Limits...
Pharmacokinetics, safety, and tolerability of saroglitazar (ZYH1), a predominantly PPARα agonist with moderate PPARγ agonist activity in healthy human subjects.

Jani RH, Kansagra K, Jain MR, Patel H - Clin Drug Investig (2013)

Bottom Line: 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.Saroglitazar did not show any clinically relevant findings in clinical laboratory investigations, physical examinations, vital signs and electrocardiograms.Saroglitazar was found to be safe and well tolerated in this study.

View Article: PubMed Central - PubMed

Affiliation: Clinical R&D, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad, 382 213, Gujarat, India, rhjani@zyduscadila.com.

ABSTRACT

Background and objectives: Dyslipidaemia 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.

Methods: This 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.

Results: Saroglitazar 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.

Conclusion: The 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.

Show MeSH

Related in: MedlinePlus

Dose linearity of the area under the plasma concentration–time curve from time zero to the time of the last measurable concentration (AUClast) and maximum plasma concentration ( Cmax) as a function of a single oral dose of saroglitazar administered to healthy subjects
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3824340&req=5

Fig3: Dose linearity of the area under the plasma concentration–time curve from time zero to the time of the last measurable concentration (AUClast) and maximum plasma concentration ( Cmax) as a function of a single oral dose of saroglitazar administered to healthy subjects

Mentions: Saroglitazar was well absorbed after oral administration under fasting conditions. The absorption was rapid, with a median tmax of less than 1 h. The Cmax values were from 3.98 to 7,461 ng/mL across the dose range. The Cmax and AUClast values increased in a dose-related manner. The pharmacokinetic parameters determined in the single-ascending-dose study are presented in Table 1. The results indicated that saroglitazar is well absorbed in humans. The exposure increased in a predictable manner with increasing doses (Fig. 3). Saroglitazar concentration–time curves (mean ± standard error of the mean) after administration of 0.125, 0.25, 0.50, 1, 2, 4, 8, 16, 32, 64 and 128 mg are shown in Figs. 4 and 5. These show that the highest dose had an extended length of drug absorption.Table 1


Pharmacokinetics, safety, and tolerability of saroglitazar (ZYH1), a predominantly PPARα agonist with moderate PPARγ agonist activity in healthy human subjects.

Jani RH, Kansagra K, Jain MR, Patel H - Clin Drug Investig (2013)

Dose linearity of the area under the plasma concentration–time curve from time zero to the time of the last measurable concentration (AUClast) and maximum plasma concentration ( Cmax) as a function of a single oral dose of saroglitazar administered to healthy subjects
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824340&req=5

Fig3: Dose linearity of the area under the plasma concentration–time curve from time zero to the time of the last measurable concentration (AUClast) and maximum plasma concentration ( Cmax) as a function of a single oral dose of saroglitazar administered to healthy subjects
Mentions: Saroglitazar was well absorbed after oral administration under fasting conditions. The absorption was rapid, with a median tmax of less than 1 h. The Cmax values were from 3.98 to 7,461 ng/mL across the dose range. The Cmax and AUClast values increased in a dose-related manner. The pharmacokinetic parameters determined in the single-ascending-dose study are presented in Table 1. The results indicated that saroglitazar is well absorbed in humans. The exposure increased in a predictable manner with increasing doses (Fig. 3). Saroglitazar concentration–time curves (mean ± standard error of the mean) after administration of 0.125, 0.25, 0.50, 1, 2, 4, 8, 16, 32, 64 and 128 mg are shown in Figs. 4 and 5. These show that the highest dose had an extended length of drug absorption.Table 1

Bottom Line: 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.Saroglitazar did not show any clinically relevant findings in clinical laboratory investigations, physical examinations, vital signs and electrocardiograms.Saroglitazar was found to be safe and well tolerated in this study.

View Article: PubMed Central - PubMed

Affiliation: Clinical R&D, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad, 382 213, Gujarat, India, rhjani@zyduscadila.com.

ABSTRACT

Background and objectives: Dyslipidaemia 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.

Methods: This 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.

Results: Saroglitazar 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.

Conclusion: The 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.

Show MeSH
Related in: MedlinePlus