Predictors of tacrolimus pharmacokinetic variability: current evidences and future perspectives

ABSTRACT

Introduction

In kidney transplantation, tacrolimus (TAC) is at the cornerstone of current immunosuppressive strategies. Though because of its narrow therapeutic index, it is critical to ensure that TAC levels are maintained within this sharp window through reactive adjustments. This would allow maximizing efficiency while limiting drug-associated toxicity. However, TAC high intra- and inter-patient pharmacokinetic (PK) variability makes it more laborious to accurately predict the appropriate dosage required for a given patient.

Areas covered

This review summarizes the state-of-the-art knowledge regarding drug interactions, demographic and pharmacogenetics factors as predictors of TAC PK. We provide a scoring index for each association to grade its relevance and we present practical recommendations, when possible for clinical practice.

Expert opinion

The management of TAC concentration in transplanted kidney patients is as critical as it is challenging. Recommendations based on rigorous scientific evidences are lacking as knowledge of potential predictors remains limited outside of DDIs. Awareness of these limitations should pave the way for studies looking at demographic and pharmacogenetic factors as well as gut microbiota composition in order to promote tailored treatment plans. Therapeutic approaches considering patients’ clinical singularities may help allowing to maintain appropriate concentration of TAC.

Graphical abstract

KEYWORDS:

• Tacrolimus
• kidney transplantation
• pharmacokinetics
• pharmacogenetics
• demographic factors
• drug interactions

Article highlights

• TAC concentrations can be affected by several factors such as genetics, demographics, drug–drug interactions or microbiota composition.

• Taking this information into account might allow individualized treatments with increased efficiency and reduced toxicity.

• We provide a scoring index for known associations between these factors and TAC PK to grade the relevance of these associations.

• For drug–drug interactions, we present clear guidelines to clinicians allowing for a better control of TAC PK.

• For demographics, ageing and ethnicity appear to be of relevance for explaining part of the TAC PK disparities.

• For Pharmacogenetics, several lines of evidences pinpoint the potential benefit of CYP3A5 pre-emptive genotyping strategy for TAC dosage individualization.

• More recently, some clues have been highlighted for a possible involvement of microbiota in TAC PK.

• In the Expert opinion section, we recap the current state of knowledge and provide perspectives for future research into TAC PK inter- and intra-individual variability.

This box summarizes key points contained in the article.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Fonds de la Recherche Scientifique – FNRS under Grant No F450919F. A. Degraeve is a research fellow of the Fonds de la Recherche Scientifique - FNRS (FC-37471). This work was also completed with the financial support of the French community of Belgium (WBI program) through FSR action (UCLouvain).