How should levetiracetam (Keppra) dosing be adjusted in an 83-year-old man with a trough concentration of 2.4 µg/mL?

Levetiracetam Level of 2.4 µg/mL in an 83-Year-Old Man

This levetiracetam level of 2.4 µg/mL is subtherapeutic and requires immediate dose escalation, particularly in an elderly patient where seizure control is critical for preventing morbidity from falls, aspiration, and cognitive decline.

Understanding the Clinical Context

The measured trough concentration of 2.4 µg/mL falls well below the established therapeutic range for levetiracetam. While routine therapeutic drug monitoring is not required for most patients on levetiracetam due to its predictable pharmacokinetics and wide therapeutic window 1, checking levels is appropriate when seizures remain uncontrolled or when assessing compliance 1. In this 83-year-old patient, the subtherapeutic level suggests either inadequate dosing, poor compliance, or altered pharmacokinetics related to age or renal function.

The therapeutic range for levetiracetam is generally considered 12–46 µg/mL, with a threshold of approximately 11 µg/mL associated with therapeutic response 2. Studies demonstrate that responders to levetiracetam therapy have mean trough concentrations of 12.9 µg/mL (range 4.6–21 µg/mL), while nonresponders average 9.5 µg/mL 2. This patient's level of 2.4 µg/mL is dramatically below even the lower threshold, indicating inadequate drug exposure.

Immediate Dosing Recommendations

For Chronic Epilepsy Management

Increase the maintenance dose immediately to achieve therapeutic levels. The standard approach for chronic epilepsy involves starting at 1000 mg/day and titrating by 1000 mg/day every 2 weeks to a target of 3000 mg/day 3. However, given this patient's critically low level, more aggressive dosing is warranted:

• Administer an oral loading dose of 1500 mg immediately to rapidly achieve therapeutic concentrations 3, 4
• Begin maintenance dosing at 1000 mg every 12 hours (2000 mg/day total) starting 12 hours after the loading dose 3
• Recheck trough level in 48 hours to confirm achievement of therapeutic range (target >12 µg/mL) 2

Oral loading with 1500 mg levetiracetam is well-tolerated in adults, achieving mean serum concentrations of approximately 30–31.5 µg/mL within 1–2 hours, with minimal side effects (only 11% report transient symptoms) 4. This approach facilitates rapid stabilization without requiring hospitalization 4.

Age-Related Pharmacokinetic Considerations

Elderly patients have prolonged elimination half-lives (10–11 hours vs. 6–8 hours in younger adults) 5, which actually works in favor of maintaining therapeutic levels once achieved. However, the primary concern in this 83-year-old is renal function, as levetiracetam clearance is directly dependent on creatinine clearance 5.

Assess renal function immediately with creatinine clearance calculation 1. Dose adjustments are mandatory for moderate to severe renal impairment 1, 5:

Creatinine Clearance	Recommended Dose	Frequency
>80 mL/min	500–1500 mg	Every 12 hours
50–80 mL/min	500–1000 mg	Every 12 hours
30–50 mL/min	250–750 mg	Every 12 hours
<30 mL/min	250–500 mg	Every 12 hours
ESRD on dialysis	500–1000 mg	Every 24 hours

3

Critical Pitfalls to Avoid

Do not assume the patient is taking the medication as prescribed. Subtherapeutic levels this low (2.4 µg/mL) strongly suggest either severe non-compliance or a dosing error 1. Before escalating the dose, verify:

• Current prescribed dose and actual patient intake
• Pharmacy dispensing records
• Pill counts if available
• Patient understanding of dosing instructions

Do not delay dose adjustment while waiting for additional workup. The wide therapeutic window of levetiracetam (minimal protein binding, no hepatic metabolism, minimal drug interactions) makes it safe to increase dosing aggressively 3, 5. The risk of maintaining subtherapeutic levels far exceeds the risk of adverse effects from dose escalation.

Do not order routine therapeutic drug monitoring after stabilization. Once therapeutic levels are achieved and seizures are controlled, routine level checks are unnecessary 1. Reserve future monitoring for suspected non-compliance, breakthrough seizures, or changes in renal function 1.

Monitoring After Dose Adjustment

• Recheck trough levetiracetam level 48 hours after initiating new maintenance dosing to confirm therapeutic range (target 12–30 µg/mL) 2, 6
• Monitor complete blood count periodically during maintenance therapy 3
• Assess for adverse effects including somnolence, fatigue, dizziness, or rarely nausea 3
• Evaluate renal function every 6–12 months in elderly patients, as declining creatinine clearance will necessitate dose reduction 1, 5

Alternative Considerations if Seizures Are Acute or Ongoing

If this patient is presenting with breakthrough seizures or status epilepticus rather than routine monitoring, immediate IV loading is indicated:

• Administer levetiracetam 30 mg/kg IV (approximately 2000–2500 mg for average adult) over 5–15 minutes as second-line therapy after benzodiazepines 7, 3
• This achieves 68–73% seizure cessation rates in benzodiazepine-refractory status epilepticus 7, 3
• Follow with maintenance dosing of 30 mg/kg IV every 12 hours (maximum 1500 mg per dose) for convulsive seizures 7

The pharmacokinetic profile supports rapid IV loading, with peak concentrations achieved within 15 minutes and steady-state reached within 24–48 hours 5, 6.

Summary Algorithm

1. Verify compliance and current dosing regimen
2. Assess renal function (creatinine clearance)
3. Administer oral loading dose of 1500 mg immediately (if patient stable and able to take oral medication) 4
4. Begin maintenance 1000 mg every 12 hours starting 12 hours after loading dose 3
5. Adjust for renal impairment if creatinine clearance <80 mL/min 3, 1
6. Recheck trough level in 48 hours (target >12 µg/mL) 2
7. Monitor CBC and renal function periodically 3, 1