Pharmacokinetic interaction between corticosteroids and tacrolimus after renal transplantation.
BACKGROUND
Tacrolimus is an immunosuppressive drug that is a substrate of cytochrome P450 3A (CYP3A) enzymes and P-glycoprotein (P-gp). After transplantation, many pharmacological interactions have been described. Corticosteroids induce both CYP3A and P-gp activity. This study was designed to investigate the presence of a clinically significant interaction between steroids and tacrolimus after renal transplantation.


METHODS
We studied 83 renal transplant recipients receiving tacrolimus after transplantation. Patients were divided into three groups, according to steroid dose (low: 0-0.15 mg/kg/day; intermediate: 0.16-0.25 mg/kg/day; and high: >0.25 mg/kg/day). All other medications, including those known to interact with CYP3A and/or P-gp, were recorded. Steroid dosage, tacrolimus dosage, tacrolimus trough concentration (C0) and tacrolimus concentration/dose ratio [C0 divided by the 24 h dosage (mg/kg)] were assessed for each dosage group after 1 and 3 months of tacrolimus treatment.


RESULTS
The three groups were not different as regards the use of non-immunosuppressive treatments or clinical events. At 1 and 3 months, the tacrolimus doses and concentration/dose ratios differed significantly in the three steroid dosage groups. With the higher doses, higher tacrolimus doses were needed to achieve the blood tacrolimus targeted trough level.


CONCLUSIONS
We demonstrated that pharmacokinetic interaction occurs between steroids and tacrolimus in renal transplant patients. The higher the steroid dosage, the higher the dosage of tacrolimus needed to achieve target trough levels in these patients. The most likely interaction mechanism is specific enzymatic induction of CYP3A and/or P-gp. Interaction is present, even when the steroid dosage is low. The clinical events liable to occur during steroid sparing or tapering must be taken into account because it may be associated with episodes of tacrolimus-related nephrotoxicity.
Anglicheau
Dany
D
Service de Néphrologie et de Transplantation Rénale, Hôpital Saint Louis, Paris, France. dany.anglicheau@biomedicale.univ-paris5.fr
Flamant
Martin
M
Schlageter
Marie Hélène
MH
Martinez
Frank
F
Cassinat
Bruno
B
Beaune
Philippe
P
Legendre
Christophe
C
Thervet
Eric
E
D000328:Adult; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage / Q000493:pharmacokinetics; D008875:Middle Aged; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*
D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016559:Tacrolimus; D008775:Methylprednisolone