New Horizons in Kidney TransplantationPharmacokinetics of tacrolimus: clinically relevant aspects
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.
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