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

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ClinicalTrials.gov Identifier: NCT01259115
Recruitment Status : Completed
First Posted : December 13, 2010
Results First Posted : January 26, 2011
Last Update Posted : May 19, 2014
Sponsor:
Information provided by (Responsible Party):
Purdue Pharma LP

Tracking Information
First Submitted Date  ICMJE December 10, 2010
First Posted Date  ICMJE December 13, 2010
Results First Submitted Date  ICMJE January 7, 2011
Results First Posted Date  ICMJE January 26, 2011
Last Update Posted Date May 19, 2014
Study Start Date  ICMJE October 2002
Actual Primary Completion Date June 2003   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 24, 2011)
  • AUCt of Buprenorphine With and Without Ketoconazole. [ Time Frame: BTDS Days 3, 10, 19, and 26; ketoconazole or placebo Days 9 and 25 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 10, 2010)
Comparison of the pharmacokinetics of buprenorphine and its metabolites in the presence and absence of ketoconazole. [ Time Frame: Multiple blood samples over 12 days in each period ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 24, 2011)
  • 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 ]
    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. ]
    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]).
Original Secondary Outcome Measures  ICMJE
 (submitted: December 10, 2010)
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. ]
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]).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Buprenorphine Accumulation and Description of Its Metabolites During Co-Medication of Buprenorphine Transdermal System (BTDS) and Ketoconazole
Official Title  ICMJE 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
Brief Summary The purpose of this study is to assess the pharmacokinetics of buprenorphine and its metabolites in the presence and absence of ketoconazole.
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Condition  ICMJE Healthy
Intervention  ICMJE
  • 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.
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Buprenorphine transdermal patch
    • Drug: Ketoconazole tablet
    • Drug: Placebo to match ketoconazole tablet
  • 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.
    Interventions:
    • Drug: Buprenorphine transdermal patch
    • Drug: Ketoconazole tablet
    • Drug: Placebo to match ketoconazole tablet
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: 10.2165/11633060-000000000-00000.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 10, 2010)
20
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE June 2003
Actual Primary Completion Date June 2003   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 54 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01259115
Other Study ID Numbers  ICMJE BUP1009
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Purdue Pharma LP
Study Sponsor  ICMJE Purdue Pharma LP
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Purdue Pharma LP
Verification Date May 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP