Pharmacokinetics of tacrolimus-based combination therapies

This paper reviews the pharmacokinetics of tacrolimus, with special reference to its combination with adjunctive immunosuppressants. Oral bioavailability of tacrolimus, which is variable between patients, averages approximately 25%. This is largely due to extrahepatic metabolism of tacrolimus in the gastrointestinal epithelium. Nevertheless, intra-patient variability is low, as evidenced by the small number of dose changes required to maintain patients within the recommended tacrolimus target levels. Tacrolimus is distributed extensively in the body with most partitioned outside the blood compartment. Concentrations of tacrolimus in blood are used as a surrogate marker of clinically relevant concentration of the drug at the site(s) of action. Convenient whole-blood sampling within a +/-2-h window around 12 h post-dose (C(min)) is highly predictive of systemic exposure to tacrolimus and is thus used to optimise therapy. Sampling at other time-points offers no advantage over C(min) monitoring. The interactions of tacrolimus with other immunosuppressive agents are well characterized. After cessation of concomitant corticosteroid treatment, exposure to tacrolimus increases by approximately 25%. In contrast, there is no pharmacokinetic interaction between mycophenolate mofetil (MMF) and tacrolimus. Therefore, systemic exposure to the active metabolite of MMF, mycophenolic acid, is higher with MMF-tacrolimus combination than with MMF-cyclosporin combination. Therefore, 1 g/day MMF may be an adequate maintenance dose in tacrolimus-based regimens. Co-administration of tacrolimus and sirolimus, while having no effect on exposure to sirolimus, results in reduced exposure to tacrolimus at sirolimus doses of 2 mg/day and above. In conclusion, tacrolimus levels should be monitored when sirolimus is co-administered at doses >2 mg/day and after cessation of corticosteroid treatment.