A Pharmacokinetic Study of Saroglitazar Magnesium in Subjects With Severe Renal Impairment and Normal Renal Function

A Phase 1, Open-Label Study to Evaluate the Pharmacokinetics and Safety of Saroglitazar Magnesium in Participants With Normal Renal Function and Participants With Severe Renal Impairment.

This will be a Phase 1, Open-label Study of Participants with Normal Renal Function and Participants with Sever Renal Impairment.

Study Overview

• Status: Recruiting
• Conditions: Renal Impairment
• Intervention / Treatment: Drug: Saroglitazar magnesium

Detailed Description

A total of 32 participants will be enrolled:

Group 1 (Severe renal impairment not on HD, eGFR <30) - 16 subjects Subjects will be enrolled and dosed consecutively (i.e. first 8 subjects of group 1 will receive 2 mg dose, followed by another 8 subjects who will receive 4 mg dose).

Group 2 (Normal renal function eGFR ≥90) - 16 subjects Subjects in this group will be matched according to age (± 10 years), sex, and weight (± 10 kg) with participants in Group 1 (Severe renal impairment not on HD) on a one to one basis based on demographic characteristic. In this group, 8 participants will be administered single dose of 2 mg Saroglitazar Magnesium and 8 participants will be administered single dose of 4 mg Saroglitazar Magnesium.

• Study Type: Interventional
• Enrollment (Estimated): 32
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Farheen A. Shaikh; Phone Number: +1 6094534751; Email: fshaikh@zydustherapeutics.com

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78215
      • Recruiting
      • American Research Corporation @ Texas Liver Institute
      • Contact: Dr. Eric Lawitz, MD; Phone Number: 210-253-3426; Email: lawitz@txliver.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Ability to comprehend and willingness to sign a written ICF for the study.
2. Male or female subjects aged 18 to 80 years (inclusive) at the time of signing the ICF.
3. Participants will be classified at screening by renal function as determined by the modification of diet in renal disease (MDRD) formula for estimated glomerular filtration rate (eGFR) in subjects with chronic kidney disease (CKD). Classification will be repeated at Day -1, if the renal function classification for the participant is not the same at the two time points, enrollment of the participant will be based on eGFR at screening.
4. Group 2 (Normal renal function) subjects, should be in good health as determined by no clinically significant deviations from normal for medical history, physical examination, vital signs, 12 lead electrocardiograms (ECGs), or laboratory examinations at screening or Day-1.
5. Group 1 (Severe renal impairment not on HD, eGFR <30) subjects, may have medical findings consistent with their degree of renal impairment, as determined by medical history, physical examination, vital signs, ECGs, and clinical laboratory examinations at screening and Day -1. Participants are eligible if abnormal findings are considered not clinically significant by the Investigator.
6. Body mass index within the range 18.0 to 48.0 kg/m2 (inclusive) at screening.
7. Females must be non-pregnant, non-lactating and of non-childbearing potential or using highly efficient contraception for the full duration of the study. Female of childbearing potential and Males must agree to use contraception for the full duration of the study.
8. Ability to swallow and retain oral medication.
9. Laboratory test values within normal limits or considered not clinically significant by the investigator for subjects in Group 2 with normal renal function. Must have eGFR ≥ 90 by MDRD calculation.
10. Group 2 patients with normal renal function must match in age (± 10 years), sex, and weight (± 10 kg) with severe renal impairment participants in the Group 1.

11. Laboratory test values for severe renal impairment subjects must be clinically acceptable to the Investigator and meet all of the following parameters at screening:

    1. ALT value ≤ 3 × ULN
    2. AST value ≤ 3 × ULN
    3. Absolute neutrophil count (ANC) ≥ 750/mm3
    4. Platelets ≥ 50,000/mm3

Exclusion Criteria:

