma concentration), log transformed data were analyzed. Period 1, subjects wore BTDS 10 patch between days 3 and 10 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 1 and 11. Washout period of 4 to 18 days. Period 2, subjects wore BTDS 10 patch between days 19 and 26 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 17 and 27.	BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25
AUCinf of Nor-buprenorphine Glucuronide With and Without Ketoconazole	For nor-buprenorphine glucuronide pharmacokinetic metrics, AUCinf (the area under the plasma-concentration time course profile from time 0 [dosing] to infinity) log transformed data were analyzed. Period 1, subjects wore BTDS 10 patch between days 3 and 10 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 1 and 11. Washout period of 4 to 18 days. Period 2, subjects wore BTDS 10 patch between days 19 and 26 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 17 and 27.	BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25
Cmax of Nor-buprenorphine Glucuronide With and Without Ketoconazole	For nor-buprenorphine glucuronide pharmacokinetic metric, Cmax (maximum observed plasma concentration), log transformed data were analyzed. Period 1, subjects wore BTDS 10 patch between days 3 and 10 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 1 and 11. Washout period of 4 to 18 days. Period 2, subjects wore BTDS 10 patch between days 19 and 26 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 17 and 27.	BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25
AUCt of Buprenorphine-3-glucuronide With and Without Ketoconazole	For buprenorphine-3-glucuronide pharmacokinetic metric, AUCt (area under the plasma concentration-time curve from hour 0 to the last measurable plasma concentration), log transformed data were analyzed. Period 1, subjects wore BTDS 10 patch between days 3 and 10 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 1 and 11. Washout period of 4 to 18 days. Period 2, subjects wore BTDS 10 patch between days 19 and 26 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 17 and 27.	BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25
AUCinf of Buprenorphine-3-glucuronide With and Without Ketoconazole	For buprenorphine-3-glucuronide pharmacokinetic metric, AUCinf (the area under the plasma-concentration time course profile from time 0 [dosing] to infinity), log transformed data were analyzed. Period 1, subjects wore BTDS 10 patch between days 3 and 10 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 1 and 11. Washout period of 4 to 18 days. Period 2, subjects wore BTDS 10 patch between days 19 and 26 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 17 and 27.	BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25
Cmax of Buprenorphine-3-glucuronide With and Without Ketoconazole	For buprenorphine-3-glucuronide pharmacokinetic metric, Cmax (maximum observed plasma concentration), log transformed data were analyzed. Period 1, subjects wore BTDS 10 patch between days 3 and 10 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 1 and 11. Washout period of 4 to 18 days. Period 2, subjects wore BTDS 10 patch between days 19 and 26 and took ketoconazole (200 mg orally twice daily) or ketoconazole placebo (orally twice daily) between days 17 and 27.	BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CYP3A4 Inhibition by Observation of Plasma Nor-buprenorphine Production Assessed by the Erythromycin Breath Test.	As part of subject screening, Erythromycin Breath Tests (EBT) were done on all potential subjects (enrolled population). CYP 3A4 inhibition was calculated by taking the difference of the baseline 14C erythromycin metabolism, subtracting the 14C erythromycin metabolism during ketoconazole treatment, dividing this difference by the baseline 14C erythromycin metabolism, and multiplying by 100 to express results in the form of percent inhibition. CYP3A4 inhibition was only done when subjects were on ketoconazole.	One time at screening and one time during ketoconazole treatment
The Number of Participants With Adverse Events (AEs) as a Measure of Safety.	Safety assessments consisted of monitoring and recording medical history, physical examinations, vital signs (including temperature, heart rate, blood pressure and respiratory rate), reports of adverse experiences, and laboratory abnormalities (including electrocardiogram [ECG]).	The first day of study drug administration to 30 days after the last dose of study drug.

Collaborators and Investigators

• Sponsor: Purdue Pharma LP

Publications and helpful links

General Publications

• Kapil RP, Cipriano A, Michels GH, Perrino P, O'Keefe SA, Shet MS, Colucci SV, Noveck RJ, Harris SC. Effect of ketoconazole on the pharmacokinetic profile of buprenorphine following administration of a once-weekly buprenorphine transdermal system. Clin Drug Investig. 2012 Sep 1;32(9):583-92. doi: 10.1007/BF03261913.

Helpful Links

• Product Information

Study record dates

Study Major Dates

• Study Start: October 1, 2002
• Primary Completion (ACTUAL): June 1, 2003
• Study Completion (ACTUAL): June 1, 2003

Study Registration Dates

• First Submitted: December 10, 2010
• First Submitted That Met QC Criteria: December 10, 2010
• First Posted (ESTIMATE): December 13, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): May 19, 2014
• Last Update Submitted That Met QC Criteria: May 8, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: Transdermal; Opioid; Healthy subjects
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Analgesics, Opioid; Narcotics; Narcotic Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Buprenorphine; Ketoconazole
• Other Study ID Numbers: BUP1009