Modernization of in vivo-in Vitro Oral Bioperformance Prediction and Assessment

Modernization of in vivo-in Vitro Oral Bioperformance Prediction and Assessment: A Research Study to Evaluate the Performance of an Ibuprofen Oral Dosage Form in the Gastrointestinal Tract of Healthy Adult Volunteers

In vivo drug dissolution in the gastrointestinal (GI) tract is largely unmeasured. The purpose of this clinical study was to evaluate the in vivo drug dissolution and systemic absorption of the BCS Class IIa drug ibuprofen under fed and fasted conditions by direct sampling of stomach and small intestinal luminal content. Expanding current knowledge of drug dissolution in vivo will help to establish physiologically relevant in vitro models predictive of drug dissolution.

Study Overview

• Status: Completed
• Conditions: Human Gastrointestinal Physiology Data
• Intervention / Treatment: Drug: Single dose of ibuprofen (800 mg tablet); Dietary supplement: Pulmocare, two 8.0 oz (236.6 mL) cans

Detailed Description

This is an in vivo study designed to acquire human gastrointestinal (GI) physiology data from healthy subjects under fasting and fed conditions which are necessary for mechanistic absorption model development. Each subject will be asked to complete two GI tube insertion procedures. Subjects will complete this study twice under the same conditions of the GI tract, either fasting state or fed state, in order to provide intra-subject variability. A minimum of 7 days will separate each GI tube insertion procedure. The objectives of this study are, as follows: Objective #1: To acquire human GI physiology data including GI motility, pH of GI fluids, and GI fluid volume under fasting and fed conditions; Objective #2: To measure drug concentration and calculate drug dissolution in the GI tract in vivo under fasting and fed conditions; Objective #3: To monitor plasma drug concentration and evaluate pharmacokinetics of administered drug during GI tube insertion studies under fasting and fed conditions. These in vivo results will be used to validate in vitro dissolution methods and to support computational and mathematical modeling efforts, in order to develop an oral drug product optimization process that may be applied to future drugs to maximize oral drug safety and efficacy.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adults age 18 to 55.
2. Male or female voluntarily able to give informed consent.

Exclusion Criteria:

1. Adults unable to consent for themselves or mentally incapacitated.
2. Prisoners.
3. Significant clinical illness within 3 weeks prior to Screening.
4. Use of concomitant medications within 2 weeks prior to receiving study drug, including but not limited to prescription drugs, herbal and dietary supplements, over the counter medications, and vitamins. Birth control is permitted.
5. Received an investigational drug within 60 days prior to receiving the study drug.
6. History of gastrointestinal surgery.
7. Surgery within the past 3 months.
8. History of allergy to ibuprofen or other non-steroidal anti-inflammatory drugs (NSAIDs).
9. History of severe allergic diseases including drug allergies, with the exception of seasonal allergies.
10. Any other factor, condition, or disease, including, but not limited to, cardiovascular, renal, hepatic, or gastrointestinal disorders that may, in the opinion of the Investigator, jeopardize the safety of the patient or impact the validity of the study results.
11. History of drug addiction or alcohol abuse within the past 12 months.
12. Pregnant or lactating females.
13. Any clinically significant abnormal lab values during Screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm #1 - Fasting State, 2 study visits; Single dose of ibuprofen (800 mg tablet) administered with 250 mL of water containing phenol red; Washout period of at least 7 days; Single dose of ibuprofen (800 mg tablet) administered with 250 mL of water containing phenol red	Drug: Single dose of ibuprofen (800 mg tablet)
Experimental: Arm #2 - Fed State, 2 study visits; Pulmocare, two 8.0 oz (236.6 mL) cans, followed by single dose of ibuprofen (800 mg tablet) administered with 250 mL of water containing phenol red; Washout period of at least 7 days; Pulmocare, two 8.0 oz (236.6 mL) cans, followed by single dose of ibuprofen (800 mg tablet) administered with 250 mL of water containing phenol red	Drug: Single dose of ibuprofen (800 mg tablet); Dietary supplement: Pulmocare, two 8.0 oz (236.6 mL) cans

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Duodenal Fluid pH in Fasted Compared to Fed Participants Administered a Single Dose of Ibuprofen	The pH of duodenal fluid was measured at multiple timepoints over a 7 hour period. The reported value represents the mean and standard deviation of duodenal fluid pH.	from time 0 to 7 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Duodenal Fluid Concentration of Ibuprofen in Fasted Compared to Fed Participants Administered a Single Dose of Ibuprofen	The concentration of duodenal fluid was measured at multiple timepoints over a 7 hour period. The reported value represents the mean and standard deviation maximum concentration measured in duodenal fluid.	from time 0 to 7 hours
Average Area Under the Plasma Concentration-time Curve (AUC) in Fasted Compared to Fed Participants Administered a Single Dose of Ibuprofen	The plasma concentration of ibuprofen was measured at multiple timepoints over a 24 hour period. The reported value represents the mean and standard deviation of AUC over this time frame.	from time 0 to 24 hours

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: Food and Drug Administration (FDA)
• Investigators: Principal Investigator: Duxin Sun, Ph.D., University of Michigan

Publications and helpful links

General Publications

• Yu A, Jackson T, Tsume Y, Koenigsknecht M, Wysocki J, Marciani L, Amidon GL, Frances A, Baker JR, Hasler W, Wen B, Pai A, Sun D. Mechanistic Fluid Transport Model to Estimate Gastrointestinal Fluid Volume and Its Dynamic Change Over Time. AAPS J. 2017 Nov;19(6):1682-1690. doi: 10.1208/s12248-017-0145-x. Epub 2017 Oct 4.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): July 1, 2017

Study Registration Dates

• First Submitted: May 13, 2016
• First Submitted That Met QC Criteria: June 15, 2016
• First Posted (Estimate): June 21, 2016

Study Record Updates

• Last Update Posted (Actual): December 8, 2017
• Last Update Submitted That Met QC Criteria: November 3, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Ibuprofen
• Other Study ID Numbers: FDA_13-RFQ-1116088; HHSF223201310144C (Other Grant/Funding Number: U.S. Food and Drug Administration)