1. Cyclosporine

2. 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

3. 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

4. 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

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

6. 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.

7. Cyclosporine adverse effects
Hypertension
Nephrotoxicity
Hyperlipidemia
Tremor
Hirsutism
Gingival hyperplasia

8. Gingival hyperplasia

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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.

16. 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)

17. 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

18. 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

19. 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.

20. 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

21. 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.

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

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

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

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