Monitoring for cyclosporine is complicated; further it is limited by the lack of studies which correlate concentration and immune suppression in animals. Thus, avoiding toxicity and determining concentrations should be the initial goal, with establishing the individual patient’s therapeutic range being important in the absence of no consensus regarding therapeutic ranges in animals.
At least 50% of cyclosporine in blood is in the red blood cell. As such, whole blood should be submitted.
Cyclosporine is metabolized to over 14 different compounds with variable activity. HPLC provides the most accurate method of measuring the parent compound but does not measure any active metabolite. Antibody based assays vary in their therapeutic ranges because the antibodies vary in the amount of metabolite detected. Presumably monoclonal antibody-based assays interfere with non-parent compounds (that is, metabolites) the least but will nonetheless consistently measure cyclosporine higher than HPLC. The assay used by this laboratory is approved by the FDA for monitoring of cyclosporine in humans.
Target concentrations vary with the condition. For immune mediated disease or host versus graft rejection, dosing should occur at12 hr intervals. For our laboratory (using a monoclonal antibody-based assay), a peak concentration of 800 to 1400 ng/ml and a trough concentration of 400 to 600 ng/ml (monoclonal based assay) is recommended. The target peak concentration is easier to reach in a patient: Because of the short half-life of cyclosporine in most patients (e.g., 5 hr average), a trough target of 400 to 600 ng/ml will require peak concentrations of 1600 to 2400 ng/ml. In animals, there is not data supporting better response if target trough or peak concentrations are met but the more aggressive approach would be to target the trough concentrations. For renal transplantation, trough concentrations of 750 ng/ml are suggested for the first month (peak concentration of 2600 to 3000 ng/ml or more may be necessary, depending on half-life of cyclosporine in the patient) and 350 to 400 ng/ml, thereafter. For chronic allergic inflammatory disorders, lower trough concentrations are recommended: 250 ng/ml trough concentrations for chronic inflammatory bowel disorders, and for perianal fistulae, 12 hour trough concentrations at 100 to 600 ng/ml (the higher for induction, the lower for maintenance).
Cyclosporine generally does not accumulate and therefore monitoring can occur within days to 1 week of a new dosing regimen. The exception occurs if the patient is receiving another drug that prolongs the half-life of cyclosporine.
Our laboratory offers the following recommendations for monitoring of patients receiving cyclosporine for induction of immune-mediated disease therapy (for a patient being treated every 12 hours). Assuming a “normal” half-life (for example, the patient is not receiving drugs that inhibit drug metabolizing enzymes), a 2 hr peak and 11 to 12 hr, (just before the next dose) trough sample is recommended within 3 to 5 days of initiating therapy; the more life threating the target disease, the more important a peak and trough sample may be.
For less serious situations, or as treatment shifts from induction to maintenance, a single 2 hr peak sample may be sufficient for establishing and maintaining a target.
If therapy is initiated such that CsA disposition might change (whether intentional, such as the addition of ketoconazole, or inadvertent, such as co-treatment with diltiazem or azithromycin or others), a peak and trough sample prior to and 1 week after therapy is initiated is suggested such that a half-life can be calculated and the time to steady-state concentrations can be determined.
For chronic allergic – inflammatory diseases, recommendations vary from those for immune mediated diseases. Recommendations (again from human medicine, with the exception of perianal fistulae) are largely based on trough concentrations. For atopy in particular, no recommendations are available, and the role of monitoring is to establish a baseline therapeutic range in the patient and to assure that concentrations are sufficiently high that response can be expected. Concentrations are not likely to be detectable at trough when dosing at 48 hr intervals. Thus, a single peak concentration may be reasonable if a monitoring program is to be implemented in such a patient.
Whole blood should be submitted.
Samples do not need to be sent on ice. Cyclosporine has been demonstrated to be stable for 7 days at ambient temperature.
Cyclosporine is involved in a large number of drug interactions both at p glycoprotein (an efflux protein that will impact drug absorption and distribution) and cytochrome P450. It is metabolized by and is subject to inhibition / induction of activity of CYP 3A4, which is a major enzyme responsible for the metabolism of many other drugs. We have detected interactions with imidazole antifungals and azithromycin.
The frequency of monitoring should vary with the disease being treated and patient response. We recommend monitoring is recommended weekly to biweekly in critical patients, then monthly for the first several months of therapy or until concentrations are stable. For long term maintenance, the frequency of sampling might range from 3 to 6 months.
In situations in which generic preparations are being used, because oral bioavailability of different generic products may differ in the same dog initiated, proactive monitoring is recommended if one product is shifted to another. In such cases, a single 2 hr peak concentration before and 3 to 5 days after the switch is recommended.