Study To Evaluate Pharmacokinetics Of Sirolimus In Stable Renal Transplant Recipients

An Open-Label, Non-Randomized Study To Evaluate The Steady-State Pharmacokinetics Of Sirolimus Tablets In Chinese Patients With Stable Renal Allografts

Sirolimus, 1 mg, white, triangular tablets (Rapamune®) was approved on 03 April 2007 in China for prophylaxis of organ rejection in renal transplantation. A pharmacokinetic (PK) study to be conducted in renal allograft recipients was requested by State Food and Drug Administration (SFDA) to provide further guidance for clinical use.

To minimize risk to patients, this study is designed to collect blood PK samples from renal allograft recipients who are currently under sirolimus (1 mg tablets) treatment with or without concomitant medication(s). PK samples will be collected from these patients to characterize the steady state PK of sirolimus during sirolimus maintenance therapy. This study will not involve any changes to the established treatment regimen for the patients who enroll in the study

Study Overview

• Status: Completed
• Conditions: Renal Transplantation; Transplant Rejection
• Intervention / Treatment: Drug: Sirolimus

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Chongqing, China, 400038
    • Pfizer Investigational Site
  • Shanghai, China, 200127
    • Pfizer Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female, above 18 years of age and Body Mass Index (BMI) of 18.0 to 25.0 kg/m2, inclusive;
• Subjects must have received a primary or secondary renal allograft for at least 2 months prior to Screening;
• Subjects must be currently taking Rapamune tablets for prophylaxis of renal rejection. The dosages of any medications must be stable for at least 2 weeks prior to screening and continue with no change until completion of the last PK sample collection.

Exclusion Criteria:

• Acute rejection or vascular rejection episode in the 4 weeks prior to Screening; or patients dependent on dialysis; or inadequate renal function (in the opinion of the investigator);
• Recipients of multiple organ transplants (i.e., prior or concurrent transplantation of any organs other than renal transplant);
• Current use of strong inducers or inhibitors of CYP3A4 within 2 weeks prior to collection of the first PK sample and until collection of the final PK sample;
• Any clinically significant medical or psychiatric condition or laboratory abnormality, in the judgment of the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: sirolimus; Subjects must be taking sirolimus (1 mg tablet formulation) with or without concomitant medications, unless specifically excluded below, for prophylaxis of renal rejection.	Drug: Sirolimus; Sirolimus, 1 mg, white, triangular tablets, daily dose, dosages of any of these medications must be stable for at least 2 weeks prior to screening and continue with no change until completion of the last PK sample collection.; Other Names: Rapamune

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Blood Concentration at Steady State (Cmax,ss)		Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours post dose
Time to Reach Maximum Observed Blood Concentration at Steady State (Tmax,ss)		Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours post dose
Observed Blood Trough Concentration at Steady State (Ctrough,ss)		Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours post dose
Average Blood Concentration at Steady State (Cave,ss)		Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours post dose
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) at Steady State		Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours post dose
Degree of Fluctuation (DF)	DF, also known as peak to trough fluctuation (PTF) (calculated as [Cmax minus Ctrough] divided by Cave), is a unit-less ratio of the Cmax to Ctrough decrease expressed as a fraction of the average concentration during a dosing interval.	Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours post dose
Apparent Oral Clearance (CL/F)	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.	Predose (0 hour) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12 and 24 hours post dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Serum Creatinine Levels More Than (>) 1.3 Times the Upper Limit of Normal	Serum creatinine, an indicator of kidney function, formed from the metabolism of creatine, commonly found in blood, urine, and muscle tissue, is removed from blood by kidneys and excreted in urine. Increased creatinine in blood indicates decreased kidney function. Creatinine levels are age, gender and race dependent as they are related to an individual's muscle mass. Renal transplant recipients may have elevated serum creatinine. For this study an abnormal serum creatinine level is defined as 1.3 times the upper limit of normal (ULN) for the laboratory where the determination was performed.	From baseline up to Day 4
Number of Participants With Estimated Glomerular Filtration Rate (GFR) Less Than (<) 60 mL/Min/1.73 m^2	GFR, an index of kidney function, describes flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. GFR was calculated using the Simplified Modification of Diet in Renal Dysfunction (MDRD) GFR equation. Normal GFR is >90 mL/min/1.73 m^2; children and older people usually have lower GFR. Often, kidney transplant recipients do not have normal GFRs. Lower values indicate poor kidney function. GFR <15 mL/min/1.73 m^2 is consistent with kidney failure. For this posting, the number of subjects with a GFR <60 mL/min/1.73 m^2 is listed.	From baseline up to Day 4

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Wang HF, Qiu F, Wu X, Fang J, Crownover P, Korth-Bradley J, Schulman S. Steady-state pharmacokinetics of sirolimus in stable adult Chinese renal transplant patients. Clin Pharmacol Drug Dev. 2014 May;3(3):235-41. doi: 10.1002/cpdd.96. Epub 2014 Feb 10.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): April 1, 2011
• Study Completion (Actual): April 1, 2011

Study Registration Dates

• First Submitted: November 5, 2010
• First Submitted That Met QC Criteria: November 5, 2010
• First Posted (Estimate): November 7, 2010

Study Record Updates

• Last Update Posted (Estimate): March 1, 2012
• Last Update Submitted That Met QC Criteria: February 29, 2012
• Last Verified: April 1, 2011

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Organ Transplants; Anti-Rejection Therapy
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: B1741018