Zortress Information
Zortress () Warning Immunosuppression, Renal Function, And Graft Thrombosis
• Only physicians experienced in immunosuppressive therapy and management of transplant patients should prescribe Zortress () .Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. [ ]
• Increased nephrotoxicity can occur with use of standard doses of cyclosporine in combination with everolimus. Therefore reduced doses of cyclosporine should be used in combination with everolimus in order to reduce renal dysfunction. It is important to monitor the cyclosporine and everolimus whole blood trough concentrations. [ ]
• An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, was reported, mostly within the first 30 days post-transplantation. [ ]
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Zortress () clinical Pharmacology
Everolimus inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes.
In cells, everolimus binds to a cytoplasmic protein, the FK506 Binding Protein-12 (FKBP-12), to form an immunosuppressive complex (everolimus: FKBP-12) that binds to and inhibits the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. In the presence of everolimus phosphorylation of p70 S6 ribosomal protein kinase (p70S6K), a substrate of mTOR, is inhibited. Consequently, phosphorylation of the ribosomal S6 protein and subsequent protein synthesis and cell proliferation are inhibited. The everolimus: FKBP-12 complex has no effect on calcineurin activity.
In rats and non-human primate models, everolimus effectively reduces kidney allograft rejection resulting in prolonged graft survival.
Everolimus pharmacokinetics have been characterized after oral administration of single and multiple doses to adult kidney transplant patients, hepatically-impaired patients, and healthy subjects.
Absorption
After oral dosing, peak everolimus concentrations occur 1 to 2 h post dose. Over the dose range of 0.5 mg to 2 mg twice daily, everolimus C and AUC are dose proportional in transplant patients at steady-state.
Food Effect
In 24 healthy subjects, a high-fat breakfast (44.5 g fat) reduced everolimus C by 60%, delayed t by a median 1.3 hours, and reduced AUC by 16% compared with a fasting administration. To minimize variability, everolimus should be taken consistently with or without food. [ ]
Distribution
The blood-to-plasma ratio of everolimus is concentration dependent ranging from 17% to 73% over the range of 5 ng/mL to 5000 ng/mL. Plasma protein binding is approximately 74% in healthy subjects and in patients with moderate hepatic impairment. The apparent distribution volume associated with the terminal phase (Vz/F) from a single-dose pharmacokinetic study in maintenance kidney transplant patients is 342 to 107 L (range 128 to 589 L).
Metabolism
Everolimus is a substrate of CYP3A4 and P-glycoprotein. The main metabolic pathways identified in man were monohydroxylations and O-dealkylations. Two main metabolites were formed by hydrolysis of the cyclic lactone. Everolimus was the main circulating component in blood. None of the main metabolites contribute significantly to the immunosuppressive activity of everolimus.
Excretion
After a single dose of radiolabeled everolimus was given to transplant patients receiving cyclosporine, the majority (80%) of radioactivity was recovered from the feces and only a minor amount (5%) was excreted in urine. Parent drug was not detected in urine and feces.
Steady-state is reached by Day 4 with an accumulation in blood levels of 2- to 3-fold compared with the exposure after the first dose.
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The half-life estimates from 12 maintenance renal transplant patients who received single doses of everolimus capsules at 0.75 mg or 2.5 mg with their maintenance cyclosporine regimen indicate that the pharmacokinetics of everolimus are linear over the clinically-relevant dose range. Results indicate the half-life of everolimus in maintenance renal transplant patients receiving single doses of 0.75 mg or 2.5 mg everolimus during steady-state cyclosporine treatment was 30 ± 11 hours (range 19 to 53 hours).
Drug-Drug Interactions
Everolimus is known to be a substrate for both cytochrome CYP3A4 and P-gp. The pharmacokinetic interaction between everolimus and concomitantly administered drugs is discussed below. Drug interaction studies have not been conducted with drugs other than those described below. [ ]
In a single-dose study in healthy subjects, cyclosporine (Neoral) administered at a dose of 175 mg increased everolimus AUC by 168% (range, 46% to 365%) and C by 82% (range, 25% to 158%) when administered with 2 mg everolimus compared with administration of everolimus alone. [ ]
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Hepatic Impairment
Everolimus AUC was increased an average 2-fold in 8 patients with moderate hepatic impairment (Child-Pugh Class B) compared with 8 healthy subjects. AUC was positively correlated with serum bilirubin concentration and with prolongation in prothrombin time and negatively correlated with serum albumin concentration. The AUC of everolimus tended to be greater than that of healthy subjects if bilirubin was >34 μmol/L, prothrombin time was >1.3 INR >4 sec prolongation, and/or albumin concentration was
Renal Impairment
No pharmacokinetic studies in patients with renal impairment were conducted. Post-transplant renal function (creatinine clearance range 11 to 107 mL/min) did not affect the pharmacokinetics of everolimus, therefore, no dosage adjustments are needed in patients with renal impairment.
Pediatrics
The safety and efficacy of everolimus has not been established in pediatric patients.
Geriatrics
A limited reduction in everolimus oral CL of 0.33% per year was estimated in adults (age range studied was 16 to 70 years. There is no evidence to suggest that elderly patients will require a different dosage recommendation from younger adult patients.
Race
Based on analysis of population pharmacokinetics, oral clearance (CL/F) is, on average, 20% higher in Black transplant patients.
Based on exposure-efficacy and exposure-safety analyses of clinical trials, kidney transplant patients achieving everolimus whole blood trough concentrations ≥3.0 ng/mL have been found to have a lower incidence of treated biopsy-proven acute rejection compared with patients whose trough concentrations were below 3.0 ng/mL. Patients who attained everolimus trough concentrations within the range of 6 to 12 ng/mL had similar efficacy and more adverse events than patients who attained lower trough concentrations between 3 to 8 ng/mL. [ ]
In the clinical trial [ ], everolimus whole blood trough concentrations were measured at Days 3, 7, and 14 and Months 1, 2, 3, 4, 6, 7, 9, and 12. The proportion of patients receiving 0.75 mg twice daily everolimus treatment regimen who had everolimus whole blood trough concentrations within the protocol specified target range of 3 to 8 ng/mL at Days 3, 7, and 14 were 55%, 71% and 69%, respectively. Approximately 80% of patients had everolimus whole blood trough concentrations within the 3 to 8 ng/mL target range by Month 1 and remained stable within range through Month 12. The median everolimus trough concentration for the 0.75 mg twice daily treatment group was between 3 and 8 ng/mL throughout the study duration.
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