Effect of Corticosteroid Withdrawal on Tacrolimus and Mycophenolate Mofetil Exposure in a Randomized Multicenter Study

Abstract

As corticosteroid-sparing protocols are increasingly utilized in kidney transplant recipients, it is crucial to understand potential drug interactions between tacrolimus (TAC) and the effect of corticosteroid withdrawal as well as to characterize dose adjustments of mycophenolate mofetil (MMF) in this setting. This prospective, multicenter, randomized, double-blind study included 397 patients who were randomized on posttransplant day 8 to receive either placebo (CSWD) or corticosteroid continuance (CCS). TAC trough levels at week two posttransplant were significantly greater in the CSWD group whereas TAC doses were comparable to the CCS group. This interaction was not observed in the African American subgroup. Higher serum creatinine and potassium levels were also observed in the CSWD group. MMF dose was significantly reduced in the CSWD group by the investigators because of decreased WBC counts, mostly outside of study protocol criteria, despite similar incidence of neutropenia and reported cytomegalovirus infection. Understanding TAC and MMF exposure in the context of corticosteroid-sparing protocols should allow for improved dosing of immunosuppressants and better management of posttransplant patients.

A randomized, crossover pharmacokinetic study comparing generic tacrolimus vs. the reference formulation in subpopulations of kidney transplant patients

“…It seems likely that these differences arise from variations in interstitial CYP 3A or P‐glycoprotein activities between ethnic groups . There is also robust evidence that concomitant steroid administration enhances tacrolimus clearance in a dose‐dependent manner , with an increase in dose‐adjusted tacrolimus exposure observed following steroid dose reduction or following steroid withdrawal . In our cohort, similarly, we observed markedly lower bioavailability of tacrolimus in African American recipients as well as in patients receiving steroids.…”

“…One analysis reported reduced tacrolimus bioavailability in diabetic transplant recipients , but elsewhere only a delayed time to peak concentration was observed, with no difference in AUC . Indeed, a recent trial demonstrated that kidney transplant recipients with pre‐transplant diabetes required lower mean tacrolimus doses to maintain similar trough concentrations to non‐diabetic patients . It is possible that gastroparesis, which occurs frequently in diabetic individuals , could delay tacrolimus absorption for a while.…”

Predictors of reduced tacrolimus dose and trough level through 36 months post‐transplant among 578 adult primary kidney transplant recipients

“…The cytochrome P450 3A4 isoenzyme is the principal enzyme responsible for TAC metabolism in the liver , and this isoenzyme is also known to be induced by corticosteroids . Thus, an increased rate of TAC metabolism (thus, lower TAC blood levels) would be expected to occur in the presence of corticosteroid use, and our results along with some other reports appear to confirm this relationship.…”

“…The results of our multivariable analyses of TAC dose and trough levels among 578 adult primary kidney transplant recipients support the results of other studies in that the TAC dose administered during the first 36 months post‐transplant was significantly higher among African American and younger transplant recipients and also significantly higher during the first 12 months post‐transplant among patients who were receiving maintenance corticosteroids . None of the other baseline and demographic variables, including recipient gender, influenced the TAC dose.…”

“…Any influence of recipient gender on TAC bioavailability has not been established, as one study reported female recipients having significantly poorer bioavailability , whereas another study found no such association . In addition, a number of studies have shown that TAC bioavailability is significantly lower in the presence of maintenance corticosteroids being used . We were therefore interested in analyzing our rather large single‐center cohort of 578 TAC‐assigned kidney transplant recipients (which includes a high percentage of African Americans and Hispanics) to determine in a multivariable fashion the significant baseline and immunosuppression‐related predictors of absolute TAC dose (mg), TAC trough level (ng/mL), and dose‐adjusted TAC trough level (a surrogate measure of TAC bioavailability) during the first 36 months post‐transplant, the time period in which patients are at the greatest risk of developing an acute rejection episode.…”