1. Any significant, unstable medical condition or other instability that would prevent the subject from participating in the study as determined by the investigator or designee.
2. History of malignancy of any type in the last 3 years of screening, with the exception of the following: in situ cervical or breast cancer or surgically excised non-melanoma skin cancers (i.e. basal cell or squamous cell carcinoma).
3. History of stomach or intestinal surgery or resection within the six months prior to screening that would potentially alter absorption and/or excretion of orally administered drugs (uncomplicated appendectomy, cholecystectomy, and hernia repair will be allowed).
4. History of any significant drug allergy (such as anaphylaxis) deemed clinically relevant by the investigator.
5. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of asymptomatic gallstones) or other hepatic abnormalities that in the opinion of the investigator would preclude the subject from participation in the study.
6. Any major surgery within 3 months of screening.
7. Donation of blood or blood products within 3 months prior to screening.
8. Blood transfusion within 2 weeks of Day -1.
9. Current active infectious disease requiring systemic antibiotic, antifungal, or antiviral treatment.
10. Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's Wort, within 21 days prior to screening, unless deemed acceptable by the Investigator.
11. Receiving or has received any investigational drug within the 30 days or 5 halflives (whichever is longer), before receiving Saroglitazar Magnesium.
12. Group 2 (Normal renal function) subjects, who have a history of renal disease or renal injury as indicated by an abnormal BUN or creatinine at screening or Day-1.
13. Group 1 (Severe renal impairment) subjects, who have had a change in renal disease status within 30 days of screening, as documented by the participant's medical history and deemed clinically significant by the investigator.
14. For healthy renal function subjects, QT interval corrected for heart rate using Fridericia's method (QTcF) > 450 msec, confirmed by repeat measurement. In renal impaired subjects QTcF > 500 msec, confirmed by repeat measurement; no second or third degree AV block.
15. Group 1 subjects, who use or intend to use any over-the-counter (vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations) or prescription medications within 30 days or 5 half-lives (whichever is longer) prior to enrollment, with the exception of hormone replacement therapy and therapies for renal disease and treatments of associated disorders that have been stable for at least 30 days prior to screening and until Day 1, unless deemed acceptable by the investigator (or designee).
16. Group 2 Subjects who have taken any prescription medications or over-the counter medications, including herbal products, within 14 days prior to start of study drug dosing, with the exception of vitamins, acetaminophen, hormonal contraceptive medications and/or any other over-the-counter product approved by the investigator.
17. Positive alcohol breath test at the time of check-in or those subjects who have current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance or subject safety.
18. Positive test for drugs of abuse at screening or admission.
19. Any subject with poor peripheral venous access.
20. Human immunodeficiency virus (HIV) type 1 antibody, HBsAg or HCV-Ab positive at screening.

21. Additional exclusion criteria for Severe Renal Impairment subjects:

    1. History of nephrectomy or renal transplant
    2. Any type of dialysis within 3 months prior to screening
    3. Electrolyte abnormality or other screening laboratory value deemed clinically significant by investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; Subjects in severe renal impairment group will be enrolled and dosed consecutively (i.e. first 8 subjects of group 1 will receive 2 mg dose, followed by another 8 subjects who will receive 4 mg dose).	Drug: Saroglitazar magnesium; 1 dose of 2mg and 4 mg Saroglitazar magnesium will be given to subjects on Day 1; Other Names: not any
Experimental: Group 2; Subjects (Normal renal function eGFR ≥90) will be matched according to age (± 10 years), sex, and weight (± 10 kg) with participants in Group 1 (Severe renal impairment not on HD) on a one to one basis based on demographic characteristic. Here, 8 participants will be administered single dose of 2 mg Saroglitazar Magnesium and 8 participants will be administered single dose of 4 mg Saroglitazar Magnesium.	Drug: Saroglitazar magnesium; 1 dose of 2mg and 4 mg Saroglitazar magnesium will be given to subjects on Day 1; 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-∞)	The area under the plasma concentration versus time curve from zero to infinity will be calculated by adding Ct/Kel to AUCt, where Ct is the last quantifiable concentration and Kel is the elimination rate constant.	Before dosing on Day 1 through Day 7
AUC from time zero to the last quantifiable concentration (AUC0-t)	The area under the plasma concentration versus time curve will be calculated using the linear trapezoidal rule from the zero time point to the last quantifiable concentration.	Before dosing on Day 1 through Day 7
Cmax	Maximum measured plasma concentration over the time span specified.	Before dosing on Day 1 through Day 7
Tmax	Time of the maximum measured plasma concentration.	Before dosing on Day 1 through Day 7
t1/2	The half-life will be calculated by the equation tHalf = 0.693/ Kel. Kel (The terminal elimination rate constant) will be obtained from the slope of the line, fitted by linear least squares regression, through the terminal points of the natural log of the concentration versus time plot for these points	Before dosing on Day 1 through Day 7
CL/F	Clearance	Before dosing on Day 1 through Day 7
Vz/F	Volume of distribution	Before dosing on Day 1 through Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urine Pharmacokinetic: Ae	Amount of drug excreted during each collection interval	Before dosing on Day 1 through Day 5
Incidence of AEs	Incidence and severity of AEs as a measure of safety and tolerability will be measured and reported.	Before dosing on Day 1 through Day 12
Unbound Fraction	Unbound fraction in plasma of Saroglitazar	Day 1
Unbound concentration	Unbound concentration in plasma of Saroglitazar	Day 1

Collaborators and Investigators

• Sponsor: Zydus Therapeutics Inc.
• Investigators: Study Director: Deven Parmar, MD, Zydus Therapeutics Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 27, 2020
• Primary Completion (Estimated): March 30, 2024
• Study Completion (Estimated): August 30, 2024

Study Registration Dates

• First Submitted: June 15, 2020
• First Submitted That Met QC Criteria: June 22, 2020
• First Posted (Actual): June 25, 2020

Study Record Updates

• Last Update Posted (Actual): October 10, 2023
• Last Update Submitted That Met QC Criteria: October 6, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Renal Insufficiency
• Other Study ID Numbers: SARO.19.004

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No