Is there an interaction between phenytoin and tacrolimus or sirolimus?/nThe question concerns a 9-y

Fråga: Is there an interaction between phenytoin and tacrolimus or sirolimus?

The question concerns a 9-year-old girl with a history of hypothyreosis and aplastic anemia, who has received a bone marrow transplant and has been treated with sirolimus and tacrolimus, as well as fluconazole, levothyroxine, prednisolone, omeprazole, ursodeoxycolic acid. Fluconazole 200 mg daily was added day 26 and, due to a seizure episode, phenytoin and acyclovir were added at day 33 after the transplantation. The tacrolimus concentration increased after the fluconazole addition, necessitating a dose reduction. However, after the further addition of phenytoin, drug levels fell below the limit of quantification. Also, the serum concentration of sirolimus decreased to subtherapetic levels.

Sammanfattning: Phenytoin is a known enzyme inducer and can therefore be expected to increase the metabolism of, and thus lower the concentrations of both tacrolimus and sirolimus. Somewhat surprisingly, the evidence supporting this possible interaction is scarce and limited to a few case reports.

Svar: Phenytoin is a known inducer of the CYP3A enzymes (1), and as both tacrolimus and sirolimus are metabolised by CYP3A4, there is a pharmacokinetic basis for interactions (2,3). However, we have found no formal studies of these possible interactions and the evidence is thus limited to a few case reports:

Two case reports describe the effect of phenytoin on the serum concentration of tacrolimus in renal transplant recipients. The first report concerns a patient who initially needed a daily tacrolimus dose of 250 ug/kg (rendering a blood level of 9 ng/ml) during phenytoin treatment but in whom the dose had to be decreased to 160 ug/ml (blood level 11 ng/ml) after stopping phenytoin (4). The other report concerns a 19-year-old girl, where phenytoin was judged to cause widely varying serum concentrations of tacrolimus, resulting in a transplant rejection (5).

We also found one case report descibing an interaction between sirolimus and phenytoin. A liver transplanted patient had sirolimus trough levels below 5 ng/ml during concomitant phenytoin, despite a daily sirolimus dose of 15 mg. After discontinuation of phenytoin, the sirolimus level gradually increased to 20 ng/ml (6).

In the present case, both the dose reduction (from 10 to 4 mg daily) and the addition of phenytoin may have contributed to subtherapeutic tacrolimus levels. We suggest that the physician in charge continue to increase the doses of tacrolimus, as well as sirolimus, while closely monitoring the serum concentrations. Future changes in prescriptions of phenytoin, fluconazole, or other substrates known to inhibit or induce CYP3A4 should be followed by similar close monitoring of serum concentrations. Fenantoin Recip. Summary of product characteristics (SPC). Recip. Rapamune. Summary of product characteristics (SPC). Wyeth. Prograf. Summary of product characteristics (SPC). Astellas Pharma. Moreno M, Latorre A, Manzanares C, Morales E, Herrero JC, et al. Clinical management of tacrolimus drug interactions in renal transplant patients. Transplant Proc 1999;31:2252-3. Formea CM, Evans CG, Karlix JL. Altered Cytochrome P450 metabolism of Calcineurin inhibitors: Case report and review of the litterature. Pharmacotherapy 2005;25:1021-9. Fridell JA, Jain AK, Patel K, Virji M, Rao KN et al. Phenytoin decreases the blood concentrations of sirolimus in a liver transplant recipient: a case report. Ther Drug Monit. 2003;25:117-9.