Effects of Genetic Polymorphisms on the Pharmacokinetics of Calcineurin Inhibitors

Kyle N. Utecht; Jon J. Hiles; Jill Kolesar


Am J Health Syst Pharm. 2006;63(23):2340-2348. 

In This Article

Calcineurin inhibitors

Cyclosporine and tacrolimus comprise the calcineurin inhibitors. Currently, there are two formulations of cyclosporine approved for use by the Food and Drug Administration, Sandimmune and Neoral, both manufactured by Novartis Pharmaceuticals. Sandimmune, or cyclosporine, is an immediate- release capsule. Neoral, or cyclosporine (modified), is a microemulsionforming formulation that minimizes intraindividual absorption variability. Sandimmune and Neoral are not bioequivalent and should not be substituted without appropriate dose adjustments.[3,4] There are, however, generic formulations that are bioequivalent to both Sandimmune and Neoral. Tacrolimus is available as an immediate-release capsule under the brand name Prograf (Astellas Pharma US). Other formulations include cyclosporine injectable products, cyclosporine oral solutions, cyclosporine eye drops, a topical tacrolimus ointment, and a tacrolimus injectable product.

Calcineurin inhibitors suppress the immune system by preventing interleukin-2 (IL-2) production in T cells. Cyclosporine and tacrolimus are chemically distinct molecules that bind to the intracellular immunophilins cyclophilin and FKBP-12, respectively.[3,4,5] When bound, both molecules inhibit the phosphatase action of calcineurin, which is required for the movement of nuclear factors in activated T cells to the chromosomes where subsequent cytokine synthesis occurs. Decreased secretion of IL-2 prevents proliferation of the inflammatory response via B cells and T cells. The attenuated inflammatory response greatly reduces the overall function of the immune system.

Cyclosporine and tacrolimus are highly lipophilic molecules yet display dissimilar absorption kinetics. Cyclosporine depends greatly on gastrointestinal function and bile secretion for adequate absorption. Therefore, Sandimmune absorption kinetics display high interindividual and intraindividual variability. Peak blood concentrations occur within 2-6 hours.[3] Neoral provides patients with rapid and consistent absorption, where peak blood concentrations occur within 1.5-2 hours.[4] The elimination half-life is 19 and 8.4 hours for Sandimmune and Neoral, respectively. Tacrolimus is consistently absorbed and eliminated, with a half-life of 8.7 hours.[5] Pharmacokinetic variability of approximately 20-30% among patients is noted in product labeling.[3,4,5]

The bioavailability and metabolism of cyclosporine and tacrolimus are primarily controlled by efflux pumps and members of the cytochrome P-450 (CYP) isoenzyme system found in the liver and gastro-intestinal tract. The main efflux pump involved in transporting cyclosporine and tacrolimus is P-glycoprotein (PGP), which is encoded by the multidrug resistance-1 (MDR1), also known as the ABCB1, gene.[6,7] PGP is a transmembrane transporter capable of transporting numerous endogenous substances from the cytoplasm to the exterior of the cell. In the intestines, PGP limits oral bioavailability of drugs by expelling them from the interior of enterocytes into the gut lumen (Figure 1).[6] After tacrolimus and cyclosporine reach the blood-stream, they are subject to metabolism and systemic clearance by CYP enzymes, specifically CYP3A4 and CYP3A5.[6,7] Many clinically useful drugs are substrates of the CYP3A4 and CYP3A5 enzymes.[6] They are found in high concentrations in the cells of the intestine and, along with PGP, may reduce the oral bioavailability of many drugs. CYP3A4 and CYP3A5 are also concentrated in the liver and account for much of the first-pass clearance from the hepatic portal vein and systemic clearance of tacrolimus and cyclosporine.

Figure 1.

Metabolism of calcineurin inhibitors. Calcineurin inhibitors are metabolized by cytochrome P-450 (CYP) isoenzyme systems 3A4 and 3A5 in the gut lumen before they even reach the portal vein. P-glycoprotein (PGP) prevents drug absorption from the gut by promoting efflux into the lumen of the intestine. PGP also has a role in systemic clearance of drugs by promoting efflux into the bile for excretion.[31] After drugs are absorbed, they are subject to first-pass metabolism and systemic metabolism by CYP3A4 and CYP3A5 in the liver. When CYP3A5 is expressed, it accounts for 50% of the total hepatic CYP3A content.[15] A change in the level of expression of CYP3A4, CYP3A5, or PGP would theoretically affect both the bioavailability and metabolism of calcineurin inhibitors.

Patients using calcineurin inhibitors experience many adverse effects. In general, the number and severity of adverse effects are related to the overall exposure, measured by length of therapy and blood drug concentration. Patients taking cyclosporine may develop hypertension, tremor, nephrotoxicity, hyperlipidemia, gingival hyperplasia, and hirsutism.[3,4] Patients receiving tacrolimus may develop hypertension, tremor, gastrointestinal disturbances, nephrotoxicity, headaches, hepatotoxicity, abnormal glucose control, pruritis, leukocytosis, hyperkalemia, and hypomagnesemia. [5] Tacrolimus causes a greater number of and more severe adverse events than does cyclosporine. [8] Dosage reduction may decrease toxicities; however, additional pharmacotherapy is often required to counteract the adverse effects of calcineurin inhibitor therapy. The nephrotoxicity seen with cyclosporine and tacrolimus is particularly problematic in kidney transplant recipients and may negate a kidney transplant. Calcineurin inhibitor doses are often tapered postoperatively because of such toxicities.

Calcineurin inhibitors are effective in both the induction and maintenance of postoperative immunosuppression. Improved outcomes require achieving therapeutic levels of calcineurin inhibitors immediately after solid-organ transplantation. Reaching therapeutic levels with cyclosporine as early as three days postoperatively has been shown to decrease the rate of acute organ rejection in kidney transplant recipients. [9] Suggested starting dosages are 9 mg/kg/day for Neoral,[4] 10-14 mg/kg/day for Sandimmune,[3] and 0.2 mg/kg/day for tacrolimus.[5]

Blood drug concentration measurements should be used to minimize the adverse effects of these agents and ensure adequate immunosuppression. The most widely used measure of calcineurin inhibitor exposure is the predose trough concentration; however, some authors debate its ability to accurately predict outcomes in kidney transplant recipients.[10] Proposed alternatives include the area under the concentration-time curve (AUC) at 4 hours (AUC0–4 hr) and 12 hours (AUC0–12 hr) and blood drug concentrations at 2, 3, or 4 hours after administration. Therapeutic cyclosporine concentrations differ with the measurement technique, institution, surgical procedure, and protocol. In general, the therapeutic trough whole blood and serum concentrations of cyclosporine are 375-400 and 150-250 ng/mL, respectively, when measured with radioimmunoassay and 100-300 and 75-150 ng/mL, respectively, when measured with high-performance liquid chromatography.[3,4] Therapeutic trough whole blood concentrations of tacrolimus are 15-20 (initial concentration), 10-15 (at one month), and 5-12 ng/mL (at three months posttransplantation) (equivalent to free plasma concentrations of 0.5-2 ng/mL).[5] Published serum concentrations for the calcineurin inhibitors are only a guide, and individual therapy should be tailored specifically to each patient based on risk factors and the clinical situation.


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