HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Sign In to gain access to subscriptions and/or personal tools.

This Article Full Text Full Text (PDF) All Versions of this Article: 0091270008325672v1 49/1/50    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rohatagi, S. Articles by Carrothers, T. J. Search for Related Content PubMed PubMed Citation Articles by Rohatagi, S. Articles by Carrothers, T. J. Social Bookmarking                         What's this?

Use of an Exposure-Response Model to Aid Early Drug Development of an Oral Sphingosine 1-Phosphate Receptor Modulator

From Daiichi Sankyo Pharma Development, Edison, New Jersey (Dr Rohatagi, Dr Zahir, Dr Moberly, Dr Truitt); Daiichi Sankyo Inc, Tokyo, Japan (S. Inaba, Dr Shimozato); and Pharsight, Mountain View, California (Dr Carrothers).

Pharmacokinetic (PK) and exposure-response modeling of a selective sphingosine 1-phosphate receptor-1 modulator (CS-0777) was conducted in an iterative process to guide early clinical development decisions. A model based on preclinical data from monkeys was extrapolated to humans to support a single ascending dose (SAD) study. The model was updated after each cohort, providing guidance on both maximal inhibition and time to recovery for lymphocyte counts. A 2-compartment PK model with first-order absorption and elimination was found to describe the monkey and human datasets. The relationship between lymphocyte counts and active metabolite (M-1) concentrations was modeled via an indirect response model, whereby M-1 inhibited the reentry of lymphocytes to the circulation. The indirect-response model based on SAD data had an I_max of approximately 85% and an IC₅₀ of 0.24 ng/mL. Additionally, based on SAD data, similar models were developed for lymphocyte subsets, including CD4 cells. Subsequently, simulations were utilized to design a multiple ascending dose study with adaptive dosing regimens that would meet targeted pharmacodynamic (PD) response thresholds (eg, minimum 40% reduction in lymphocytes) while maintaining CD4 counts above a reasonable safety threshold. In conclusion, model-based development and use of adaptive designs for dose optimization can reduce the time and number of subjects needed in early clinical development.

Key Words: CD4 • CS-0777 • dose optimization • lymphocytes • PK/PD • sphingosine-1 phosphate receptor

Address for reprints: Shashank Rohatagi, PhD, MBA, Daiichi Sankyo Pharma Development, 399 Thornall Street, Edison, NJ 08837; e-mail: srohatagi{at}dsus.com.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				N. O'Brien, S. T. Jones, D. G. Williams, H. B. Cunningham, K. Moreno, B. Visentin, A. Gentile, J. Vekich, W. Shestowsky, M. Hiraiwa, et al. Production and characterization of monoclonal anti-sphingosine-1-phosphate antibodies J. Lipid Res., November 1, 2009; 50(11): 2245 - 2257. [Abstract] [Full Text] [PDF]