What is the recommended dosing of tofacitinib (Janus kinase inhibitor) in patients with chronic renal failure (Impaired renal function)?

Tofacitinib Dosing in Chronic Renal Failure

For patients with chronic renal failure, tofacitinib dose should be reduced to 5 mg once daily when creatinine clearance is less than 30 mL/min. 1

Dosing Recommendations Based on Renal Function

Tofacitinib dosing should be adjusted according to the severity of renal impairment:

• Mild to Moderate Renal Impairment (CrCL 50-80 mL/min)

  • No dose adjustment needed
  • Standard dosing: 5 mg twice daily

• Moderate Renal Impairment (CrCL 30-60 mL/min)

  • For baricitinib: Reduce to 2 mg daily
  • For tofacitinib: No dose adjustment needed at this level

• Severe Renal Impairment (CrCL <30 mL/min)

  • Reduce tofacitinib to 5 mg once daily
  • Baricitinib should not be used at all

• End-Stage Renal Disease (ESRD) on Hemodialysis

  • Tofacitinib 5 mg once daily
  • Dose should be administered after dialysis session on dialysis days
  • No supplemental doses needed if a dose was taken before dialysis 1, 2

Pharmacokinetic Considerations

The pharmacokinetic profile of tofacitinib is altered in renal impairment:

• Tofacitinib is metabolized approximately 70% by hepatic metabolism and 30% by renal excretion 2
• In patients with severe renal impairment, AUC increases by approximately 223% compared to patients with normal renal function 3
• In ESRD patients, mean AUC is approximately 40% higher compared to healthy subjects 2
• Terminal half-life increases with severity of renal impairment 3

Monitoring Recommendations

Regular monitoring is essential for patients with renal impairment on tofacitinib:

1. Laboratory Monitoring Schedule:

   • Initial assessment: Full blood count, transaminases, renal function
   • Follow-up: At 1 month, 3 months, then every 3 months
   • Lipid levels: At 3 months after starting therapy 1

2. Blood Count Parameters:

   • Discontinue if lymphocyte count <500 cells/mm³ (confirmed by repeat testing)
   • Interrupt dosing if ANC 500-1000 cells/mm³; resume when >1000 cells/mm³
   • Discontinue if ANC <500 cells/mm³
   • Interrupt dosing if hemoglobin decreases by >2 g/dL or is <8.0 g/dL 1, 2

Important Clinical Considerations

• Contraindications: Tofacitinib should not be used in patients with severe hepatic impairment (Child-Pugh C) 1

• Drug Interactions: Dose reduction to 5 mg once daily is recommended when tofacitinib is co-administered with potent CYP3A4 inhibitors (e.g., ketoconazole) or medications that result in both moderate CYP3A4 inhibition and potent CYP2C19 inhibition (e.g., fluconazole) 1, 2

• Combination Therapy: Tofacitinib can be used with methotrexate but should not be combined with potent immunosuppressants (e.g., azathioprine, cyclosporine) or biologic agents 1

• Infection Risk: Patients with renal impairment may have increased risk of infections; monitor closely, particularly in patients >65 years with cardiovascular risk factors 1

• Dialysis Efficiency: Despite a mean dialyzer efficiency of 0.73, hemodialysis is unlikely to result in significant elimination of tofacitinib due to its extensive non-renal clearance 3

By following these dosing recommendations and monitoring parameters, the risk of adverse events can be minimized while maintaining efficacy in patients with chronic renal failure requiring tofacitinib therapy.