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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Purdue Pharma LP
ClinicalTrials.gov Identifier:
NCT01259115
First received: December 10, 2010
Last updated: August 27, 2012
Last verified: August 2012
  Purpose

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


Condition Intervention Phase
Healthy
Drug: Buprenorphine transdermal patch
Drug: Ketoconazole tablet
Drug: Placebo to match ketoconazole tablet
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Purdue Pharma LP:

Primary Outcome Measures:
  • AUCt of Buprenorphine With and Without Ketoconazole. [ Time Frame: BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25 ] [ Designated as safety issue: No ]

    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.


  • AUCinf of Buprenorphine With and Without Ketoconazole. [ Time Frame: BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25 ] [ Designated as safety issue: No ]

    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.


  • Cmax of Buprenorphine With and Without Ketoconazole. [ Time Frame: BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25 ] [ Designated as safety issue: No ]

    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.


  • AUCt of Nor-buprenorphine With and Without Ketoconazole [ Time Frame: BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25 ] [ Designated as safety issue: No ]

    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.


  • AUCinf of Nor-buprenorphine With and Without Ketoconazole [ Time Frame: BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25 ] [ Designated as safety issue: No ]

    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.


  • Cmax of Nor-buprenorphine With and Without Ketoconazole [ Time Frame: BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25 ] [ Designated as safety issue: No ]

    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.


  • AUCt of Nor-buprenorphine Glucuronide With and Without Ketoconazole [ Time Frame: BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25 ] [ Designated as safety issue: No ]

    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.


  • AUCinf of Nor-buprenorphine Glucuronide With and Without Ketoconazole [ Time Frame: BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25 ] [ Designated as safety issue: No ]

    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.


  • Cmax of Nor-buprenorphine Glucuronide With and Without Ketoconazole [ Time Frame: BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25 ] [ Designated as safety issue: No ]

    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.


  • AUCt of Buprenorphine-3-glucuronide With and Without Ketoconazole [ Time Frame: BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25 ] [ Designated as safety issue: No ]

    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.


  • AUCinf of Buprenorphine-3-glucuronide With and Without Ketoconazole [ Time Frame: BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25 ] [ Designated as safety issue: No ]

    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.


  • Cmax of Buprenorphine-3-glucuronide With and Without Ketoconazole [ Time Frame: BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25 ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • CYP3A4 Inhibition by Observation of Plasma Nor-buprenorphine Production Assessed by the Erythromycin Breath Test. [ Time Frame: One time at screening and one time during ketoconazole treatment ] [ Designated as safety issue: No ]
    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.

  • The Number of Participants With Adverse Events (AEs) as a Measure of Safety. [ Time Frame: The first day of study drug administration to 30 days after the last dose of study drug. ] [ Designated as safety issue: Yes ]
    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]).


Enrollment: 20
Study Start Date: October 2002
Study Completion Date: June 2003
Primary Completion Date: June 2003 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: 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.

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.

  Eligibility

Ages Eligible for Study:   18 Years to 54 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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.

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01259115

Locations
United States, Louisiana
Clinical Research Center
New Orleans, Louisiana, United States, 70119
Sponsors and Collaborators
Purdue Pharma LP
  More Information

Additional Information:
Publications:
Responsible Party: Purdue Pharma LP
ClinicalTrials.gov Identifier: NCT01259115     History of Changes
Other Study ID Numbers: BUP1009
Study First Received: December 10, 2010
Results First Received: January 7, 2011
Last Updated: August 27, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Purdue Pharma LP:
Healthy subjects
Opioid
Transdermal

Additional relevant MeSH terms:
Buprenorphine
Ketoconazole
Analgesics, Opioid
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Central Nervous System Depressants
Narcotic Antagonists
Narcotics
14-alpha Demethylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antifungal Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on April 22, 2014