Opportunities to Optimize Tacrolimus Therapy in Solid Organ Transplantation: Report of the European Consensus Conference

Abstract

In 2007, a consortium of European experts on tacrolimus (TAC) met to discuss the most recent advances in the drug/dose optimization of TAC taking into account specific clinical situations and the analytical methods currently available and drew some recommendations and guidelines to help clinicians with the practical use of the drug. Pharmacokinetic, pharmacodynamic, and more recently pharmacogenetic approaches aid physicians to individualize long-term therapies as TAC demonstrates a high degree of both between- and within-individual variability, which may result in an increased risk of therapeutic failure if all patients are administered a uniform dose. TAC has undoubtedly benefited from therapeutic drug monitoring, but interpretation of the blood concentration is confounded by the relative differences between the assays. Single time points, limited sampling strategies, and area under concentration-time curve have all been considered to determine the most appropriate sampling procedure that correlates with efficacy. Therapeutic trough TAC concentration ranges have changed since the initial introduction of the drug, while still maintaining adequate immunosuppression and avoiding drug-related adverse effects. Pharmacodynamic markers have also been considered advantageous to the clinician, which may better reflect efficacy and safety, taking into account the between-individual variability rather than whole blood concentrations. The choice of method, differences between methods, and potential pitfalls of the method should all be considered when determining TAC concentrations. The recommendations of this consensus meeting regarding the analytical methods include the following: encourage the development and promote the use of analytical methods displaying a lower limit of quantification (1 ng/mL), perform careful validation when implementing a new analytical assay, participate in external proficiency testing programs, promote the use of certified material as calibrators in high-performance liquid chromatography with mass spectrometric detection methods, and take account of the assay and intermethod bias when comparing clinical trial outcomes. It is also important to consider that TAC concentrations may also be influenced by other factors such as specific pharmacokinetic characteristics associated with the population, drug interactions, pharmacogenetics, adverse events that may alter TAC concentrations, and any change in the oral formulation that may result in pharmacokinetic changes. This meeting emphasized the importance of obtaining multicenter prospective trials to assess the efficacy of alternative strategies to TAC trough concentrations whether it is other single time points or area under the concentration-time curve Bayesian estimation using limited sampling strategies and to select, standardize, and validate routine biomarkers of TAC pharmacodynamics.

Rapid measurement of tacrolimus in whole blood by paper spray-tandem mass spectrometry (PS-MS/MS)

“…Dose adjustment based on therapeutic drug monitoring (TDM) leads to better clinical outcome, especially in pediatric transplant recipients (1,2)]. Most clinical laboratories use either immunoassay or liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure tacrolimus.…”

Dosing equation for tacrolimus using genetic variants and clinical factors

“…It has a narrow therapeutic window with wide inter-individual variability in pharmacokinetics and clearance (CL) [2,3]. Higher troughs are associated with increased risk of toxicity whereas lower troughs are associated with increased risk of rejection [4].…”

The Monitoring of Immunosuppressive Therapy with Tacrolimus in Patients with Kidney Transplant, Based on the Pharmacokinetic Criteria

“…During monitoring 252 blood determinations of tacrolimus concentration at steady-state C min(trough) have been performed with a mean of 7 determinations per patient. 58 of these determinations were not in the therapeutic range (4-11 ng/ml), established by the current therapeutic guides [6]. 44 samples pointed at underdose, being under 4 ng/ml and 14 determinations were over 11 ng/ml, being over the therapeutic range, pointing at overdosage and toxic level.…”