What are the considerations for switching from tacrolimus to ciclosporin (cyclosporine)?

Switching from Tacrolimus to Cyclosporin: Clinical Considerations

Direct Answer

Switching from tacrolimus to cyclosporin is generally not recommended in stable transplant patients, as the evidence suggests tacrolimus provides superior outcomes in most transplant settings. However, when conversion is necessary due to specific tacrolimus-related adverse effects, it can be performed safely with appropriate monitoring and dose adjustments 1, 2.

When Conversion May Be Indicated

Acceptable Clinical Scenarios for Switching

• Neurological toxicity is the most common indication for conversion from tacrolimus to cyclosporin, accounting for 54% of conversions in liver transplant patients 3
• Gastrointestinal complications (16% of conversions) 3
• Hematological adverse effects (14% of conversions) 3
• New-onset diabetes mellitus after tacrolimus, which occurs in approximately 20% of patients 4
• Primary biliary cholangitis (PBC) recurrence prevention after liver transplantation, where cyclosporin may offer protective effects 5, 6

Contraindications to Switching

• Stable patients without adverse effects should remain on tacrolimus, as conversion to cyclosporin results in worse renal function, higher blood pressure, and worse lipid profiles 7
• Lung transplant patients with bronchiolitis obliterans syndrome (BOS) should convert FROM cyclosporin TO tacrolimus, not the reverse 5

Critical Timing and Safety Protocols

Timing Requirements

• Tacrolimus must be discontinued at least 24 hours before initiating cyclosporin to avoid overlapping calcineurin inhibitor toxicity 1
• In the presence of elevated tacrolimus concentrations, cyclosporin initiation should be further delayed beyond 24 hours 1
• Mean time to conversion in stable liver transplant patients was 443 days post-transplant (range 22-1641 days) 3

Monitoring Protocol After Conversion

• Therapeutic drug monitoring is mandatory for both agents 1
• Measure cyclosporin trough levels within 3-5 days of conversion 8
• Follow-up levels every 1-2 weeks until stable therapeutic targets achieved 8
• Target cyclosporin trough level should be approximately 20 times the previous tacrolimus trough level 6
• Monitor renal function closely, as conversion may result in rising creatinine levels 2

Expected Metabolic and Clinical Changes

Anticipated Adverse Changes

• Plasma cholesterol increases significantly (mean rise from 5.2 to 5.5 mmol/L, p=0.033) after conversion to cyclosporin 2
• Blood pressure control may worsen, requiring additional antihypertensive medications 4
• Cardiovascular risk profile deteriorates compared to remaining on tacrolimus 7
• Renal function may decline, with creatinine rising from 142 to 157 μmol/L in patients continuing cyclosporin versus stable function on tacrolimus 7

Potential Benefits

• Plasma magnesium levels improve (rise from 0.73 to 0.82 mmol/L, p=0.037) 2
• Resolution of tacrolimus-specific toxicities (neurological, gastrointestinal, hematological) 3
• Lower incidence of new-onset diabetes compared to continuing tacrolimus 4
• Possible protection against PBC recurrence in liver transplant patients 5, 6

Pharmacokinetic Considerations

Drug Variability Profiles

• Cyclosporin (Neoral formulation) exhibits significantly less inter-patient and intra-patient variability than tacrolimus for AUC, Cmax, Cmin, and Tmax 2
• Both agents are CYP3A4 substrates, requiring careful attention to drug-drug interactions 5
• Grapefruit and grapefruit juice must be avoided with both agents 1

Risk of Rejection and Reconversion

Rejection Risk

• Patient and graft survival was 100% at 3 months after elective conversion in stable renal transplant patients 2
• No rejection episodes occurred in the immediate post-conversion period in stable patients 2
• 24% of patients required reconversion back to tacrolimus (mean 282 days after cyclosporin initiation) 3

Reasons for Reconversion to Tacrolimus

• Acute cellular rejection (44% of reconversions) 3
• Elevated hepatic enzymes (33% of reconversions) 3
• Chronic rejection (11% of reconversions) 3
• Worsening neurological symptoms (11% of reconversions) 3

Importantly, reconversion to tacrolimus did not result in recurrence of the original symptoms that prompted the initial switch 3

Special Population Considerations

HIV-Infected Transplant Patients

• Complex drug-drug interactions exist between antiretrovirals and both calcineurin inhibitors 5
• Protease inhibitors dramatically increase immunosuppressant exposure, requiring dose reductions to 1-2% of typical doses 5
• NNRTIs (e.g., efavirenz) modestly decrease tacrolimus concentrations, requiring compensatory dose increases 5
• Consider raltegravir-based antiretroviral regimens to minimize interactions with either calcineurin inhibitor 5

Liver Transplant Patients with PBC

• Cyclosporin may offer protective effects against PBC recurrence when initiated as tacrolimus followed by conversion to cyclosporin 5, 6
• In two patients with high pre-transplant antimitochondrial M2 antibody titers, levels did not elevate after conversion to cyclosporin 6
• However, evidence is insufficient to routinely recommend cyclosporin over tacrolimus for PBC recurrence prevention 5

Practical Conversion Protocol

Step-by-Step Approach

1. Verify compelling indication for conversion (neurological toxicity, diabetes, specific adverse effects) 3
2. Obtain baseline tacrolimus trough level and renal function 2
3. Discontinue tacrolimus and wait minimum 24 hours 1
4. Initiate cyclosporin at target trough 20 times previous tacrolimus trough 6
5. Transiently increase maintenance corticosteroid dosing during conversion period 5
6. Measure cyclosporin trough within 3-5 days 8
7. Monitor every 1-2 weeks until stable levels achieved 8
8. Assess for rejection, renal function, lipids, and blood pressure at each visit 2, 7

Common Pitfalls to Avoid

• Do not overlap tacrolimus and cyclosporin administration - maintain 24-hour washout minimum 1
• Do not convert stable patients without clear indication - tacrolimus provides superior long-term outcomes 7
• Do not assume conversion is permanent - 24% require reconversion to tacrolimus 3
• Do not neglect cardiovascular risk monitoring - expect worsening lipids and blood pressure 2, 7
• Do not convert lung transplant patients with BOS - the opposite direction (cyclosporin to tacrolimus) is indicated 5