Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

ABSTRACT

Introduction: Tacrolimus (Tac) is the cornerstone of immunosuppressive therapy after solid organ transplantation and will probably remain so. Excluding belatacept, no new immunosuppressive drugs were registered for the prevention of acute rejection during the last decade. For several immunosuppressive drugs, clinical development halted because they weren’t sufficiently effective or more toxic.

Areas covered: Current methods of monitoring Tac treatment, focusing on traditional therapeutic drug monitoring (TDM), controversies surrounding TDM, novel matrices, pharmacogenetic and pharmacodynamic monitoring are discussed.

Expert opinion: Due to a narrow therapeutic index and large interpatient pharmacokinetic variability, TDM has been implemented for individualization of Tac dose to maintain drug efficacy and minimize the consequences of overexposure. The relationship between predose concentrations and the occurrence of rejection or toxicity is controversial. Acute cellular rejection also occurs when the Tac concentration is within the target range, suggesting that Tac whole blood concentrations don’t necessarily correlate with pharmacological effect. Intracellular Tac, the unbound fraction of Tac or pharmacodynamic monitoring could be better biomarkers/tools for adequate Tac exposure – research into this has been promising. Traditional TDM, perhaps following pre-emptive genotyping for Tac-metabolizing enzymes, must suffice for a few years before these strategies can be implemented in clinical practice.

KEYWORDS:

• Immunosuppressive drugs
• kidney
• pharmacodynamics
• pharmacogenetics
• pharmacokinetics
• tacrolimus
• TDM
• transplantation

Article highlights

• Acute cellular rejection can occur when the tacrolimus concentration is within the target concentration range, demonstrating that tacrolimus whole blood concentrations do not always fully reflect its pharmacological effect.

• Immunoassays remain the backbone of assay services for tacrolimus now, so we must ensure that they are being used correctly.

• A high tacrolimus intra-patient variability is considered a risk factor for poor long-term transplantation outcomes.

• Other strategies for TDM, including pharmacodynamic monitoring, are promising clinical tools to ensure adequate tacrolimus exposure and optimal efficacy of the drug.

• Pharmacogenetics-assisted tacrolimus monitoring, especially when incorporated in dosing algorithms, could be useful to determine the starting dose of tacrolimus

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Declaration of Interest

Dennis Hesselink has received grant support and lecture and consulting fees from Astellas Pharma and Chiesi Pharmaceuticals, as well as a lecture fee from Hikma Pharma. Teun Van Gelder has received a study grant from Chiesi Pharmaceuticals, lecture fees from Chiesi Pharmaceuticals. Astellas Pharma. Roche Pharma and Novartis Pharma, and consulting fees from Astellas Pharma, Novartis Pharma, and Teva Pharma. Brenda de Winter has received travels support from Astellas Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper is not funded.