Cyclosporine

Therapeutic And Toxic Concentrations The therapeutic range of cyclosporine used by clinicians varies greatly according to the type of assay used to measure cyclosporine and whether blood or serum concentrations are determined by the clinical laboratory (Table) Because cyclosporine is bound to red blood cells, blood concentrations are higher than simultaneously measured serum or plasma concentrations High pressure liquid chromatography (HPLC) assay techniques are specific for cyclosporine measurement in blood, serum, or plasma Older immunoassays conducted via fluorescence polarization (polyclonal TDx assay, Abbott Diagnostics) or radioimmunoassay (polyclonal RIA, various manufacturers) are nonspecific and measure both cyclosporine and its metabolites

Therapeutic And Toxic Concentrations Newer monoclonal fluorescence polarization (monoclonal TDx assay) and radioimmunoassays (various) are now available that are relatively specific for cyclosporine and produce results similar to the HPLC assay. As a result, cyclosporine concentrations measured simultaneously in a patient using the specific high pressure liquid chromatography technique or one of the specific immunoassays will be lower than that determined using a nonspecific immunoassay Since cyclosporine metabolites are excreted in the bile, liver transplant patients immediately after surgery can have very high cyclosporine metabolite concentrations in the blood, serum, and plasma because bile production has not begun yet in the newly transplanted organ

Therapeutic And Toxic Concentrations If nonspecific immunoassays are used to measure cyclosporine concentrations in liver transplant patients immediately after surgery before the graft has begun to produce bile, the predominate species measured with this assay methodology may be cyclosporine metabolites and not cyclosporine One reason some laboratories favor the use of immunoassays for the measurement of cyclosporine concentrations, even though they are less specific for the parent compound, is that it takes less time to conduct the technique so that cyclosporine concentrations can be returned to clinicians more rapidly

Assay Biologic Fluid Ther Conc (ng/mL) HPLC, monoclonal fluorescence polarization immunoassay, or monoclonal radioimmunoassay Blood 100-400 HPLC, monoclonal fluorescence polarization immunoassay, or monoclonal radioimmunoassay Plasma 50–150 Polyclonal fluorescence polarization immunoassay, or polyclonal radioimmunoassay 200–800 100–400

Therapeutic And Toxic Concentrations Target cyclosporine concentrations differ between the various types of organ transplants, change with time during the posttransplantation phase, and are determined by protocols specific to the transplantation service and institution.

Cyclosporine adverse effects Hypertension Nephrotoxicity Hyperlipidemia Tremor Hirsutism Gingival hyperplasia

Gingival hyperplasia

Basic Clinical Pharmacokinetic Parameters Cyclosporine is almost completely eliminated by hepatic metabolism (>99%) Hepatic metabolism is mainly via the CYP3A4 enzyme system, and the drug is a substrate for P-glycoprotein Within the therapeutic range, cyclosporine follows linear pharmacokinetics There is a large amount of intrasubject variability in cyclosporine concentrations obtained on a day-to-day basis, even when the patient should be at steady state Cyclosporine has low water solubility, and its gastrointestinal absorption can be influenced by many variables

Formulations Sandimmune® (original formulation) Bile dependent for absorption Not equivalent to Neoral or its generics Neoral® (microemulsion formulation) Decreased intrapatient variability Less bile dependent absorption Better correlation with trough and AUC levels

Children Cyclosporine bioavailability is lower and its clearance is higher in pediatric compared with adult transplant recipients, and higher doses are typically required to achieve therapeutic Cyclosporine levels in children after transplantation

Race There are important differences in Cyclosporine pharmacokinetics between ethnic groups, particularly in patients of African origin The bioavailability of Cyclosporine in patients of African origin is less than half that in white patients This is thought to contribute to the higher rates of rejection and graft loss in these patients compared with patients of other racial backgrounds

Comorbidities Various coexisting conditions can affect Cyclosporine exposure in transplant recipients For example, the bioavailability of Cyclosporine in patients with cystic fibrosis is less than half that in other patients, requiring a ≥2-fold increase in dose In patients with diabetes, Cyclosporine absorption can be adversely affected by autonomic neuropathy, gastroparesis, and villous atrophy The bioavailability of Cyclosporine in diabetic renal transplant recipients is nearly half that in nondiabetic controls

Cyclosporine: TDM-how? Two methods: 12 hours trough level (prior to the morning dose) C2 level (2 hours after the morning dose) “Target level” – Patient dependent General 100 to 400ng/ml (12 hours trough) Adjust dose to achieve target level

Clearance Estimate Cyclosporine is almost completely metabolized by the liver. Unfortunately, there is no good way to estimate the elimination characteristics of liver metabolized drugs using an endogenous marker of liver function in the same fashion that serum creatinine and estimated creatinine clearance are used to estimate the elimination of agents that are renally eliminated Because of this, a patient is categorized according to the disease states and conditions that are known to change cyclosporine clearance, and the clearance previously measured in these studies is used as an estimate of the current patient’s clearance rate For example, an adult transplant patient with normal liver function would be assigned a cyclosporine clearance rate equal to 0.36 L/hr/kg, while a pediatric transplant patient with the same profile would be assumed to have a cyclosporine clearance of 0.6 L/hr/kg.

Clearance Estimate All transplant groups (with normal liver function): Adults: The clearance is 0.36 L/hr/kg, a volume of distribution equal to 5 L/kg, and a half-life of 10 hours for adults Children (≤16 years old): The clearance is higher (0.6 L/hr/kg) and mean half-life is shorter (6 hours)

Clearance Estimate Because the drug is primarily eliminated by hepatic metabolism, clearance is lower (0.18 L/hr/kg) and half-life prolonged (20 hours) in patients with liver failure. Renal failure does not change cyclosporine pharmacokinetics, and the drug is not significantly removed by hemodialysis or peritoneal dialysis

Initial dosage determination Calculate Cl Calculate Maintainance dose: where Tau is set to 12 hours; F is 0.3 or 30% for most patient populations and oral dosage forms

Steady-state Concentration Selection The generally accepted therapeutic ranges for cyclosporine in blood, serum, or plasma using various specific and nonspecific (parent drug + metabolite) assays More important than these general guidelines are the specific requirements for each graft type as defined by the transplant center where the surgery was conducted Although it is unlikely that steady state has been achieved, cyclosporine concentrations are usually obtained on a daily basis, even when dosage changes were made the previous day, owing to the critical nature of the therapeutic effect provided by the drug.

Example 1 HO is a 50-year-old, 75-kg (5 ft 10 in) male renal transplant patient 2 days post transplant surgery. The patient’s liver function tests are normal. Suggest an initial oral cyclosporine dose designed to achieve a steady-state cyclosporine trough blood concentration equal to 250 ng/mL

Example 1 Cl = 0.36 L/hr/kg×75 kg= 27 L/h D = (Css ⋅ Cl ⋅ τ) /F = (250 μg/L ⋅ 27 L/h ⋅ 12 h) / (0.3 ⋅ 1000 μg/mg) = 270 mg rounded to 300 mg every 12 hours.

Use Of Cyclosporine Concentrations To Alter Doses Linear Pharmacokinetics Method Pharmacokinetic Parameter Method

Linear Pharmacokinetics Method Requirements: one steady state concentration If Tau was fixed then: If dose was fixed:

Pharmacokinetic Parameter Method Calculate clearance using: Cl = [F(D/τ)] / Css Calculate the new dose using: D = (Css⋅Cl⋅τ) / F

Self reading Effects of disease states and conditions on cyclosporine pharmacokinetics and dosing Drug interactions Reference: Applied clinical pharmacokinetics by Larry A. Bauer