Increase in tacrolimus trough levels after steroid withdrawal

Abstract

Although there are experimental reports of cytochrome P450 3A4 iso-enzyme (CYP3A4) induction by glucocorticoids, there are no clinical reports about an interaction between tacrolimus and steroids. Therefore, tacrolimus trough level and dose were compared after dose-normalization before and after withdrawal of prednisolone. After withdrawal of 5 mg prednisolone, the median tacrolimus dose-normalized level increased by 14% in the retrospective ( n=54), and by 11% in the prospective ( n=8) part of the study. After withdrawal of 10 mg, this increase was 33% ( n=30) and 36% ( n=14), respectively. An additional pharmacokinetic part of the study ( n=8) revealed an 18% increase in AUC ( P=0.05) after withdrawal of 5 mg prednisolone, which is compatible with a reduced metabolism after steroid withdrawal. The significant increase in tacrolimus exposure after steroid withdrawal may on the one hand counteract the reduction in immunosuppression intended by steroid withdrawal, and, on the other hand, may result in an increase of serum creatinine which could be misinterpreted as rejection.

The interactions of age, sex, body mass index, genetics, and steroid weight-based doses on tacrolimus dosing requirement after adult kidney transplantation

“…Several clinical studies indicate that tacrolimus dose requirement is higher when used in combination with corticosteroids [26][27][28][29][30][31]. Therefore, to avoid any undesirable alterations in tacrolimus levels, monitoring the tacrolimus level is crucial during pulse steroid therapy [26] or when tapering or withdrawing steroids [32].…”

“…Little data are available on the clinical impact of the pharmacokinetic interaction between tacrolimus and corticosteroids following kidney transplantation [26][27][28][29][30][31][32]. Patients with the highest weight-adjusted steroid dose appear to require the highest tacrolimus doses to achieve the targeted trough concentrations [18].…”

A New Functional CYP3A4 Intron 6 Polymorphism Significantly Affects Tacrolimus Pharmacokinetics in Kidney Transplant Recipients

“…In an additional mixed-model analysis in which we adjusted for Tac assay by introducing a dummy variable as a random effect, the effect of CYP3A4 intron 6 genotype was still significant, both for the Tac daily dose (Ϫ20% for carriers of the T allele, P ϭ 0.007) and for the dose-adjusted C 0 (ϩ37% for T allele carriers, P Ͻ 0.001). Second, corticosteroids are known to influence Tac exposure (31,32 ). Given that corticosteroid tapering was recommended but not mandatory, the different centers may have used different corticosteroid regimens, which we cannot exclude from having influenced the analysis.…”

Clinical Pharmacokinetics of Triple Immunosuppression Scheme in Kidney Transplant (Tacrolimus, Mycophenolate Mofetil and Corticosteroids)

“…Indeed, studies in adults have documented increased tacrolimus levels upon steroid withdrawal, but similar data on pediatric patients are not available. In recent years, tacrolimus has been used both steroid based and steroid-free immunosuppressive protocols (van Duijnhoven et al, 2003;Anglicheau et al, 2003). Steroid avoidance or rapid elimination of steroids may have an advantage over steroid withdrawal.…”