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A Pharmacokinetic Analysis of Tacrolimus ER Dosing in Obese Kidney Transplant Recipients (Tacrolimus ER)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02444143
Recruitment Status : Completed
First Posted : May 14, 2015
Results First Posted : November 7, 2018
Last Update Posted : November 7, 2018
Sponsor:
Collaborator:
Astellas Pharma US, Inc.
Information provided by (Responsible Party):
Patricia West-Thielke, University of Illinois at Chicago

Tracking Information
First Submitted Date  ICMJE November 20, 2014
First Posted Date  ICMJE May 14, 2015
Results First Submitted Date  ICMJE May 18, 2018
Results First Posted Date  ICMJE November 7, 2018
Last Update Posted Date November 7, 2018
Study Start Date  ICMJE May 2015
Actual Primary Completion Date February 28, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 6, 2018)
Difference in Tacrolimus Exposure (AUC-0-24)) in Obese Patients Who Received an Initial TAC -ER Dose of 0.15 mg/kg Using aBW Versus IBW [ Time Frame: Days 1-14 ]
Difference in tacrolimus exposure (area under the concentration-time curve from time 0 to 24 hours (AUC-0-24)) in obese patients who received an initial TAC -ER dose of 0.15 mg/kg using aBW versus IBW
Original Primary Outcome Measures  ICMJE
 (submitted: May 11, 2015)
Difference in AUC [ Time Frame: Days 1, 7, and 14 ]
Difference in tacrolimus exposure (AUC24) in obese patients dosed using aBW compared to IBW.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 6, 2018)
Difference in Time to Therapeutic Level [ Time Frame: Days 1 to 7 ]
Difference in the time to a therapeutic tacrolimus trough level in the aBW group compared to the IBW group.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 11, 2015)
Difference in time to therapeutic level [ Time Frame: Days 1 to 7 ]
Difference in the time to a therapeutic tacrolimus trough level in the aBW group compared to the IBW group.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Pharmacokinetic Analysis of Tacrolimus ER Dosing in Obese Kidney Transplant Recipients
Official Title  ICMJE A Pharmacokinetic Analysis of Tacrolimus ER Dosing in Obese Kidney Transplant Recipients
Brief Summary Tacrolimus extended release (Astagraf) has recently been approved by the FDA as a once a day dosing regimen. This formulation has the potential to improve compliance. Current dosing recommendation for the extended release formulation in renal transplant is 0.15 mg/kg/day administered once daily in the morning. There are no specifications on appropriate dosing in obese patients or on whether to use actual, ideal or and adjusted weight. It will be advantageous to understand the pharmacokinetics of this medication in the obese to determine the appropriate dosing regimen. In this study, obese patients will be randomized to receive tacrolimus extended release 0.15 mg/kg/day based on either ideal body weight (IBW) or adjusted body weight (aBW).
Detailed Description

Tacrolimus exhibits significant inter- and intra-individual variability of its absorption and metabolism. Because of this variability, standard dosing is not an accurate predictor of drug exposure. In clinical use, tacrolimus whole blood trough concentrations are measured to ensure efficacy and safety. Furthermore, the relatively low bioavailability of tacrolimus is thought to be a result of the combination of poor water-solubility, pre-systemic metabolism of tacrolimus in the gastrointestinal tract and activity of the P-glycoprotein efflux pump found in the enterocytes of the GI tract. Tacrolimus is extensively metabolized by the cytochrome P-450 system (CYP3A). The plasma protein binding of tacrolimus is approximately 99%. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein. The distribution of tacrolimus between blood and plasma depends on several factors including hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration.

Pharmacodynamic studies have revealed that, depending on time following transplantation, maintaining whole blood trough levels between 5 and 20 ng/mL provides adequate protection against acute rejection and limits the occurrence of adverse events. The management of tacrolimus blood levels is complicated by variable intra- and inter-patient absorption, interaction with food and concomitant medications, and the relatively low bioavailability of tacrolimus from the Prograf formulation (17 ± 10% in adult kidney transplant patients).

Previous studies examining immunosuppressants have shown that drug levels in the immediate post-transplant period are a major determinant of subsequent acute cellular rejection. It is known that tacrolimus (TAC) < 10 ng/mL is associated with increased rates of acute cellular rejection by one month post-transplant.

There is controversy regarding the appropriate dosing weight to use for immunosuppressants (IS). Weights use range from ideal body weight (IBW) to total body weight (TBW) depending on the institution and drug being dosed. This becomes particularly important in the obese population when there are significant differences between IBW and TBW. Our institution has always used IBW for the dosing of all IS due to concerns for nephrotoxicity with initial high blood levels of tacrolimus. The concern in obese patients is that the investigators are underdosing this population that could be at higher risk for rejection due to higher circulating concentrations of pro-inflammatory cytokines. The introduction of the novel use of a robotic transplantation procedure at our institution for this patient population has led to increasing numbers of transplant in obese recipients; therefore, the investigators decided to re-evaluate our dosing protocol. Data from an internal study at UIC show that our use of IBW for tacrolimus dosing is not sufficient for the obese population (body mass index [BMI] ≥30). The dose used through month 3 was closer to 0.1 mg/kg/day when total body weight was utilized. However, the use of an adjusted body weight (aBW) is common for medication dosing in obese patients. Adjusted body weight is calculated if the TBW is greater than 30% of the calculated IBW. aBW = IBW + 0.4(TBW - IBW). There is limited data available supporting the use of either IBW or aBW in dosing tacrolimus within obese patients as these patients are typically excluded from most clinical trials, particularly the pharmacokinetic trials. In addition, no literature is available comparing the two dosing weights to determine which leads to therapeutic concentrations most effectively.

Summary and Present Study Tacrolimus extended release (Astagraf) has recently been approved by the FDA as a once a day dosing regimen. This formulation has the potential to improve compliance. Current dosing recommendation for the extended release formulation in renal transplant is 0.15 mg/kg/day administered once daily in the morning. There are no specifications on appropriate dosing in obese patients or on whether to use actual, ideal or and adjusted weight. It will be advantageous to understand the pharmacokinetics of this medication in the obese to determine the appropriate dosing regimen. In this study, obese patients will be randomized to receive tacrolimus extended release 0.15 mg/kg/day based on either ideal body weight (IBW) or adjusted body weight (aBW).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Kidney Transplantation
Intervention  ICMJE Drug: tacrolimus extended release
Other Name: Astagraf XL
Study Arms  ICMJE
  • Active Comparator: IBW
    tacrolimus extended release 0.15 mg/kg/day based on Ideal Body Weight (IBW)
    Intervention: Drug: tacrolimus extended release
  • Experimental: ABW
    tacrolimus extended release 0.15 mg/kg/day based on adjusted Body Weight (aBW)
    Intervention: Drug: tacrolimus extended release
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 11, 2015)
20
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE June 9, 2017
Actual Primary Completion Date February 28, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. The subject is a recipient of a living donor or deceased donor kidney only transplant
  2. Subject is > 18 years of age
  3. BMI≥30 on POD 0

Exclusion Criteria:

  1. Multi-organ transplant
  2. Subjects taking tacrolimus pre-transplant (i.e. positive crossmatch transplants or re-transplants)
  3. Patients undergoing simultaneous sleeve gastrectomy at the time of transplant.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02444143
Other Study ID Numbers  ICMJE 2014-XXXX
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Patricia West-Thielke, University of Illinois at Chicago
Study Sponsor  ICMJE University of Illinois at Chicago
Collaborators  ICMJE Astellas Pharma US, Inc.
Investigators  ICMJE Not Provided
PRS Account University of Illinois at Chicago
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP