• Rajendra H Jani, Kevinkumar Kansagra, Mukul R Jain, and Harilal Patel.
• Clinical R&D, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad, 382 213, Gujarat, India, rhjani@zyduscadila.com.
• Clin Drug Investig. 2013 Nov 1;33(11):809-16.

Background And ObjectivesDyslipidaemia is a major cardiovascular risk factor associated with type 2 diabetes mellitus. Saroglitazar (ZYH1) is a novel peroxisome proliferator-activated receptor (PPAR) agonist with predominant PPARα and moderate PPARγ activity. It has been developed for the treatment of dyslipidaemia and has favourable effects on glycaemic parameters in type 2 diabetes mellitus. The objective of this phase 1 study was to evaluate the pharmacokinetics, safety and tolerability of saroglitazar in healthy human subjects.MethodsThis was a randomized, double-blind, placebo-controlled, single-centre, phase I study in healthy human volunteers, and was performed in two parts; part I evaluated single ascending oral doses of saroglitazar (0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64 and 128 mg) in healthy subjects, and part II measured the effects of food and sex on the pharmacokinetics of 1 mg saroglitazar, the human equivalent efficacy dose derived from pre-clinical studies. A total of 96 subjects were enrolled in the study, which included 88 healthy male subjects in part I and 16 healthy subjects (8 males from part I of the study and 8 females) in part II.ResultsSaroglitazar was rapidly and well absorbed across all doses in the single-dose pharmacokinetic study, with a median time to the peak plasma concentration (t(max)) of less than 1 h (range 0.63-1 h) under fasting conditions across the doses studied. The maximum plasma concentration ranged from 3.98 to 7,461 ng/mL across the dose range. The area under the plasma concentration-time curve increased in a dose-related manner. The average terminal half-life of saroglitazar was 5.6 h. Saroglitazar was not eliminated via the renal route. There was no effect of sex on the pharmacokinetics of saroglitazar, except for the terminal half-life, which was significantly shorter in females than in males. Food had a small effect on the pharmacokinetics; however, it was not consistent in males and females. Single oral doses of saroglitazar up to 128 mg were well tolerated. No serious adverse events were reported. Adverse events were generally mild and moderate in nature. Saroglitazar did not show any clinically relevant findings in clinical laboratory investigations, physical examinations, vital signs and electrocardiograms.ConclusionThe highest dose of saroglitazar evaluated in this study was 128 mg, several times the estimated therapeutic doses (1-4 mg). The pharmacokinetics of saroglitazar support a once daily dosage schedule. Saroglitazar was found to be safe and well tolerated in this study.

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