Cyclosporine Therapeutic Drug Monitoring

Ciclosporin is a calcineurin inhibitor used in transplantation, nephrotic syndrome, severe psoriasis, rheumatoid arthritis, atopic dermatitis, uveitis, aplastic anaemia and graft-versus-host disease. It has a narrow therapeutic window with variable absorption, so dose is directed by blood levels and kidney function.

Formulations. The microemulsion formulation is the one used clinically; it is not interchangeable with older oil-based preparations. Do not switch formulation or manufacturer without monitoring.

Sampling. Trough (C0) in whole blood, taken immediately before the morning dose, 12 hours after the evening dose, in an EDTA tube. A 2 hour post-dose level (C2) can guide dosing in transplantation where available.

Transplantation. Initial dose 8 to 10 mg/kg daily in 2 divided doses for kidney transplantation (lower in liver and heart transplantation), adjusted by level.

Indicative trough ranges (units vary).

• Kidney transplant: 150 to 300 ng/mL in the first 3 months, then 100 to 200 ng/mL.
• Liver and heart transplant: about 150 to 350 ng/mL early, then 100 to 250 ng/mL.
• Non-transplant use: levels are not routinely used; dose is set by response and creatinine.

Autoimmune disease.

• Rheumatoid arthritis: start 2.5 mg/kg daily in 2 divided doses, increase by 0.5 to 0.75 mg/kg every 4 weeks to a maximum of 4 mg/kg daily.
• Psoriasis: 2.5 mg/kg daily in 2 divided doses, increasing to 5 mg/kg daily; use for no more than 1 to 2 years continuously.
• Nephrotic syndrome (adults): 3 to 5 mg/kg daily in 2 divided doses with prednisolone.
• Atopic dermatitis and uveitis: 3 to 5 mg/kg daily.

Titration. Adjust by 10 to 25% at intervals of 1 to 2 weeks for transplantation, and by 0.5 to 1 mg/kg daily every 2 to 4 weeks for autoimmune disease.

Creatinine rule (non-transplant use). Measure creatinine twice before starting to set a baseline. If creatinine rises by more than 25% from baseline on 2 readings 2 weeks apart, reduce the dose by 25 to 50%. If the rise is still over 25% after 1 month, or reaches 50% at any time, stop.

Interactions.

• Raise levels: azoles, macrolides, diltiazem, verapamil, amiodarone, grapefruit, oral contraceptives, protease inhibitors.
• Lower levels: rifampicin, carbamazepine, phenytoin, phenobarbital, St John’s wort, orlistat.
• Additive nephrotoxicity: NSAIDs, aminoglycosides, amphotericin B, co-trimoxazole, methotrexate.
• Statins: raised myopathy risk; limit simvastatin and lovastatin, and avoid high doses of others.
• Potassium supplements and potassium-sparing diuretics: hyperkalaemia.

Kidney impairment. Not a dose adjustment issue, but baseline eGFR under 60 mL/min is a relative contraindication in non-transplant use.

Liver impairment. Reduce dose and monitor levels.

Pregnancy and breastfeeding. Compatible in pregnancy with monitoring of blood pressure and levels; breastfeeding generally acceptable with infant monitoring.

Adverse effects. Nephrotoxicity (acute and chronic), hypertension, hyperkalaemia, hypomagnesaemia, hyperlipidaemia, hyperuricaemia and gout, gingival hyperplasia, hirsutism, tremor, headache and increased skin cancer risk.

Baseline. Blood pressure on 2 occasions, creatinine on 2 occasions, eGFR, urea and electrolytes, magnesium, uric acid, fasting lipids, liver tests, full blood count and a pregnancy test.

Ongoing. Blood pressure and creatinine every 2 weeks for the first 3 months (or until the dose is stable) then monthly; potassium, magnesium and lipids every 3 months. Trough levels in transplantation twice weekly early, weekly to 3 months, then monthly.

Hypertension. Treat with amlodipine or another dihydropyridine calcium channel blocker (nifedipine can also be used); avoid verapamil and diltiazem because of levels.

Stop and escalate. Stop for a creatinine rise that persists after dose reduction, uncontrolled hypertension, severe hyperkalaemia, neurotoxicity or malignancy; refer for rejection or toxicity in transplant recipients.