What Causes Elevated Levetiracetam (Keppra) Levels?
Renal impairment is the primary cause of elevated levetiracetam levels, as 66% of the drug is eliminated unchanged through the kidneys via glomerular filtration with partial tubular reabsorption. 1
Primary Mechanism: Renal Elimination
Levetiracetam clearance is directly correlated to creatinine clearance, making any degree of renal dysfunction the most important factor in drug accumulation 1:
- Total body clearance: 0.96 mL/min/kg with renal clearance of 0.6 mL/min/kg 1
- Plasma half-life in normal renal function: 6-8 hours in adults 1
- Half-life increases significantly in elderly patients primarily due to impaired renal clearance 1
Clinical Consequences of Elevated Levels
When levetiracetam accumulates due to renal failure, serious neurological toxicity can occur 2:
- Myoclonic encephalopathy with triphasic waves on EEG has been documented with drug accumulation in chronic renal failure 2
- Metabolic encephalopathy that is reversible after dose reduction, even without improvement in renal function 2
- In acute overdose (levels 10-40 fold higher than therapeutic), CNS depression and respiratory depression occur, though recovery is rapid with supportive care 3
Specific Causes of Elevated Levels
Renal Impairment
- Any reduction in creatinine clearance will decrease levetiracetam elimination 1
- Dose adjustment is mandatory in renal dysfunction 1
- Acute kidney injury has been reported as a possible consequence of levetiracetam therapy itself, creating a potential feedback loop 4
Overdose
- Intentional or accidental ingestion produces proportionally elevated levels 3
- A case report documented levels of 400 µg/mL (therapeutic range 10-37 µg/mL) at 6 hours post-ingestion of 30 grams 3
- Elimination follows first-order kinetics even at toxic concentrations with a half-life of approximately 5.14 hours 3
Age-Related Changes
- Elderly patients experience increased plasma half-life primarily due to age-related decline in renal clearance 1
Important Clinical Considerations
Levetiracetam has minimal drug-drug interactions because 1:
- It is not metabolized by cytochrome P450 enzymes 1
- Less than 10% protein binding eliminates competition for binding sites 1
- No clinically significant interactions with other antiepileptic drugs (phenytoin, valproate, carbamazepine) 1
- The only documented interaction is with probenecid, which can decrease renal clearance of the primary metabolite through competition for active tubular secretion 1
Enzyme-inducing AEDs cause a 22% increase in apparent total body clearance in pediatric patients, but this does not typically require dose adjustment 1
Monitor for encephalopathy in patients with any degree of renal impairment taking levetiracetam, as toxic accumulation can present as metabolic encephalopathy with triphasic waves that resolves with dose reduction 2.