Correlation of Mesalamine Pharmacokinetics With Local Availability

This study is designed to provide data to the FDA correlating pharmacokinetics with local availability of medications within the gastrointestinal tract. This study will support the establishment of scientifically based standards for evaluating drugs which act locally within the gastrointestinal tract. Specific objectives of this study are to: (1) quantify how the plasma concentrations of mesalamine, an agent used to treat inflammatory bowel disease, are correlated with the concentrations in gastrointestinal fluids; and (2) improve the physiologically based models for drug absorption from the intestine. Information from this study in concert with in vitro dissolution data will be used to evaluate in vivo-in vitro correlation (IVIVC) for concentrations in plasma and intestinal lumen and dissolution of mesalamine products.

Study Overview

• Status: Completed
• Conditions: Local Drug Concentration in Gastrointestinal Tract
• Intervention / Treatment: Drug: Pentasa 500 mg capsule x 2 with 240 mL water; single dose; Drug: Apriso 375 mg capsule x 3 with 240 mL water; single dose; Drug: Lialda 1200 mg tablet x 1 with 240 mL water; single dose; Drug: Delzicol 100 mg mesalamine x 1 with 245 mL water; single dose

Detailed Description

This study evaluated the pharmacokinetics of mesalamine and its major metabolite of mesalamine known as N-acetyl-mesalamine in plasma. Mesalamine is available in different formulations that control the rate at which they are released in the gastrointestinal tract. Three formulations of mesalamine, Pentasa, Apriso, and Lialda, were studied in the crossover phase, while an oral solution formulation of mesalamine was studied in the single-arm phase. Each subject participated in a crossover phase study with one of the three formulations assigned at random using block randomization. Then the subject entered the single-arm phase study. After participation in one crossover phase study and one single-arm phase study, the subject could opt to participate in crossover phase studies using the other formulations also chosen at random until all three formulations were studied. The single-arm phase study was not repeated on returning subjects who participated in more than one crossover phase study.

• Study Type: Interventional
• Enrollment (Actual): 30
• 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.
3. Body mass index (BMI) 18.5 to 35.

