What Keppra (levetiracetam) dose adjustments are needed for a 61-year-old female with impaired renal function, serum creatinine 0.87 mg/dL, and eGFR of 88?

Estimated Creatinine Clearance Calculation and Levetiracetam Dosing

Creatinine Clearance Calculation

Using the Cockcroft-Gault formula, this patient's estimated creatinine clearance (eCrCl) is approximately 79 mL/min, which indicates mild renal impairment and requires levetiracetam dose adjustment. 1, 2

Calculation Details

Using the Cockcroft-Gault equation for a 61-year-old female weighing 153 lbs (69.4 kg) with serum creatinine of 0.87 mg/dL (77 µmol/L):

• eCrCl = [(140 - 61) × 69.4 × 0.85] / (0.87 × 72) = 74-79 mL/min 1

The eGFR of 88 mL/min/1.73 m² reported in this case uses the MDRD formula, which is not appropriate for drug dosing decisions—the Cockcroft-Gault formula should be used instead for medication dose adjustments. 1, 2

Levetiracetam Dose Adjustment Recommendations

For this patient with eCrCl of 50-80 mL/min (mild renal impairment), the FDA-approved levetiracetam dosing is 500-1000 mg every 12 hours, representing a 40% reduction in total body clearance compared to normal renal function. 2

Specific Dosing by Renal Function

• eCrCl 50-80 mL/min (mild impairment): 500-1000 mg every 12 hours 2
• eCrCl 30-50 mL/min (moderate impairment): 250-750 mg every 12 hours 2
• eCrCl <30 mL/min (severe impairment): 250-500 mg every 12 hours 2
• End-stage renal disease (hemodialysis): 500-1000 mg every 24 hours, with 250-500 mg supplemental dose after each dialysis session 2

Key Pharmacokinetic Considerations

Levetiracetam clearance is directly correlated with creatinine clearance, with 66% of the drug excreted unchanged in urine through glomerular filtration and partial tubular reabsorption. 2

• Total body clearance decreases by 40% in mild renal impairment (eCrCl 50-80 mL/min) 2
• Total body clearance decreases by 50% in moderate renal impairment (eCrCl 30-50 mL/min) 2
• Total body clearance decreases by 60% in severe renal impairment (eCrCl <30 mL/min) 2
• In anuric patients, total body clearance decreases by 70% compared to normal subjects 2

Critical Formula Selection for Drug Dosing

The Cockcroft-Gault formula must be used for levetiracetam dose adjustments rather than MDRD-based eGFR, as all FDA dosing recommendations and clinical trials used Cockcroft-Gault calculations. 1, 2

Why Cockcroft-Gault Over MDRD/eGFR

• The MDRD formula overestimates creatinine clearance in chronic kidney disease stages 3-5 1
• Cockcroft-Gault provides creatinine clearance in mL/min (not normalized to body surface area), which correlates better with drug clearance 1
• FDA drug labeling for renally-cleared medications, including levetiracetam, is based on Cockcroft-Gault calculations 1, 2
• The units differ: MDRD reports mL/min/1.73 m² while Cockcroft-Gault reports mL/min, making them non-interchangeable for dosing decisions 1

Monitoring Recommendations

Renal function should be monitored during levetiracetam therapy, as rare cases of acute kidney injury have been reported, particularly with high doses. 3, 4

• Monitor serum creatinine and recalculate eCrCl if clinical status changes 2
• Be aware that levetiracetam can rarely cause acute kidney injury, especially at loading doses ≥4 g or in patients with status epilepticus 3, 4
• Elderly patients (>59 years) have 38% decreased clearance and 2.5-hour longer half-life due to age-related decline in renal function 2

Common Pitfalls to Avoid

Do not use eGFR (MDRD or CKD-EPI) values for levetiracetam dose adjustments—this will result in incorrect dosing. 1, 2

• Using eGFR of 88 mL/min/1.73 m² would incorrectly suggest no dose adjustment is needed 1
• The actual eCrCl of ~79 mL/min indicates mild renal impairment requiring dose reduction 2
• In elderly patients, serum creatinine may appear normal despite significantly reduced creatinine clearance 2, 5
• Patients with liver disease have significant overprediction errors with creatinine-based formulas and require alternative assessment 5