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Effect of Food on the Pharmacokinetics of Saroglitazar Magnesium, a Novel Dual PPARαγ Agonist, in Healthy Adult Subjects

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Abstract

Background and Objective

Peroxisome proliferator-activated receptors (PPARs) have recently become a focus of interest for their important roles in glucose and lipid metabolism. In humans, PPARα activation causes a decrease in plasma triglyceride (TG) levels, enhancement of high-density lipoprotein cholesterol (HDL-C) and simultaneous enhancement of very-low-density lipoprotein (VLDL) lipolysis, whereas PPARγ agonists act as insulin sensitizers and improve insulin resistance, which is very useful in patients with type 2 diabetes mellitus (T2DM). Saroglitazar magnesium is a dual PPAR agonist with potent predominant PPARα and moderate PPARγ activity and the first glitazar to be granted marketing authorization in India. This study was conducted to evaluate the oral bioavailability and safety and tolerability of a Lipaglyn™ (saroglitazar magnesium) 4-mg tablet in healthy, adult human subjects under fed relative to fasting conditions.

Methods

This was a single-dose, open-label, randomized, single-treatment, two-period, two-conditions (fed vs. fasting), two-sequence, crossover study planned in 54 healthy subjects. Food effect (high-calorie and high-fat breakfast) was examined by comparing pharmacokinetic data of saroglitazar and its metabolite saroglitazar sulfoxide in plasma samples collected pre-dose and serially up to 72 h post-dose. Pharmacokinetic data were analyzed using the standard non-compartmental approach.

Results

A total of 54 subjects were enrolled in the study, out of them 50 subjects had completed the study and were analyzed. The presence of food had a minor impact on the disposition of saroglitazar. While food reduced C max (maximum concentration) of saroglitazar by 30%, the extent of absorption as measured by AUC∞ (area under the concentration time curve from time zero to infinity) was not influenced. This was further supported by the bioequivalence data between fasted and fed conditions for saroglitazar, where 90% CIs (confidence intervals) of the adjusted geometric mean of the fed relative to the fasted condition ranged from 101.37% to 108.07% for AUC∞ and from 63.45% to 74.68% for C max. Other parameters such as T max (time of maximum concentration) and T 1/2 (elimination half-life) were not influenced by the food intake. Saroglitazar was well tolerated in the study, and the reported adverse events were mild in nature.

Conclusion

For the single-dose study, the absorption rate is affected by food as the 90% CI of C max is outside 80.00–125.00%. However, there is no impact of food on the extent of absorption of saroglitazar. The observed lower C max of saroglitazar with food has no clinical relevance since the therapeutic efficacy of saroglitazar was achieved after multiple-dose administration, suggesting the importance of total exposure.

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Authors and Affiliations

  1. Zydus Research Center, Survey No. 396/403, Sarkhej-Bavla, N.H. No. 8A, Moraiya, Ahmedabad, Gujarat, 382213, India

    Maulik R. Patel, Kevinkumar A. Kansagra, Devang P. Parikh, Deven V. Parmar, Hardik B. Patel, Harilal V. Patel, Krupi V. Parmar & Nuggehally R. Srinivas

  2. Cliantha Research Limited, Ahmedabad, India

    Mayur M. Soni, Uday S. Patil, Jaimik A. Patel & Swagat S. Gujarathi

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  1. Maulik R. Patel
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  2. Kevinkumar A. Kansagra
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  3. Devang P. Parikh
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Corresponding author

Correspondence to Maulik R. Patel.

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Conflict Interest

Maulik R. Patel, Kevinkumar A. Kansagra, Devang P. Parikh, Deven V. Parmar, Hardik B. Patel, Harilal V. Patel, Krupi V. Parmar, and Nuggehally R. Srinivas are employees of Zydus Research Centre and Mayur M. Soni, Uday S. Patil, Jaimik A. Patel, Swagat S. Gujarathi are employees of Cliantha Research Limited.

Funding

Cliantha Research Limited received funding from Cadila Healthcare Ltd. to plan, conduct, record, and report this study.

Ethical Approval

All of the study-related procedures were performed after gaining approval from the Independent Ethics Committee Aditya, Ahmedabad and in accordance with the ethical principles stipulated in the Declaration of Helsinki, ICMR ethical guidelines, International Conference on Harmonization (ICH) (Step 5) ‘Guidance on Good Clinical Practice’ (E6), Schedule Y of Drugs and Cosmetics Act, 2005.

Informed Consent

Written informed consent was obtained from all individual participants before enrollment into the study.

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Patel, M.R., Kansagra, K.A., Parikh, D.P. et al. Effect of Food on the Pharmacokinetics of Saroglitazar Magnesium, a Novel Dual PPARαγ Agonist, in Healthy Adult Subjects. Clin Drug Investig 38, 57–65 (2018). https://doi.org/10.1007/s40261-017-0584-2

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