What is the recommended dose adjustment of tofacitinib (Janus kinase inhibitor) for patients with impaired renal function?

Tofacitinib Dose Adjustment in Renal Impairment

For patients with severe renal impairment (CrCl <30 mL/min), tofacitinib dose should be reduced to 5 mg once daily. 1, 2

Renal Clearance and Pharmacokinetics

• Tofacitinib is primarily metabolized by hepatic CYP3A4 pathway (70%), with approximately 30% renal excretion 1
• In patients with renal impairment, tofacitinib exposure (AUC) increases proportionally to the degree of renal function decline 3
• Compared to patients with normal renal function, mean AUC increases by 37% in mild, 43% in moderate, and 123% in severe renal impairment 3

Specific Dosing Recommendations by Renal Function

Mild to Moderate Renal Impairment (CrCl 30-80 mL/min)

• No dose adjustment required for mild to moderate renal impairment (CrCl 30-80 mL/min) 1
• Standard dosing can be maintained: 5 mg twice daily for RA/PsA or 10 mg twice daily for UC 1

Severe Renal Impairment (CrCl <30 mL/min)

• Reduce tofacitinib dose to 5 mg once daily 1, 2
• If patient was taking 10 mg twice daily (UC indication), reduce to 5 mg twice daily 2
• If patient was taking 5 mg twice daily (RA/PsA indication), reduce to 5 mg once daily 2
• If patient was taking extended-release formulation (11 mg once daily), reduce to 5 mg immediate-release once daily 2

End-Stage Renal Disease (ESRD) on Hemodialysis

• For patients undergoing hemodialysis, administer dose after the dialysis session on dialysis days 2
• No supplemental doses are recommended after dialysis 2
• Mean AUC in ESRD patients on non-dialysis days is similar to that in patients with moderate renal impairment 3
• Despite dialyzer efficiency of 0.73, extensive non-renal clearance means dialysis does not significantly eliminate tofacitinib 3

Monitoring Recommendations in Renal Impairment

• Monitor renal function periodically during treatment 1
• Monitor complete blood count with differential, as renal impairment may increase risk of cytopenias 1
• Check hemoglobin levels regularly; interrupt dosing if hemoglobin decreases by >2 g/dL or falls below 8 g/dL 1
• Monitor for infections more closely, as impaired renal function may increase infection risk 1
• Consider checking lipid levels approximately 3 months after starting treatment 1, 4

Important Considerations and Precautions

• Tofacitinib is contraindicated in patients with severe active infections 1
• Patients with renal impairment may have higher risk of serious infections, particularly with higher doses 1
• Consider drug interactions that may further affect tofacitinib metabolism:
  • Reduce dose to 5 mg once daily when used with potent CYP3A4 inhibitors (e.g., ketoconazole) 1, 2
  • Reduce dose to 5 mg once daily when used with medications that result in both moderate CYP3A4 inhibition and potent CYP2C19 inhibition (e.g., fluconazole) 1, 2
• Avoid use in patients with severe hepatic impairment (Child-Pugh C) regardless of renal function 1

Remember that dose adjustments are crucial for optimizing efficacy while minimizing adverse effects in patients with renal impairment, as inappropriate dosing can lead to increased toxicity or treatment failure 5.