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Population Analysis of the Pharmacokinetics and Pharmacodynamics of Seratrodast in Patients With Mild to Moderate Asthma

Population Analysis of the Pharmacokinetics and Pharmacodynamics of Seratrodast in Patients With Mild to Moderate Asthma

E Samara, G Cao, C Locke, G R Granneman, R Dean, A Killian

Clin Pharmacol Ther. 1997 Oct;62(4):426-35.

PMID: 9357394

Abstract:

Background:
Seratrodast, a potent thromboxane receptor antagonist, is approved in Japan for the treatment of asthma and currently is being developed in the United States.
Methods:
This was a phase II, randomized, double-blind, parallel-group, placebo-controlled 15-center study of seratrodast in patients with mild to moderate asthma. A total of 183 patients were randomly assigned to receive daily doses of either placebo, or 80 mg seratrodast, or 120 mg seratrodast for 8 weeks. Pharmacokinetic and pharmacodynamic modeling was carried out by means of the population approach. A two-compartment model with zero-order input and first-order elimination best fitted the plasma concentration-time data.
Results and conclusions:
The pharmacokinetics of seratrodast were linear after single and multiple dosing for 8 weeks. The population estimates for oral clearance and apparent volume of distribution were 8.5 ml/hr/kg and 43.3 ml/kg, respectively. All pharmacokinetic parameters (the oral central compartment clearance, the volumes of distribution of the central and peripheral compartments, and the intercompartmental clearance) were estimated with a precision of 10% or less and were found to be associated with body weight. The residual variability was 30%. The values of oral clearance estimated in this study in male patients were similar to those previously estimated in healthy male subjects. Seratrodast at a dose of 120 mg daily produced an increase in forced expiratory volume in 1 second (FEV1) from baseline that was linearly correlated with its plasma concentrations. The average slope of the concentration-effect relationship was 0.222% and 0.470% per microgram/ml after single and multiple dosing, respectively. Interpatient variability in response was mainly affected by the initial severity of the disease. A lower percentage of predicted FEV1 (i.e., more severe obstruction) was associated with higher slopes, and greater increases in FEV1.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP112665437	Seratrodast		112665-43-7	Price

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