Mechanistic Investigation Of Intestinal Cytochrome p450 3A4 Following Roux-en-Y Surgery And Its Effect on Plasma Concentrations of Buspirone

This study is to compare intestinal Cytochrome P450 3A4 (CYP3A4) activity in 9-18 month post weight loss surgery Roux-en-Y Gastric Bypass (RYGB) versus control subjects who have not had a weight loss surgery and are of similar age, gender, body mass index as the gastric bypass group. For this purpose, we will compare post-bariatric surgery patients with control subjects on alterations in systemic exposure of buspirone, a CYP3A4 substrate, when administered with grapefruit juice, a selective intestinal CYP3A4 inhibitor.

Study Overview

• Status: Terminated
• Conditions: Gastric Bypass
• Intervention / Treatment: Drug: Buspirone; Drug: Buspirone and Grapefruit Juice

• Study Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or Female
2. Age 18-65 (inclusive, at time of informed consent)
3. No tobacco use in the past three months.
4. Underwent Roux-en-Y Gastric Bypass weight loss surgery 9-18 months prior to study OR has not had a weight loss surgery but matches the gastric bypass patients on age, gender, and BMI.
5. Ability to read, write and understand English.
6. Expresses the ability/willingness to consume grapefruit juice.

Exclusion Criteria:

1. Taking a medication that has a clinically significant interaction with buspirone or grapefruit juice or an interaction that may alter the study data.
2. Hypersensitivity to buspirone or any excipient contained within the dosage forms or grapefruit juice.
3. Inability to tolerate repeated blood draws.
4. Any history of bipolar disorder or a psychotic disorder.
5. Current major depressive disorder or current suicidality.
6. Alcohol or substance dependence in the past year.
7. Currently pregnant or lactating or unwillingness to use medically accepted contraception during study.
8. Taking a medication which significantly alters gastrointesinal transit time.
9. Medical conditon which may increase participant risk with buspirone or grapefruit juice.
10. Self reported history of viral hepatits or HIV.
11. Positive urine drug screen unless documented prescription of a non-interacting medication.
12. Renal impairment as evidenced by an estimated glomerular filtration rate (eGFR) of less than or equal to 60 ml/min/1.73 m2 or other abnormality on a renal panel that the medical provider feels puts the participant at risk.
13. Hepatic insufficiency as defined by any hepatic enzyme greater than 3x the upper limit of normal or other hepatic laboratory abnormalities at the discretion of the medical provider.
14. Any contraindication to bioelectrical impedance analysis (BIA) such as pregnancy, the presence of a pacemaker or other implanted mechanical device.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Buspirone; Buspirone alone	Drug: Buspirone; The primary aim of this study is to compare the relative difference between the area-under-the-curve (AUC) of buspirone alone (buspirone) with the AUC of buspirone in the presence of grapefruit juice (buspirone + GFJ) in patients who underwent RYGB 9-18 months prior versus a control group of participants who have not undergone bariatric surgery.; Drug: Buspirone and Grapefruit Juice; Grapefruit juice will be given before and during buspirone administration to inhibit intestinal CYP3A4.
Active Comparator: Buspirone plus grapefruit juice	Drug: Buspirone; The primary aim of this study is to compare the relative difference between the area-under-the-curve (AUC) of buspirone alone (buspirone) with the AUC of buspirone in the presence of grapefruit juice (buspirone + GFJ) in patients who underwent RYGB 9-18 months prior versus a control group of participants who have not undergone bariatric surgery.; Drug: Buspirone and Grapefruit Juice; Grapefruit juice will be given before and during buspirone administration to inhibit intestinal CYP3A4.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area-under-the-curve	The primary aim of this study is to compare the relative difference between the area-under-the-curve (AUC) of buspirone alone (buspirone) with the AUC of buspirone in the presence of grapefruit juice (buspirone + GFJ) in patients who underwent RYGB 9-18 months prior versus a control group of participants who have not undergone bariatric surgery.	9-18 months following RYGB

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of pharmacokinetic measures compared between buspirone and buspirone with grapefruit juice in participants who have undergone RYGB and nonsurgical control participants.	General pharmacokinetic comparisons (Cmax, Tmax, half-life, etc.) will be made between the two conditions.	9-18 months following RYGB
Compare GLP-2 levels between the buspirone and buspirone with grapefruit juice in participants who have undergone RYGB and nonsurgical control participants.	To compare GLP-2 levels between participants and drug conditions.	9-18 months following RYGB

Collaborators and Investigators

• Sponsor: North Dakota State University
• Collaborators: Neuropsychiatric Research Institute, Fargo, North Dakota

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): June 1, 2018
• Study Completion (Actual): June 1, 2018

Study Registration Dates

• First Submitted: June 22, 2015
• First Submitted That Met QC Criteria: June 24, 2015
• First Posted (Estimate): June 29, 2015

Study Record Updates

• Last Update Posted (Actual): August 24, 2018
• Last Update Submitted That Met QC Criteria: August 22, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: pharmacokinetics; Cytochrome P450 3A4; buspirone
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Serotonin Receptor Agonists; Anti-Anxiety Agents; Buspirone
• Other Study ID Numbers: bus-000