Study to Evaluate Absorption, Metabolism and Excretion of Single-dose [14C]-Saroglitazar in Healthy Male Subjects

Study Overview
=================
Brief Summary
-----------------
This will be a Phase I, open-label, nonrandomized, single-dose study in healthy male subjects.

Detailed Description
-----------------
Potential subjects will be screened to assess their eligibility to enter the study within 28 days prior to the dose administration. Subjects will be admitted into the Clinical Research Unit (CRU) on Day -1 and be confined to the CRU until at least Day 8. On Day 1, subjects will receive a single oral dose of [14C]-saroglitazar magnesium. Subjects will be discharged if the following discharge criteria are met: plasma radioactivity levels below the limit of quantitation for 2 consecutive collections and ≥ 90% mass balance recovery, or ≤ 1% of the total radioactive dose is recovered in combined excreta (urine and feces) in 3 consecutive 24-hour periods in which both are collected. If discharge criteria are not met by Day 8, subjects will remain in the CRU up to Day 12.

Official Title
-----------------
A Phase I, Open-label Study of the Absorption, Metabolism, and Excretion of [14C]-Saroglitazar Following a Single Oral Dose of [14C]-Saroglitazar Magnesium in Healthy Male Subjects

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: Saroglitazar magnesium


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males, of any race, between 18 and 55 years of age, inclusive. Body mass index (BMI) between 18.0 and 32.0 kg/m2, inclusive. In good health, determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital sign measurements, and clinical laboratory evaluations at Screening and/or Check-in as assessed by the Investigator (or designee). Able to comprehend and willing to sign an ICF and to abide by the study restrictions. History of a minimum of 1 bowel movement per day. Exclusion Criteria: Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the Investigator (or designee). History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator (or designee). Known hypersensitivity to either saroglitazar magnesium or other PPAR agonists, and/or the excipients in the saroglitazar magnesium formulation. History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs (uncomplicated appendectomy and hernia repair will be allowed). History of cholecystectomy will not be allowed. Subjects with congenital nonhemolytic hyperbilirubinemia (eg, suspicion of Gilbert's syndrome based on total and direct bilirubin). History of alcoholism or drug/chemical abuse within 1 year prior to Check-in. Alcohol consumption of > 14 units per week. One unit of alcohol equals 12 oz (360 mL) of beer, 1½ oz (45 mL) of liquor, or 5 oz (150 mL) of wine. Positive urine drug screen at Screening or positive alcohol breath test result or positive urine drug screen at Check-in. Positive hepatitis panel and/or positive human immunodeficiency virus test ( Appendix 2). Participation in a clinical study involving administration of an investigational drug (new chemical entity) in the past 90 days prior to dosing or 5 times the t1/2 (whichever is longer). Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's wort, within 30 days prior to Check-in, unless deemed acceptable by the Investigator (or designee). Use or intend to use any prescription medications/products within 14 days prior to Check-in, unless deemed acceptable by the Investigator (or designee). Use or intend to use slow-release medications/products considered to still be active within 14 days prior to Check-in, unless deemed acceptable by the Investigator (or designee). Use or intend to use any nonprescription medications/products including vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior to Check-in, unless deemed acceptable by the Investigator (or designee). Use of tobacco- or nicotine-containing products within 3 months prior to Check-in, or positive cotinine at Screening or Check-in. Receipt of blood products within 2 months prior to Check-in. Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior to Screening. Poor peripheral venous access. Have previously completed or withdrawn from this study or any other study investigating saroglitazar magnesium, and have previously received the investigational product. Subjects with exposure to significant diagnostic or therapeutic radiation (eg, serial X-ray, computed tomography scan, barium meal) or current employment in a job requiring radiation exposure monitoring within 12 months prior to Check-in. Subjects who have participated in a radiolabeled drug study where exposures are known to the Investigator within the previous 4 months prior to admission to the clinic for this study or participated in a radiolabeled drug study where exposures are not known to the Investigator within the previous 6 months prior to admission to the clinic for this study. The total 12-month exposure from this study and a maximum of 2 other previous radiolabeled studies within 4 to 12 months prior to this study will be within the Code of Federal Regulations (CFR) recommended levels considered safe, per United States (US) Title 21 CFR 361.1: less than 5,000 mrem whole-body annual exposure with consideration given to the half-lives of the previous radiolabeled study drugs received. Subjects who, in the opinion of the Investigator (or designee), should not participate in this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Treatment<br>4 mg [14C]-saroglitazar magnesium (approximately 100 μCi) oral suspension | Drug: Saroglitazar magnesium<br>* On Day 1, subjects will receive a single oral dose of [14C]-saroglitazar magnesium<br>* Other names: not any;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC from time zero to infinity (AUC0-∞) | Area under the time curve from time zero to infinity will be calculated for saroglitazar and saroglitazar sulfoxide in plasma, and total radioactivity in whole blood and plasma | At predose to maximum up to Day 12 | 
| AUC from time zero to the last quantifiable concentration (AUC0-t) administration of [14C]-saroglitazar magnesium | Area under the time curve from time zero to the last quantifiable concentration will be calculated for saroglitazar and saroglitazar sulfoxide in plasma, and total radioactivity in whole blood and plasma | At predose to maximum up to Day 12 | 
| Cmax | Maximum observed concentration will be calculated for saroglitazar and saroglitazar sulfoxide in plasma, and total radioactivity in whole blood and plasma | At predose to maximum up to Day 12 | 
| Tmax | Time to reach maximum observed concentration will be calculated for saroglitazar and saroglitazar sulfoxide in plasma, and total radioactivity in whole blood and plasma | At predose to maximum up to Day 12 | 
| t1/2 | Apparent terminal elimination half-life will be calculated for saroglitazar and saroglitazar sulfoxide in plasma, and total radioactivity in whole blood and plasma | At predose to maximum up to Day 12 | 
| Apparent total clearance (CL/F) | The apparent total clearance (CL/F) will be determined for saroglitazar | At predose to maximum up to Day 12 | 
| Apparent volume of distribution (Vz/F) during the terminal elimination phase | The Apparent volume of distribution (Vz/F) during the terminal elimination phase will be determined for saroglitazar | At predose to maximum up to Day 12 | 
| AUC0-∞ of plasma saroglitazar relative to AUC0-∞ of plasma total radioactivity (AUC0-∞ Plasma saroglitazar/Total Radioactivity Ratio) | AUC0-∞ of plasma saroglitazar relative to AUC0-∞ of plasma total radioactivity (AUC0-∞ Plasma saroglitazar/Total Radioactivity Ratio) will be calculated | At predose to maximum up to Day 12 | 
| AUC0-∞ of whole blood total radioactivity to AUC0-∞ of plasma total radioactivity (AUC0 ∞ Blood/Plasma Ratio) | AUC0-∞ of whole blood total radioactivity to AUC0-∞ of plasma total radioactivity (AUC0 ∞ Blood/Plasma Ratio) will be calculated | At predose to maximum up to Day 12 | 
| Mean residence time | Mean residence time for saroglitazar and saroglitazar sulfoxide will be calculated | At predose to maximum up to Day 12 | 
| Total radioactivity amount excreted in urine and feces | Amount of radioactivity excreted in urine and Feces will be calculated. | At predose to maximum up to Day 12 | 
| Percentage radioactivity excreted in urine and feces | Percentage radioactivity excreted in urine and Feces will be calculated. | At predose to maximum up to Day 12 | 
| Renal clearance (CLR) | Renal clearance for saroglitazar and saroglitazar sulfoxide will be determined | At predose to maximum up to Day 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic profile/ identifications of metabolites and probable structure elucidation for saroglitazar in plasma, urine, and feces | Metabolic profile/ identifications of metabolites and probable structure elucidation for saroglitazar in different matrices like plasma, urine, and feces will be performed and reported | Maximum up to Day 12 | 
| Number of Participants with Adverse Events (AEs) as a Measure of Safety and Tolerability | Incidence and severity of AEs as a measure of safety and tolerability will be measured and reported | Maximum up to Day 12 |