Pilot Comparative Bioavailability Study of 6Mercaptopurine (Delayed Release vs. Purinethol) in Crohns Disease Patients
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Purpose
The study is being conducted to evaluate the pharmacokinetic parameters (Cmax, Tmax and AUC) of the new delayed release, lowered dose, 40 mg 6MP test formulation as compared to standard 6MP (100 mg Purinethol) in 12 patients with Crohn's Disease.
The study is being undertaken to prove that the new test formulation is indeed delayed-release and targeted to the ileum, and that the levels of 6MP in the blood following local absorption are lower than that seen following standard Purinethol dosing. This should result in lower, safer mercaptopurine dosing, allowing for uninterrupted treatment with fewer side effects.
| Condition | Intervention | Phase |
|---|---|---|
|
Crohns Disease |
Drug: Delayed Release 6 mercaptopurine Drug: 6 Mercaptopurine |
Phase 1 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Pharmacokinetics/Dynamics Study Intervention Model: Crossover Assignment Masking: Single Blind (Outcomes Assessor) |
| Official Title: | Pilot, Randomized, Open-Label, Two-Way Crossover Comparative Bioavailability Study of 40 mg Delayed Release Oral 6Mercaptopurine Versus 100 mg Purinethol in Patients With Crohns Disease |
- PK parameters: AUC, Cmax and Tmax [ Time Frame: Following single dose of test or reference drug ] [ Designated as safety issue: Yes ]
- FACS analysis of peripheral blood lymphocytes following single dose of test vs. reference formulation [ Time Frame: Comparison of values from blood collected at 0, 12 and 24 hours post-dose ] [ Designated as safety issue: No ]
| Enrollment: | 12 |
| Study Start Date: | December 2008 |
| Study Completion Date: | February 2009 |
| Primary Completion Date: | February 2009 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: 1 6MP Test Formulation
1 x 40 mg Oral Tablet, 6 MP Delayed Release Test Formulation, for targeted ileal delivery
|
Drug: Delayed Release 6 mercaptopurine
oral tablet, 1 x 40 mg Delayed Release 6MP tablet, single-dose
Other Name: Administration 1 (A): 1 x 40 mg Delayed Release 6MP TEST
|
|
Active Comparator: 2. 6MP Reference Formulation
2 x 50 mg oral tablet, PURINETHOL
|
Drug: 6 Mercaptopurine
Oral Tablet, 2 x 50 mg 6MP Reference, single-dose
Other Name: Administration 2 (B): 2 x 50 mg Purinethol REFERENCE
|
Detailed Description:
A new delayed release, faster-disintegrating, lower dose oral formulation of 6 mercaptopurine for targeted delivery to the ileum (the most commonly effected area of Crohns Disease (CD) bowel involvement), was developed and shown to be effective in the three efficacy parameters evaluated in a small group of Crohns Disease patients. Twelve weeks of daily treatment with once-nightly dosing of 40 mg local 6MP resulted in: (1) inducing clinical remission (CDAI scores below 150 as early as weeks 2 and 4), (2) effecting local mucosal healing (as evidenced by lowered CDEIS scores and descriptive conolonoscopy reports) and (3) reducing systemic immunological scores (lowered IFN-gamma Elispot levels).
The current study is being undertaken to confirm, via pharmacokinetic profiles (Cmax, AUC and Tmax), the underlying premises of the above-noted clinical feasibility study. This PK study is being conducted to establish that (1) The delayed release test formulation delivers drug distally to the lower intestine and (2) The delayed release test formulation has the potential for reduced systemic toxicity. The first aspect will be established by comparing the Tmax of the delayed release test formulation vs. oral Purinethol, while the second aspect will be established by comparing the Cmax and AUC of the 40 mg test dose vs. standard 100 mg Purinethol. It is anticipated that the delayed release test formulation will exhibit a later Tmax and reduced Cmax and AUC as compared to reference Purinethol.
Additionally, immunology testing to measure the effect of the new 6MP formulation on immunological FACS analysis will be performed on peripheral blood lymphocytes at 0, 12 and 24 hours post-dosing of each formualtion. Lymphocytes will be tested for surface marker expression (ex: CD3, CD4, CD8, CD25, NKT, etc.), with anticipated results a greater lowering of immune parameters after even 1 dose of 40 mg delayed release test drug, as compared to 100 mg Purinethol.
Eligibility| Ages Eligible for Study: | 18 Years to 50 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- 12 male and non-pregnant females, aged 18-50 years, with Crohns Disease (CDAI up to 200), non-smoking.
Crohns Disease diagnosis via colonoscopy with biopsy within the past 12 years No CD medications allowed during study other than 5-ASA and symptomatic relief (anti-diarrheals) Screening lab tests: HGB>= 8.5 g/dl, platelets >= 100,000/mm3, WBC: 3500-12000/mm3, serum albumin above 2.5 g/dl, amylase, lipase and total bilirubin within normal limits; ALT, AST, alkaline phosphatase up to 1.5 x normal limits
Exclusion Criteria:
- No more than 2 bowel movements/24 hour period in week prior to screening No patients on methotrexate, cyclosporine, or other anti-TNF alpha, or anti-neoplastics within 3 months of study start NO fistulizing CD or isolated small bowle CD No symptomatic stenosis or ileal strictures,or x-ray evidnece of fibrosed bowel
Contacts and Locations More Information
No publications provided
| Responsible Party: | Prof. Yaron Ilan, Hadasssah Medical Center |
| ClinicalTrials.gov Identifier: | NCT00774982 History of Changes |
| Other Study ID Numbers: | C1/13/6MP-02 |
| Study First Received: | October 16, 2008 |
| Last Updated: | July 16, 2009 |
| Health Authority: | Israel: Ministry of Health |
Keywords provided by Teva GTC:
|
Crohns Disease Pharmacokinetics Local Targeted Delivery to the Ileum |
Delayed Release Immunology Measurements Pharmacokinetics in Crohns Disease Patients |
Additional relevant MeSH terms:
|
Crohn Disease Inflammatory Bowel Diseases Gastroenteritis Gastrointestinal Diseases Digestive System Diseases Intestinal Diseases 6-Mercaptopurine Antimetabolites Molecular Mechanisms of Pharmacological Action |
Pharmacologic Actions Antimetabolites, Antineoplastic Antineoplastic Agents Therapeutic Uses Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Nucleic Acid Synthesis Inhibitors Enzyme Inhibitors |
ClinicalTrials.gov processed this record on May 21, 2013