New Horizons in Kidney Transplantation
Pharmacokinetics of tacrolimus: clinically relevant aspects

https://doi.org/10.1016/S0041-1345(99)00788-5Get rights and content

Section snippets

Absorption

Tacrolimus is absorbed rapidly following oral administration of Prograf® capsules (the marketed formulation of tacrolimus). At an oral dose of 0.15 mg/kg/12 hours at steady state, the peak concentration (Cmax) averages 45 ng/mL, with a corresponding mean time to peak concentration (Tmax) of 1.5 hours. The mean oral bioavailability of tacrolimus is approximately 20% (range 6% to 43%). This degree of interpatient variability in bioavailability requires the dosage to be individualized to achieve

Distribution

Tacrolimus binds strongly to erythrocytes in the systemic circulation, resulting in a whole blood/plasma concentration distribution ratio of approximately 20:1.5 In plasma, the drug is highly bound to plasma proteins (>98.8%), mainly to serum albumin and α-1-acid glycoprotein.

Tacrolimus is distributed extensively in the body. At steady state, the plasma volume of distribution is greater than 1,000 L and in whole blood is approximately 50 L. This indicates that at steady state the majority of

Metabolism and excretion

Systemically available tacrolimus is cleared by hepatic metabolism. Cytochrome P450 3A4 (CYP3A4) isoenzyme is the principal enzyme responsible for its metabolism.6 In man, CYP3A enzymes are also expressed in the upper gastrointestinal tract. Presystemic metabolism by gastrointestinal CYP3A averages around 50% and is considered to be responsible for the limited bioavailability of tacrolimus.

Eight metabolites have so far been characterized using 14C-labeled tacrolimus in in vitro preparations of

Clearance

Tacrolimus is a low clearance drug, with an extraction ratio of <3% of hepatic blood flow. The clinical implication of low clearance and extensive distribution of the drug outside the blood compartment is that dosage changes may take several days to reach steady-state blood levels. Clearance of tacrolimus also changes with time posttransplant; changes in hematocrit and albumin levels, and corticosteroid dose are significant factors affecting clearance.10 Thus, during maintenance therapy, lower

Interactions

Drugs or compounds that inhibit or induce the CYP3A4 isoenzyme may increase or decrease tacrolimus blood levels, respectively. Examples of strong inhibitors include ketoconazole, itraconazole and fluconazole. Concomitant oral administration of such drugs with tacrolimus necessitates, on average, a 50% reduction in the oral dose of tacrolimus in order to maintain tacrolimus blood levels. Conversely, concomitant oral administration of strong inducers, eg, rifampicin and phenytoin, often requires

Therapeutic range

Data from several multicenter studies have been evaluated to determine the relationship between tacrolimus blood levels and toxicity and efficacy. Kershner and Fitzsimmons13 examined data from a dose optimization study performed in the USA. The results showed statistically significant relationships between both acute rejection, toxicity and tacrolimus blood concentration.

The relationship between low systemic exposure to tacrolimus and acute rejection has been confirmed in another evaluation14

Additional evaluations

The relationship between tacrolimus trough blood levels and adverse events has also been investigated using data from renal allograft recipients randomized to treatment with tacrolimus in a European, multicenter, phase III comparative study of the efficacy and safety of tacrolimus and cyclosporine.15 A total of 303 patients were randomized to treatment with tacrolimus. Their mean age was 46.6 years (range 18 to 72 years) and their mean weight was 67.6 kg (range 33 kg to 130 kg); 196 of the 303

Discussion and conclusion

The therapeutic range of tacrolimus, based on trough whole blood concentration, is considered to be 10 to 20 ng/mL during the early posttransplant period, as shown in the published literature and the evaluations reported here. Exposure to concentrations <10 ng/mL is associated with an increased risk of acute rejection, whereas extended exposure to concentrations >20 ng/mL increases the risk of developing adverse events. Other factors, such as concomitant medication and demographic features have

Acknowledgements

The authors would like to acknowledge the physicians who participated in the multicenter trials of tacrolimus in renal transplantation.

First page preview

First page preview
Click to open first page preview

References (15)

  • N.A Undre et al.

    Transplant Proc

    (1998)
  • K Zucker et al.

    Transpl Immunol

    (1997)
  • N.A Undre et al.

    Transplant Proc

    (1998)
  • N.A Undre et al.

    Transplant Proc

    (1999)
  • N Yoshimura et al.

    J Immunol Immunopharmacol

    (1990)
  • F.T Aweeka et al.

    Clin Pharmacol Ther

    (1993)
  • C Lee et al.

    Clin Pharmacol Ther

    (1993)
There are more references available in the full text version of this article.

Cited by (67)

  • In vitro selection of tacrolimus binding aptamer by systematic evolution of ligands by exponential enrichment method for the development of a fluorescent aptasensor for sensitive detection of tacrolimus

    2020, Journal of Pharmaceutical and Biomedical Analysis
    Citation Excerpt :

    TDM of TAC is required because of its narrow therapeutic window [3]. The concentration of TAC in whole blood must be retained at 6.21–24.87 nM to reduce its side effects [4,5]. Therefore, development of an easy and sensitive method is needed for the determination of TAC concentration in blood samples [6].

  • Individualizing Transplant Therapy

    2017, Individualized Drug Therapy for Patients: Basic Foundations, Relevant Software and Clinical Applications
  • Long-Term Kidney Transplant Outcomes: Role of Prolonged-Release Tacrolimus

    2020, Transplantation Proceedings
    Citation Excerpt :

    As such, prolonged-release tacrolimus could be the most appropriate choice, particularly in patients where levels of tacrolimus are targeted toward the lower end of the target therapeutic range. Prolonged exposure above the upper limit of the recommended therapeutic window (tacrolimus trough levels > 15 ng/mL) could carry a greater risk of drug-related adverse events versus being within the therapeutic window [34,36,49]. An association between increasing tacrolimus trough levels and tacrolimus toxicity (increased creatinine levels, nephrotoxicity, neurotoxicity) has been observed [34,36,49–51].

View all citing articles on Scopus
View full text