Santarusposter3.qxd (page 1)

Targeted Delivery of Azathioprine (AZA) to the Ileum and Colon for the Treatment of Crohn’s Disease (DCD):
Scintigraphic and Pharmacokinetic (PK) Evaluation of a Novel Azathioprine Delayed-Release (AZA-DR) Formulation
William J. Sandborn M.D., Mayo Clinic, Rochester, MN; Bonnie Hepburn M.D., Barry Goldlust Ph.D., Santarus, Inc., San Diego, CA;
Walter Doll Ph.D., Erik Sandefer Ph.D., Scintipharma, Inc., Lexington, KY; Arthur H. Goldberg Ph.D., Pharmaceutical Development Group, Menlo Park, CA
Patient #3
Introduction
Conclusions
Azathioprine (AZA) is effective in treating Crohn's disease Scintigraphy and PK Data
but has a narrow therapeutic window. A novel delayed- release (DR) formulation, AZA-DR, was developed to for Patient #3
All 3 AZA-DR formulations showed delayed-release improve the safety profile and increase the efficacy of oral disintegration and PK characteristics.
immediate-release AZA (Imuran®) in the treatment of Data for this patient is representative of the Crohn’s disease, by delivering AZA directly to the ileum and behavior of AZA-DR minitablets prepared with a colon. Imuran, generic AZA, and a related compound 6- medium-coat thickness of Eudragit-S.
◆ The PK results were consistent with absorption and mercaptopurine are used extensively in the treatment ofCrohn’s disease, although these drugs do not have FDA- Each capsule contained sixty 5 mg minitablets.
metabolism of AZA from AZA-DR in the distal ileal and approved labeling for this indication.
Five of the 60 tablets were radiolabeled and can colonic mucosa (low blood levels and low stool AZA content).
be visualized as they pass from the esophagusthrough the stomach, small bowel and colon. Inthis patient, the minitablets reached the terminal ◆ The medium-coat AZA-DR minitablet formulation (B) was ileum in 4 hours and AZA is first detected in theblood at this time. No discreet tablets can be visu- selected over A and C for further development based on Objective
lower systemic exposure (vs. A) and a greater tendency to This study was designed to determine the release and phar- initiate disintegration of minitablets preferentially in the ileum macokinetic (PK) profiles of 3 different AZA-DR formulations 0 hours 0 min.
0 hours 27 min.
2 hours 0 min.
3 hours 57 min.
4 hours 29 min.
16 hours 0 min.
in order to identify the formulation best suited for furtherdevelopment.
◆ A controlled trial of medium-coat AZA-DR is warrantedand is now being conducted in CD patients to evaluate efficacy and safety of this new formulation.
AZA minitablets (5 mg) were covered with low, medium, or high thickness coats of Eudragit®-S (a polymer that disinte-grates at a pH of 7.0). Five samarium-radiolabeled AZA minitablets and 55 unlabeled AZA minitablets were com- bined in a gelatin capsule containing 300 mg AZA. A randomized crossover study was conducted in 8 normalsubjects. One 300 mg AZA-DR capsule was administered toeach subject at weekly intervals until all subjects hadreceived all 3 AZA-DR formulations. At week 4, subjectsswallowed a remotely-controlled InteliSite® capsule that Scintigraphy
Pharmacokinetics
released 300 mg of a solution of AZA with a radioactive iso- Disintegration of Minitablet Coatings
AZA Pharmacokinetics and Fecal AZA Recovery
tope to the terminal ileum. Standardized meals were pro- After AZA-DR and the InteliSite Solution
vided at 4 and 10 hours after each dose of AZA-DR or ◆ The medium-coat formulation of AZA-DR (B) showed ◆ Systemic exposure (AUC) to AZA was less with all AZA-DR InteliSite capsule. Water or caffeine-free liquids were initial coating disintegration predominantly in the ileum in formulations compared to the InteliSite solution.
Disintegration: mean (range)
6 of 8 subjects and occurred sooner than for the heavy-coat AZA-DR (C) [4 of 8 subjects]. Complete
Mean (SD)
◆ Mean AUCs for the medium-coat (B) and high- coat (C) The site of AZA release from each AZA-DR formulation was AZA-DR were similar, and were less than for the low-coat AZA- Time (hr)
Time (hr)
AUC (0 – t)
monitored by gamma scintigraphy. To determine the relative ◆ The medium-coat formulation of AZA-DR (B) disinte- DR (A), indicating less systemic exposure to AZA from B and Formulation
After Dosing
Location
After Dosing
Location
bioavailability of AZA, serial blood samples were obtained grated completely prior to or in the ascending colon for 7 Formulation
Absorption
ng • hr / mL
Recovery
C, without an increase of AZA in the stool.
after administration of all formulations. AZA was also meas- of the 8 subjects. The mean time to complete disinte- ured in the stools by collecting total stool output from the gration of minitablets was approximately 10 hours.
Asc. colon
◆ The onset of absorption was delayed 2-fold for the medium- time of AZA-DR dose administration until all radioactivity coat (B) and high-coat (C) AZA-DR vs. low-coat AZA-DR (A), was recovered or for a maximum of 48 hours postdose. For ◆ Food ingestion stimulated GI motility and the move- suggesting that B and C were releasing AZA more distally in the InteliSite capsule dose administration, total stool output ment of the minitablets through the GI tract. However, was obtained until the capsules were recovered.
the disintegration of the AZA-DR minitablet coatings did Asc. colon
not begin until these minitablets had reached the mid- ◆ The elimination half-lives (T_) for all 3 AZA-DR formulations ileum or beyond where a neutral pH allowed the pH-sen- were longer than for the InteliSite solution suggesting that sitive minitablet coatings to disintegrate.
release of AZA from minitablets was a prolonged process.
Asc. colon
Scintigraphy Trial Design
InteliSitec
a Mean dose: AZA-DR = 3.6 mg/kg; InteliSite = 3.2 mg/kg.
b For AZA-DR, time zero is ingestion of capsule. For InteliSite, time zero is opening of capsule.
Data for the 3 subjects showing opening of capsule in distal ileum. P value < 0.05 (Student’s t test) = *

Source: http://harveyclark.com/Images/PDF-files/SantarusPoster03.pdf