At what creatinine clearance level should abemaciclib be discontinued?

Discontinuation of Abemaciclib Based on Creatinine Clearance

Abemaciclib should be discontinued when creatinine clearance falls below 30 mL/min.

Rationale for Discontinuation Threshold

Abemaciclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor used in the treatment of hormone receptor-positive, HER2-negative breast cancer. While the drug itself can cause elevations in serum creatinine without affecting true renal function 1, there are important considerations for patients with actual renal impairment.

Pharmacokinetic Considerations

• Abemaciclib can increase serum creatinine levels through competition with creatinine for renal tubular secretion via organic cation transporter 2 (OCT2) and multidrug and toxic compound extrusion (MATE) transporters 2
• In patients with actual renal impairment, this effect can be compounded, potentially leading to drug accumulation
• The half-life of abemaciclib is approximately 17.5 hours in patients with normal renal function, but may be prolonged in those with renal impairment 3

Evidence-Based Recommendations

While there are no specific guidelines exclusively addressing abemaciclib discontinuation based on creatinine clearance, several general principles apply:

1. General Medication Guidelines in Renal Impairment:

   • Medications that undergo renal clearance typically require dose adjustment when creatinine clearance falls below 30 mL/min 4
   • For many anticancer drugs, a creatinine clearance <30 mL/min represents a threshold for either significant dose reduction or discontinuation 5

2. CDK4/6 Inhibitor Considerations:

   • Increased drug exposure in patients with renal impairment may lead to higher rates of hematologic toxicities 2
   • Abemaciclib concentrations are significantly associated with neutropenia and thrombocytopenia 2

3. Risk Assessment:

   • When creatinine clearance falls below 30 mL/min, the risk-benefit ratio shifts significantly for many medications
   • Patients with severe renal impairment (CrCl <30 mL/min) are at increased risk for both thrombotic and bleeding complications 4

Monitoring Recommendations

For patients on abemaciclib with borderline renal function:

• Monitor serum creatinine before every dose
• Calculate creatinine clearance using the Cockcroft-Gault formula
• Consider alternative methods to assess true renal function, as abemaciclib itself can elevate serum creatinine without affecting GFR 1
• Monitor closely for hematologic toxicities, which may be exacerbated in patients with renal impairment 2

Important Considerations

• Distinguishing Drug Effect from True Renal Impairment: Abemaciclib can cause elevations in serum creatinine without affecting true renal function 1. Consider alternative biomarkers or measured GFR when available.

• Hematologic Toxicity: Patients with renal impairment may experience increased hematologic toxicity with abemaciclib, particularly neutropenia and thrombocytopenia 2.

• Drug Interactions: Be cautious with concomitant medications that may further impair renal function or compete for the same elimination pathways.

Clinical Decision Algorithm

1. Calculate creatinine clearance before initiating abemaciclib and before each dose
2. If CrCl falls below 30 mL/min:
   • Discontinue abemaciclib
   • Consider alternative treatment options
3. If CrCl is between 30-45 mL/min:
   • Continue abemaciclib with increased monitoring
   • Monitor complete blood count weekly
   • Reassess renal function weekly
4. If patient develops Grade 3-4 hematologic toxicity:
   • Consider dose reduction or discontinuation regardless of renal function

By following these guidelines, clinicians can optimize the safety profile of abemaciclib while maintaining treatment efficacy in appropriate patients.