Study To Evaluate Pharmacokinetics Of Sirolimus In Stable Renal Transplant Recipients

Study Overview
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Brief Summary
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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

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

Conditions
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Transplant Rejection, Renal Transplantation

Intervention / Treatment
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* Drug: Sirolimus


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sirolimus<br>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<br>* 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.<br>* Other names: Rapamune;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Organ Transplants, Anti-Rejection Therapy, Pharmacokinetics