Computational Repositioning of the Anticonvulsant Topiramate for Inflammatory Bowel Disease

Sir,

We read with interest the article by Dudley et al, "Computational Repositioning of the Anticonvulsant Topiramate for Inflammatory Bowel Disease". The authors used a single type of data, namely public microarray data, to create gene expression signatures for drugs and diseases, and compared these signatures to arrive at novel repositioning candidates for Inflammatory Bowel Disease (IBD). They found topiramate to be a promising candidate and showed its efficacy in a rat model of IBD.

Surprisingly, diarrhea, a prominent symptom of IBD, is also one the most frequent adverse reactions of topiramate, occurring in more than 10% of patients [1]. Furthermore, in migraine clinical trials, where topiramate is used as preventive treatment, diarrhea appeared even at low doses, such as 50mg/day or 100mg/day, and increased in frequency dose- dependently [2]. These doses are considerably lower than the 80mg/kg that showed efficacy in the rat model reported in this article, which corresponds to a Human Equivalent Dose of 12.9mg/kg, or 903.2mg/day (for a person weighing 70kg) [3].

With these in mind, it would be difficult to envision a development path for topiramate as a treatment for IBD. This example illustrates our earlier observation [4], that the integration of more than one complementary types of data is important for the identification of viable repositioning candidates, that are likely to be both efficacious and well- tolerated in the specific patients subpopulations that they are targeted to; such an integration allows for non-accurate predictions made on the basis of one data type to be rejected, by using additional data types as further refinement criteria.

Sincerely Yours,

Spyros Deftereos

1. Topamax Drug Label. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020505s040s045,020844s035s037lbl.pdf. Accessed September 7, 2011. 2. Freitag FG, Forde G, Neto W, Wang DZ, Schmitt J, Wu SC, Hulihan J. Analysis of pooled data from two pivotal controlled trials on the efficacy of topiramate in the prevention of migraine. J Am Osteopath Assoc. 2007 Jul;107(7):251-8. 3. The Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry - Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. July 2005. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078932.pdf. Accessed September 7, 2011. 4. Deftereos SN, Andronis C, Friedla EJ, Persidis A, Persidis A. Drug repurposing and adverse event prediction using high-throughput literature analysis. Wiley Interdiscip Rev Syst Biol Med. 2011 May-Jun;3(3):323-34.

CONFLICT OF INTEREST Spyros N Deftereos is the VP of Drug Discovery and Christos Andronis the VP of R&D at Biovista Inc, a private company that specializes in Drug Repositioning and Adverse Event Prediction