What is the therapeutic window and what are the most common adverse effects associated with Ciclosporin (Cyclosporine)?

From the Guidelines

The therapeutic window for ciclosporin (cyclosporine) is typically 100-400 ng/mL, though target levels vary based on transplant type, time post-transplant, and concomitant immunosuppressants. Blood level monitoring is essential as ciclosporin has a narrow therapeutic index, meaning the difference between effective and toxic concentrations is small. The most common adverse effects of ciclosporin include:

• Nephrotoxicity (kidney damage), which can be dose-dependent and may lead to increased creatinine and decreased glomerular filtration rate, affecting up to 71% of patients treated for an average of 4.5 years 1
• Hypertension, which can affect approximately 50% of patients and often requires antihypertensive treatment
• Neurotoxicity, which can manifest as tremors, headaches, and rarely seizures or encephalopathy
• Other common side effects include hirsutism (excessive hair growth), gingival hyperplasia (gum overgrowth), hyperlipidemia, hyperkalemia, hypomagnesemia, and increased susceptibility to infections
• GI adverse effects tend to be mild and short-lived, including abdominal pain, diarrhea, nausea, and vomiting
• Respiratory effects such as dyspnea, cough, and rhinitis can occur in approximately 5% of patients
• Hyperuricemia and hypomagnesemia can also occur Ciclosporin also carries an increased risk of malignancies, particularly skin cancers and lymphomas with long-term use. These adverse effects necessitate regular monitoring of renal function, blood pressure, electrolytes, lipids, and drug levels to optimize therapy while minimizing toxicity, as recommended by the joint american academy of dermatology-national psoriasis foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies 1. It is essential to follow the guidelines for the safe and effective prescribing of oral ciclosporin in dermatology, including using single or intermittent short courses of up to 16 weeks to reduce nephrotoxicity and reducing the dose during therapy to minimize adverse effects 1. The british association of dermatologists guidelines for the safe and effective prescribing of oral ciclosporin in dermatology 2018 provide recommendations for baseline monitoring, including history and physical examination, blood pressure, BUN, creatinine, urinalysis, and consideration of latent tuberculosis test, as well as ongoing monitoring of blood pressure, renal function, electrolytes, lipids, and drug levels 1. The risk of adverse events with cyclosporin in idiopathic glomerular disease associated with the nephrotic syndrome is similar to that observed in adults with other conditions, and the risk of nephrotoxicity appears to be low if guidelines on cyclosporin dosing are followed 1. Overall, the therapeutic window and adverse effects of ciclosporin must be carefully managed to minimize toxicity and optimize therapy.

From the FDA Drug Label

The principal adverse reactions of cyclosporine capsules therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia. Hypertension, which is usually mild to moderate, may occur in approximately 50% of patients following renal transplantation and in most cardiac transplant patients Genitourinary Renal Dysfunction 32 62 53 83 7 Cardiovascular Hypertension 26 18 13 53 27 Cramps 4 < 1 2 < 1 0 Skin Hirsutism 21 < 1 2 1 2 8 45 Acne 6 8 2 2 1 Central Nervous System Tremor 12 0 2 1 3 1 55 Convulsions 3 1 1 4 5 Headache 2 < 1 2 1 1 5 4 The therapeutic window for ciclosporin is not explicitly stated in the provided drug labels. The most common adverse effects associated with ciclosporin are:

• Renal dysfunction
• Hypertension
• Tremor
• Hirsutism
• Gum hyperplasia 2 2

From the Research

Therapeutic Window of Ciclosporin

• The therapeutic range of blood Ciclosporin concentrations is still poorly defined, but most authors recommend concentrations of 100-250 ng/ml for the first three months when renal function is satisfactory 3.
• The therapeutic window of Ciclosporin is narrow, and the drug requires total blood levels to be monitored with a specific assay to avoid nephrotoxicity 3.
• The microemulsion formulation of Ciclosporin (Neoral) has improved bioavailability, and monitoring levels 2 hours after dosing (C2) is a more precise method for optimizing Ciclosporin dosing 4.

Adverse Effects of Ciclosporin

• The most common adverse effects associated with Ciclosporin include:
  • Nephrotoxicity 5, 6
  • Hypertension 5
  • Hypertrichosis 7
  • Gingival hyperplasia 7
  • Neurological effects 7
  • Gastrointestinal effects 7
• Changes in laboratory variables indicating renal dysfunction are relatively common, although serious irreversible damage is rare 7.
• Reducing the dose of Ciclosporin or using protocols without calcineurin inhibition may minimize the risk of drug toxicity and improve allograft and patient survival 6.