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

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

Detailed Description
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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.

Official Title
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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

Conditions
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Healthy

Intervention / Treatment
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* Drug: Buprenorphine transdermal patch
* Drug: Ketoconazole tablet
* Drug: Placebo to match ketoconazole tablet


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 54 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence A<br>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<br>* Buprenorphine 10 mcg/hour patch applied transdermally for 7-day wear.<br>* Other names: Butrans™;Drug: Ketoconazole tablet<br>* Ketoconazole 200 mg tablets taken orally twice daily.<br>Drug: Placebo to match ketoconazole tablet<br>* Placebo to match ketoconazole 200 mg tablets taken orally twice daily.<br>|
| Experimental: Sequence B<br>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<br>* Buprenorphine 10 mcg/hour patch applied transdermally for 7-day wear.<br>* Other names: Butrans™;Drug: Ketoconazole tablet<br>* Ketoconazole 200 mg tablets taken orally twice daily.<br>Drug: Placebo to match ketoconazole tablet<br>* Placebo to match ketoconazole 200 mg tablets taken orally twice daily.<br>|

What is the study measuring?
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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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy subjects, Opioid, Transdermal