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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01259115

Enrollment

Registered

2010-12-13

Start date

2002-10-31

Completion date

2003-06-30

Last updated

2014-05-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy

Keywords

Healthy subjects, Opioid, Transdermal

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.

Interventions

DRUGBuprenorphine transdermal patch

Buprenorphine 10 mcg/hour patch applied transdermally for 7-day wear.

DRUGKetoconazole tablet

Ketoconazole 200 mg tablets taken orally twice daily.

DRUGPlacebo to match ketoconazole tablet

Placebo to match ketoconazole 200 mg tablets taken orally twice daily.

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 54 Years

Healthy volunteers

Yes

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.

Design outcomes

Primary

Measure	Time frame	Description
Cmax of Buprenorphine-3-glucuronide With and Without Ketoconazole	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.
AUCt of Buprenorphine-3-glucuronide With and Without Ketoconazole	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	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.
AUCt of Buprenorphine With and Without Ketoconazole.	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.	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.	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	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	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	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	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	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	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.

Secondary

Measure	Time frame	Description
The Number of Participants With Adverse Events (AEs) as a Measure of Safety.	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 \[ECG\]).
CYP3A4 Inhibition by Observation of Plasma Nor-buprenorphine Production Assessed by the Erythromycin Breath Test.	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.

Countries

United States

Participant flow

Recruitment details

21-Oct-2002 (first subject, first visit) to 20-Jun-2003 (last subject, last visit). Study conducted at 1 site in New Orleans, LA.

Pre-assignment details

Healthy male and female subjects aged 18 to 54 years, demonstrating successful inhibition of CYP3A4 using the EBT (erythromycin breath test) probe were randomized.

Participants by arm

Arm	Count
Overall Study Subjects received BTDS 10 with ketoconazole 200 mg or ketoconazole placebo tablets twice daily in period 1; Washout Period for 4 to 18 days; Subjects received BTDS 10 with ketoconazole 200 mg or ketoconazole placebo tablets twice daily in period 2.	20
Total	20

Withdrawals & dropouts

Period	Reason	FG000	FG001
Period 1	Adverse Event	1	0
Period 1	Lost to Follow-up	0	1
Period 1	Protocol Violation	2	0
Period 2	Adverse Event	1	0

Baseline characteristics

Characteristic	Overall Study
Age, Continuous	31.8 years STANDARD_DEVIATION 8.62
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	14 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	6 Participants
Sex: Female, Male Female	4 Participants
Sex: Female, Male Male	16 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	19 / 19	16 / 17
serious Total, serious adverse events	0 / 19	0 / 17

Outcome results

Primary

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.