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. Oral contraception is permitted.
5. History of gastrointestinal surgery.
6. History of allergy to non-steroidal anti-inflammatory drugs (NSAIDs) or to any of the ingredients of Asacol, Pentasa, Apriso, or Lialda.
7. History of severe allergic diseases including drug allergies, with the exception of seasonal allergies.
8. 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.
9. History of drug addiction or alcohol abuse within the past 12 months.
10. Pregnant or lactating females.
11. Surgery within the past 3 months.
12. Received an investigational drug within 60 days prior to receiving the study drug.
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: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: Pentasa then Delzicol then Apriso then Lialda; Pentasa 500 mg capsule x 2 with 240 mL water, single dose.; Washout period of 10 days.; Delzicol 100 mg mesalamine x 1 with 245 mL water, single dose.; Washout period of 10 days.; Apriso 375 mg capsule x 3 with 240 mL water, single dose.; Washout period of 10 days.; Lialda 1200 mg tablet x 1 with 240 mL water, single dose.	Drug: Pentasa 500 mg capsule x 2 with 240 mL water; single dose; Drug: Apriso 375 mg capsule x 3 with 240 mL water; single dose; Drug: Lialda 1200 mg tablet x 1 with 240 mL water; single dose; Drug: Delzicol 100 mg mesalamine x 1 with 245 mL water; single dose
Experimental: Arm 2: Pentasa then Delzicol then Lialda then Apriso; Pentasa 500 mg capsule x 2 with 240 mL water, single dose.; Washout period of 10 days.; Delzicol 100 mg mesalamine x 1 with 245 mL water, single dose.; Washout period of 10 days.; Lialda 1200 mg tablet x 1 with 240 mL water, single dose.; Washout period of 10 days.; Apriso 375 mg capsule x 3 with 240 mL water, single dose.	Drug: Pentasa 500 mg capsule x 2 with 240 mL water; single dose; Drug: Apriso 375 mg capsule x 3 with 240 mL water; single dose; Drug: Lialda 1200 mg tablet x 1 with 240 mL water; single dose; Drug: Delzicol 100 mg mesalamine x 1 with 245 mL water; single dose
Experimental: Arm 3: Apriso then Delzicol then Pentasa then Lialda; Apriso 375 mg capsule x 3 with 240 mL water, single dose.; Washout period of 10 days.; Delzicol 100 mg mesalamine x 1 with 245 mL water, single dose.; Washout period of 10 days.; Pentasa 500 mg capsule x 2 with 240 mL water, single dose.; Washout period of 10 days.; Lialda 1200 mg tablet x 1 with 240 mL water, single dose.	Drug: Pentasa 500 mg capsule x 2 with 240 mL water; single dose; Drug: Apriso 375 mg capsule x 3 with 240 mL water; single dose; Drug: Lialda 1200 mg tablet x 1 with 240 mL water; single dose; Drug: Delzicol 100 mg mesalamine x 1 with 245 mL water; single dose
Experimental: Arm 4: Apriso then Delzicol then Lialda then Pentasa; Apriso 375 mg capsule x 3 with 240 mL water, single dose.; Washout period of 10 days.; Delzicol 100 mg mesalamine x 1 with 245 mL water, single dose.; Washout period of 10 days.; Lialda 1200 mg tablet x 1 with 240 mL water, single dose.; Washout period of 10 days.; Pentasa 500 mg capsule x 2 with 240 mL water, single dose.	Drug: Pentasa 500 mg capsule x 2 with 240 mL water; single dose; Drug: Apriso 375 mg capsule x 3 with 240 mL water; single dose; Drug: Lialda 1200 mg tablet x 1 with 240 mL water; single dose; Drug: Delzicol 100 mg mesalamine x 1 with 245 mL water; single dose
Experimental: Arm 5: Lialda then Delzicol then Pentasa then Apriso; Lialda 1200 mg tablet x 1 with 240 mL water, single dose.; Washout period of 10 days.; Delzicol 100 mg mesalamine x 1 with 245 mL water, single dose.; Washout period of 10 days.; Pentasa 500 mg capsule x 2 with 240 mL water, single dose.; Washout period of 10 days.; Apriso 375 mg capsule x 3 with 240 mL water, single dose.	Drug: Pentasa 500 mg capsule x 2 with 240 mL water; single dose; Drug: Apriso 375 mg capsule x 3 with 240 mL water; single dose; Drug: Lialda 1200 mg tablet x 1 with 240 mL water; single dose; Drug: Delzicol 100 mg mesalamine x 1 with 245 mL water; single dose
Experimental: Arm 6: Lialda then Delzicol then Apriso then Pentasa; Lialda 1200 mg tablet x 1 with 240 mL water, single dose.; Washout period of 10 days.; Delzicol 100 mg mesalamine x 1 with 245 mL water, single dose.; Washout period of 10 days.; Apriso 375 mg capsule x 3 with 240 mL water, single dose.; Washout period of 10 days.; Pentasa 500 mg capsule x 2 with 240 mL water, single dose.	Drug: Pentasa 500 mg capsule x 2 with 240 mL water; single dose; Drug: Apriso 375 mg capsule x 3 with 240 mL water; single dose; Drug: Lialda 1200 mg tablet x 1 with 240 mL water; single dose; Drug: Delzicol 100 mg mesalamine x 1 with 245 mL water; single dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The AUC of Mesalamine in Plasma	The AUC is the area under the concentration-time curve from time 0 to last time point. The data are organized by the different drug formulations of mesalamine, which include Pentasa (0 to 72 hours), Apriso (0 to 72 hours), Lialda (0 to 96 hours), and Delzicol (0 to 24 hours). The AUC is measured in units of nanomoles of mesalamine per liter of plasma (nM) multiplied by time in hours (nM*h). The AUC results are reported over the time-period because this provides a more meaningful comparison of potential differences in the bioequivalence of formulations.	0 hours pre-dose and up to 96 hours post-dose
The AUC of Metabolite (N-acetyl-mesalamine) in Plasma	The AUC is the area under the concentration-time curve from time 0 to last time point. The data are organized by the different drug formulations of mesalamine, which include Pentasa (0 to 72 hours), Apriso (0 to 72 hours), Lialda (0 to 96 hours), and Delzicol (0 to 24 hours). The AUC is measured in units of nanomoles of N-acetyl-mesalamine per liter of plasma (nM) multiplied by time in hours (nM*h). The AUC results are reported over the time-period because this provides a more meaningful comparison of potential differences in the bioequivalence of formulations.	0 hours pre-dose and up to 96 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The AUC of Mesalamine in Distal Jejunum	The AUC is the area under the concentration-time curve from time 0 to 7 hours. The data are organized by the different drug formulations of mesalamine, which include Pentasa, Apriso, and Lialda. The AUC is measured in units of micromoles of mesalamine per liter of plasma (µM) multiplied by time in hours (µM*h).The AUC results are reported over the time-period because this provides a more meaningful comparison of potential differences in the bioequivalence of formulations. The solution formulation (Delzicol) was not administered in this portion of the study. Therefore no results pertaining to the solution formulation are included in this outcome measure.	0 hours pre-dose and up to 7 hours post-dose
The AUC of Metabolite (N-acetyl-mesalamine) in Distal Jejunum	The AUC is the area under the concentration-time curve from time 0 to 7 hours. The data are organized by the different drug formulations of mesalamine, which include Pentasa, Apriso, and Lialda. The AUC is measured in units of micromoles of mesalamine per liter of plasma (µM) multiplied by time in hours (µM*h).The AUC results are reported over the time-period because this provides a more meaningful comparison of potential differences in the bioequivalence of formulations. The solution formulation (Delzicol) was not administered in this portion of the study. Therefore no results pertaining to the solution formulation are included in this outcome measure.	0 hours pre-dose and up to 7 hours post-dose

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Lionberger RA. FDA critical path initiatives: opportunities for generic drug development. AAPS J. 2008;10(1):103-9. doi: 10.1208/s12248-008-9010-2. Epub 2008 Feb 20.

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): September 1, 2015
• Study Completion (Actual): April 1, 2017

Study Registration Dates

• First Submitted: November 25, 2013
• First Submitted That Met QC Criteria: November 25, 2013
• First Posted (Estimate): December 3, 2013

Study Record Updates

• Last Update Posted (Actual): May 15, 2017
• Last Update Submitted That Met QC Criteria: May 2, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Mesalamine
• Other Study ID Numbers: FDA-SOL-1120920; HHSF223201300460A (Other Grant/Funding Number: U.S. Food and Drug Administration); HHSF223201000082C (Other Grant/Funding Number: U.S. Food and Drug Administration)