Evaluation of Flexible Tacrolimus Drug Concentration Monitoring Approach in Patients Receiving Extended‐Release Once‐Daily Tacrolimus Tablets

Abstract

The majority of United States kidney transplant patients are treated with tacrolimus, a drug effective in preventing graft rejection, but with a narrow therapeutic range, necessitating close monitoring to avoid increased risks of transplant rejection or toxicity if the tacrolimus concentration is too low or too high, respectively. The trough drug concentration tests are time sensitive; patients treated on a twice‐daily basis have blood draws exactly 12 hours after their previous dose. The schedule's rigidity causes problems for both patients and health care providers. Novel once‐daily tacrolimus formulations such as LCPT (an extended‐release tablet by Veloxis Pharmaceuticals, Inc., Cary, North Carolina) have allowed for blood draws on a once‐daily basis; however, even that schedule can be restrictive. Results from tests taken either before or after that 24‐hour target time may be discarded, or worse, may lead to inappropriate dose changes. Data from ASTCOFF, a phase 3B pharmacokinetic clinical trial (NCT02339246), demonstrated that the unique pharmacokinetic curve of LCPT may allow for a therapeutic monitoring window that extends for 3 hours before or after the 24‐hour monitoring target. Furthermore, important tools to help clinicians interpret these levels, such as formulas to estimate the 24‐hour trough level if an alternative monitoring time is used, were constructed from these data. These study results give treating clinicians access to data that allow them to safely use and monitor LCPT in their patients and expand the body of evidence surrounding differentiation and practical application of the novel LCPT tacrolimus formulation.

Dosing strategies for de novo once-daily extended release tacrolimus in kidney transplant recipients based on CYP3A5 genotype

“…Recommendations for all CYP3A5 expressers is to provide initial tacrolimus dosing of 1.5-2 times the recommended starting dose and to not exceed a starting dose of 0.3 mg/kg/d. CYP3A5 expressers in our study required approximately 1.5 times the recommended FDA-approved 0.14 mg/kg/d starting dose for LCPT to achieve therapeutic tacrolimus trough concentrations[ 6 ]. The majority of CYP3A5 expressers in this study required an approximate 20% reduction in the mean LCPT dose at day 30 from the time of attainment of therapeutic tacrolimus trough concentrations.…”

“…Compared to immediate release tacrolimus, once daily extended-release formulations have demonstrated similar efficacy and safety in the de novo kidney transplant setting leading to increased utilization[ 1 , 2 , 4 , 5 ]. Life cycle pharma tacrolimus (LCPT) (Envarsus ® ; Veloxis Pharmaceuticals) was designed to enhance the bioavailability of tacrolimus[ 6 ]. In published studies, utilization of LCPT has been shown to provide rapid achievement of target trough concentrations following kidney transplantation[ 1 , 2 , 7 ].…”

“…The use of LCPT has been Food and Drug Administration (FDA)-approved for the prophylaxis of organ rejection in de novo kidney transplant patients and in kidney transplant patients converted from tacrolimus immediate-release formulations[ 6 ]. The recommended FDA-approved dosing for de novo kidney transplant recipients is 0.14 mg/kg/d, however various starting doses have been evaluated in clinical trials[ 1 , 2 , 6 ]. Some kidney transplant recipients are known to metabolize tacrolimus at a higher or lower rate due to the presence of genetic polymorphisms that affect its metabolism[ 9 ].…”

Incidental Finding of Post-Transplant Erythrocytosis After Renal Transplantation in a Patient With Chronic Kidney Disease: A Case Report

“…In our case, the patient was young and a donor was available, leading the patient to undergo a kidney transplant. The patient's immunosuppressive regimen included tacrolimus as the primary choice of agent [6,7].…”

Conversion from Extended-Dose-Release Tacrolimus to Melt-Dose Tacrolimus in High Metabolizer Patients: Is the New Formulation of LPCT the Best Option for High Metabolizer Kidney Transplanted Patients?

“…LCPT formulations would allow greater flexibility in the timing of blood draws for tacrolimus concentrations. Philosophe et al (1) found that blood concentrations taken at both 21 and 27 h post-dose were highly correlated with area under the concentration-time curve over 24 h AUC. The high correlation coefficients found in this study were similar to those found by Gaber et al (3) in a phase 2 study of stable adult kidney transplant patients on IR-Tac who were converted to LCPT.…”