Buprenorphine Disposition and CYP3A

Influence of CYP3A Modulation on Buprenorphine Disposition and Clinical Effects

To evaluate role of CYP3A in buprenorphine disposition and effect

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Buprenorphine Control; Drug: Buprenorphine + Rifampin; Drug: Buprenorphine + Grapefruit juice; Drug: Buprenorphine + Ketoconazole

Detailed Description

Subjects will be studied during a maximum of seven occasions.

Study drugs are intravenous buprenorphine (0.025-0.2 mg infused over 1 hr) and sublingual buprenorphine (2-4 mg), with 1-3 week washout between sessions.

Sessions 1&2: Control (no pretreatment) - intravenous and sublingual buprenorphine. Some subjects will only undergo session 1 (IV)

Sessions 3&4: Liver and gut CYP3A induction (rifampin 600 mg daily), intravenous and sublingual buprenorphine

Session 5: Gut only CYP3A inhibition (grapefruit juice the night before), sublingual buprenorphine

Sessions 6&7: Liver and gut CYP3A inhibition (ketoconazole 400 mg daily), intravenous and sublingual buprenorphine

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 48 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Each subject must meet all of the following criteria:

1. Male or non-pregnant female volunteer, 18-50 yr old
2. Good general health with no known major medical conditions
3. BMI < 33
4. Provide informed consent

Exclusion Criteria:

Subjects will not be enrolled if any of the following criteria exist:

1. Known history of liver or kidney disease
2. Use of prescription or non-prescription medications, herbals or foods known to be metabolized by or affect CYP3A activity (this includes the use of oral contraceptives).
3. Females who are pregnant or nursing
4. Known history of drug or alcohol addiction (prior or present addiction or addiction treatment)
5. Direct physical access to and routine handling of addicting drugs in the regular course of duty (this is a routine exclusion from studies of drugs with addiction potential)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Healthy males and non-pregnant females; Subjects will be studied during a maximum of seven occasions. Study drugs are intravenous buprenorphine (0.025-0.2 mg infused over 1 hr) and sublingual buprenorphine (2-4 mg), with 1-3 week washout between sessions. Sessions 1&2: Control (no pretreatment) - intravenous and sublingual buprenorphine. Some subjects will only undergo session 1 (IV) Sessions 3&4: Liver and gut CYP3A induction (rifampin 600 mg daily), intravenous and sublingual buprenorphine Session 5: Gut only CYP3A inhibition (grapefruit juice the night before), sublingual buprenorphine Sessions 6&7: Liver and gut CYP3A inhibition (ketoconazole 400 mg daily), intravenous and sublingual buprenorphine

Drug: Buprenorphine Control; Control (no pretreatment) - intravenous and sublingual buprenorphine. Some subjects will only undergo session 1 (IV); Drug: Buprenorphine + Rifampin; Liver and gut CYP3A induction (rifampin 600 mg daily), intravenous and sublingual buprenorphine; Drug: Buprenorphine + Grapefruit juice; Gut only CYP3A inhibition (grapefruit juice the night before), sublingual buprenorphine; Drug: Buprenorphine + Ketoconazole; Liver and gut CYP3A inhibition (ketoconazole 400 mg daily), intravenous and sublingual buprenorphine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Plasma Cmax of Buprenorphine	96 hr

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Evan Kharasch, MD, PhD, Washington University School of Medicine

Publications and helpful links

General Publications

• Heel RC, Brogden RN, Speight TM, Avery GS. Buprenorphine: a review of its pharmacological properties and therapeutic efficacy. Drugs. 1979 Feb;17(2):81-110. doi: 10.2165/00003495-197917020-00001.
• Pickworth WB, Johnson RE, Holicky BA, Cone EJ. Subjective and physiologic effects of intravenous buprenorphine in humans. Clin Pharmacol Ther. 1993 May;53(5):570-6. doi: 10.1038/clpt.1993.72.
• Walsh SL, Preston KL, Bigelow GE, Stitzer ML. Acute administration of buprenorphine in humans: partial agonist and blockade effects. J Pharmacol Exp Ther. 1995 Jul;274(1):361-72.

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (Actual): March 29, 2014
• Study Completion (Actual): March 29, 2014

Study Registration Dates

• First Submitted: April 10, 2012
• First Submitted That Met QC Criteria: April 11, 2012
• First Posted (Estimate): April 12, 2012

Study Record Updates

• Last Update Posted (Actual): January 22, 2020
• Last Update Submitted That Met QC Criteria: January 8, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: buprenorphine CYP3A
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Analgesics; Sensory System Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Bacterial Agents; Analgesics, Opioid; Narcotics; Narcotic Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Leprostatic Agents; Hormone Antagonists; Cytochrome P-450 Enzyme Inducers; Antifungal Agents; Steroid Synthesis Inhibitors; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; 14-alpha Demethylase Inhibitors; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Buprenorphine; Ketoconazole; Rifampin
• Other Study ID Numbers: 201104146