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

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, PPARa 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 PPARy 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 PPARa and moderate PPARc 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 LipaglynTM (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 Cmax (maximum concentration) of saroglitazar by 30%, the extent of absorption as measured by AUCœ (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 AUCœ and from 63.45% to 74.68% for Cmax. Other parameters such as Tmax (time of maximum concentration) and T1/2 (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 Cmax is outside 80.00-125.00%. Howev