The Effect of Sevelamer on Tacrolimus Target Levels

Abstract

Herein we report on a 55-year-old male patient who received his second kidney transplant because of recurrent IgA nephropathy in 1999. The graft function had been stable during the first years following the transplantation, with the immunosuppressive therapy consisting of tacrolimus, mycophenolate mofetil, and low-dose steroid. In July 2004, cardiac surgery was performed because of severe coronary artery disease and aortic stenosis. The patient was dependent on dialysis perioperatively. Mycophenolate mofetil was discontinued because of a persistently low creatinine clearance. However, the patient refused to return on a chronic hemodialysis program and was therefore kept on low doses of tacrolimus and steroid. Intermittent dialysis treatments were performed. In August 2004, sevelamer (Renagel, 800 mg tablets by Genzyme) was started because of a high calcium-phosphate product. The oral medication was otherwise retained unchanged. Subsequently, a progressive decline in tacrolimus blood levels was observed. In spite of an increased tacrolimus dosage, target levels were measurable only temporarily in the context of further deteriorations of kidney function (Fig. 1). Significant reductions in the peak level of tacrolimus (Cmax) and the area under the curve (AUC) following one oral dose of 1.5 mg tacrolimus were found when compared to tacrolimus kinetics in the same patient three days after discontinuation of sevelamer, with Cmax 9.9 vs. 13.1 ng/ml and AUC7 4.02 vs. 9.69 ng×h/ml (Fig. 2). For performance of the pharmacokinetic study, tacrolimus levels were measured immediately before and 1, 2, 5, and 7 hr after intake of the drug by immunoassay (EMIT by Dade Behring), the calculation of the AUC was performed by the trapezoidal rule. Informed consent was obtained from the patient.FIGURE 1.: Time course of serum creatinine, tacrolimus blood levels (with the detection limit of the assay being 2.5 ng/ml), and daily tacrolimus dosage.FIGURE 2.: Tacrolimus blood levels in ng/ml (assay detection limit 2.5 ng/ml) following one dose of tacrolimus 1.5 mg p.o., with and without sevelamer 3×800 mg p.o.Sevelamer hydrochloride is a nonabsorbable, polymeric phosphate binder that does not contribute to calcium load, aluminium toxicity, or changes in acid-base status. Within the intestinal lumen, the cationic sevelamer binds phosphate through ion exchange. Sevelamer is known to reduce absorption of vitamin D, E, K, and folic acid. More importantly, decreases in the peak concentration and AUC of mycophenolate mofetil have been described (1). There are conflicting data regarding the interaction of sevelamer with cyclosporine; a marked decrease in trough levels was described in a patient on hemodialysis, whereas the pharmacokinetic profile of cyclosporine in patients with a stable graft function after renal transplantation was not significantly affected by sevelamer (1,2). Although no other drug interactions have been substantiated so far, it is recommended to take any accompanying medication at least one hour before or three hours after a dose of sevelamer when changes in absorption of oral medications may have significant clinical consequences. This is the first time a decrease in tacrolimus blood levels with concomitant intake of sevelamer is reported. A direct binding of lipophilic substances by sevelamer as discussed for cyclosporine seems to be the most likely mechanism of interaction (3).