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

• 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: University of Illinois at Chicago
• Collaborator: Astellas Pharma US, Inc.
• Information provided by (Responsible Party): Patricia West-Thielke, University of Illinois at Chicago

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Kidney Transplantation	Drug: tacrolimus extended release	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pharmacokinetic Analysis of Tacrolimus ER Dosing in Obese Kidney Transplant Recipients
• Study Start Date: May 2015
• Actual Primary Completion Date: February 28, 2017
• Actual Study Completion Date: June 9, 2017

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: IBW; tacrolimus extended release 0.15 mg/kg/day based on Ideal Body Weight (IBW)	Drug: tacrolimus extended release; Other Name: Astagraf XL
Experimental: ABW; tacrolimus extended release 0.15 mg/kg/day based on adjusted Body Weight (aBW)	Drug: tacrolimus extended release; Other Name: Astagraf XL

Outcome Measures

Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 100 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Illinois

University of Illinois Hospital & Health Sciences System

Chicago, Illinois, United States, 60612

Sponsors and Collaborators

University of Illinois at Chicago

Astellas Pharma US, Inc.

  Study Documents (Full-Text)

Documents provided by Patricia West-Thielke, University of Illinois at Chicago:

Study Protocol and Statistical Analysis Plan  [PDF] September 19, 2016

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Conley MM, McFarlane CM, Johnson DW, Kelly JT, Campbell KL, MacLaughlin HL. Interventions for weight loss in people with chronic kidney disease who are overweight or obese. Cochrane Database Syst Rev. 2021 Mar 30;3(3):CD013119. doi: 10.1002/14651858.CD013119.pub2.

Jasiak-Panek NM, Wenzler E, Patel S, Thielke JJ, Progar K, Patel S, Brandt S, Huang YJ, Benedetti E, West-Thielke PM. A randomized, open-label pharmacokinetic trial of tacrolimus extended-release dosing in obese de novo kidney transplant recipients. Clin Transplant. 2019 Aug;33(8):e13640. doi: 10.1111/ctr.13640. Epub 2019 Jul 1.

• Responsible Party: Patricia West-Thielke, Director of Clinical Research, University of Illinois at Chicago
• ClinicalTrials.gov Identifier: NCT02444143
• Other Study ID Numbers: 2014-XXXX
• First Posted: May 14, 2015
• Results First Posted: November 7, 2018
• Last Update Posted: November 7, 2018
• Last Verified: November 2018

Keywords provided by Patricia West-Thielke, University of Illinois at Chicago:

Kidney; Immunosuppression; Transplant

Additional relevant MeSH terms:

Tacrolimus; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Calcineurin Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action