cs-0777 has been researched along with sphingosine-1-phosphate* in 2 studies
1 trial(s) available for cs-0777 and sphingosine-1-phosphate
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Use of an exposure-response model to aid early drug development of an oral sphingosine 1-phosphate receptor modulator.
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 Imax 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. Topics: Administration, Oral; Adolescent; Adult; Amino Alcohols; CD4-Positive T-Lymphocytes; Cohort Studies; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Lymphocyte Count; Lymphocyte Subsets; Lymphocytes; Lysophospholipids; Male; Middle Aged; Models, Biological; Prodrugs; Pyrroles; Receptors, Lysosphingolipid; Sphingosine; Young Adult | 2009 |
1 other study(ies) available for cs-0777 and sphingosine-1-phosphate
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Pharmacological effects of CS-0777, a selective sphingosine 1-phosphate receptor-1 modulator: results from a 12-week, open-label pilot study in multiple sclerosis patients.
CS-0777 is a selective sphingosine 1-phosphate receptor-1 modulator under investigation for treatment of multiple sclerosis (MS). We conducted an open-label, pilot study in 25 MS patients to assess the safety, pharmacokinetics, pharmacodynamics and exploratory efficacy of oral CS-0777 (0.1, 0.3 and 0.6 mg), administered once weekly or every other week for 12 weeks. CS-0777 resulted in a pronounced, dose-dependent decrease in lymphocytes and CD4 T cell subsets, which returned to baseline within 4 weeks after the last dose. Overall, CS-0777 was safe and well-tolerated. These results require confirmation in a double-blind, placebo-controlled and adequately powered phase 2 study in MS. Topics: Administration, Oral; Amino Alcohols; CD4-Positive T-Lymphocytes; Dose-Response Relationship, Immunologic; Down-Regulation; Humans; Lymphocyte Subsets; Lymphopenia; Lysophospholipids; Multiple Sclerosis; Pilot Projects; Pyrroles; Receptors, Lysosphingolipid; Sphingosine | 2012 |