Local Drug Concentration in Gastrointestinal Tract
Conditions
Brief summary
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.
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.
Interventions
DRUGPentasa 500 mg capsule x 2 with 240 mL water; single dose
DRUGApriso 375 mg capsule x 3 with 240 mL water; single dose
DRUGLialda 1200 mg tablet x 1 with 240 mL water; single dose
DRUGDelzicol 100 mg mesalamine x 1 with 245 mL water; single dose
Sponsors
Food and Drug Administration (FDA)
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The AUC of Mesalamine in Plasma | 0 hours pre-dose and up to 96 hours post-dose | 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. |
| The AUC of Metabolite (N-acetyl-mesalamine) in Plasma | 0 hours pre-dose and up to 96 hours post-dose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The AUC of Mesalamine in Distal Jejunum | 0 hours pre-dose and up to 7 hours post-dose | 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. |
| The AUC of Metabolite (N-acetyl-mesalamine) in Distal Jejunum | 0 hours pre-dose and up to 7 hours post-dose | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Participants who were randomized to one of the six arms of this study:
Arm 1: Pentasa then Delzicol then Apriso then Lialda Arm 2: Pentasa then Delzicol then Lialda then Apriso Arm 3: Apriso then Delzicol then Pentasa then Lialda Arm 4: Apriso then Delzicol then Lialda then Pentasa Arm 5: Lialda then Delzicol then Pentasa then Apriso Arm 6: Lialda then Delzicol then Apriso then Pentasa | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 32.9 years STANDARD_DEVIATION 9.7 |
| Body Mass Index | 26.9 kg per m squared STANDARD_DEVIATION 5.6 |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 14 | 0 / 13 | 1 / 11 | 0 / 20 |
| serious Total, serious adverse events | 0 / 14 | 0 / 13 | 0 / 11 | 0 / 20 |
Outcome results
Primary
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.
Time frame: 0 hours pre-dose and up to 96 hours post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pentasa | The AUC of Mesalamine in Plasma | 40.8 nM*h | Standard Deviation 29.5 |
| Apriso | The AUC of Mesalamine in Plasma | 57.6 nM*h | Standard Deviation 24.1 |
| Lialda | The AUC of Mesalamine in Plasma | 36.8 nM*h | Standard Deviation 16 |
| Delzicol | The AUC of Mesalamine in Plasma | 7.9 nM*h | Standard Deviation 3.7 |
Primary
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.
Time frame: 0 hours pre-dose and up to 96 hours post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pentasa | The AUC of Metabolite (N-acetyl-mesalamine) in Plasma | 162 nM*h | Standard Deviation 59.7 |
| Apriso | The AUC of Metabolite (N-acetyl-mesalamine) in Plasma | 189 nM*h | Standard Deviation 92.2 |
| Lialda | The AUC of Metabolite (N-acetyl-mesalamine) in Plasma | 124 nM*h | Standard Deviation 80.5 |
| Delzicol | The AUC of Metabolite (N-acetyl-mesalamine) in Plasma | 20.4 nM*h | Standard Deviation 7.7 |
Secondary
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.
Time frame: 0 hours pre-dose and up to 7 hours post-dose
Population: The number of subjects that were administered Pentasa, Apriso, Lialda were 10, 7, and 9, respectively. However, we were only able to collect gastrointestinal fluid from the distal jejunum for only 3 subjects in each of these arms due to the placement of the gastrointestinal tube.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pentasa | The AUC of Mesalamine in Distal Jejunum | 8456 uM*h | Standard Deviation 7444 |
| Apriso | The AUC of Mesalamine in Distal Jejunum | 4923 uM*h | Standard Deviation 8506 |
| Lialda | The AUC of Mesalamine in Distal Jejunum | 2.9 uM*h | Standard Deviation 3.9 |
Secondary
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.
Time frame: 0 hours pre-dose and up to 7 hours post-dose
Population: The number of subjects that were administered Pentasa, Apriso, Lialda were 10, 7, and 9, respectively. However, we were only able to collect gastrointestinal fluid from the distal jejunum for only 3 subjects in each of these arms due to the placement of the gastrointestinal tube.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pentasa | The AUC of Metabolite (N-acetyl-mesalamine) in Distal Jejunum | 5048 uM*h | Standard Deviation 5553 |
| Apriso | The AUC of Metabolite (N-acetyl-mesalamine) in Distal Jejunum | 1225 uM*h | Standard Deviation 2024 |
| Lialda | The AUC of Metabolite (N-acetyl-mesalamine) in Distal Jejunum | 3.4 uM*h | Standard Deviation 3.4 |