How does renal disease affect AED levels?
- Renal insufficiency alters the pharmacokinetics of seizure medications that are metabolized by the kidneyes, leading to increased half-lives and accumulation of the drug.
- Albuminuria and acidosis that frequently occur in renal failure also decreases drug binding, increasing the free levels of AEDs and volume of distribution.
- Gastroparesis delays maximum serum levels of AEDs, intestinal edema diminishes absorption of AEDs.
Take home message: It is difficult to predict drug levels based on the creatinine clearance.
AEDs that are extensively eliminated by kidneys:
- low molecular weight
- low Vd
- little protein-bound
- Examples: gapabentin, topiramate, ethosuxamide, vigabatrin, levetiracetam
- accumulate in renal disease
- easily removed by hemodialysis and requires post-HD administration
AEDs that are not extensively eliminated by kidneys:
- high protein-bound
- Examples: carbamazepine, phenytoin, lamotrigine, benzodiazepines, valproate
- little affected by renal disease
- HD has little impact on carbamazepine, phenytoin and valproate levels
- HD has unpredictable effects on benzodiazepines or oxcarbazepine monohidroxi derivative
- 4-hour HD decreases lamotrigine levels by ~20%
Peritoneal dialysis has variable effects on AED serum levels, check free levels for drug adjustment
- CrCl >80 mL/minute/1.73 m2: 500 to 1,500 mg every 12 hours
- CrCl 50 to 80 mL/minute/1.73 m2: 500 to 1,000 mg every 12 hours
- CrCl 30 to 50 mL/minute/1.73 m2: 250 to 750 mg every 12 hours
- CrCl <30 mL/minute/1.73 m2: 250 to 500 mg every 12 hours
- End-stage renal disease (ESRD) requiring hemodialysis: Dialyzable (50%); 500 to 1,000 mg every 24 hours; supplemental dose of 250 to 500 mg is recommended posthemodialysis
- Peritoneal dialysis (PD): 500 to 1,000 mg every 24 hours (Aronoff 2007)
- Continuous renal replacement therapy (CRRT): 250 to 750 mg every 12 hours (Aronoff 2007)
- There are no dosage adjustments provided in the manufacturer’s labeling; <5% excreted as unchanged drug. Serum concentration may be difficult to interpret in renal failure. Monitoring of free (unbound) concentrations or adjustment to allow interpretation is recommended.
- Fosphenytoin: There are no dosage adjustments provided in the manufacturer’s labeling. Free (unbound) phenytoin levels should be monitored closely in patients with renal disease or in those with hypoalbuminemia; furthermore, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance in these patients leading to increase frequency and severity of adverse events.
- Dosage adjustments are not required or recommended in the manufacturer’s labeling; however, the following guidelines have been used by some clinicians:
- Children and Adults:
- GFR <10 mL/minute: Administer 75% of dose
- Hemodialysis, peritoneal dialysis: Administer 75% of dose (postdialysis)
- Continuous renal replacement therapy (CRRT):
- Adults: No dosage adjustment recommended
- Children: Administer 75% of dose
- There are no specific dosage adjustments provided in the manufacturer’s labeling; reduced doses are recommended.
- The following guidelines have been used by some clinicians:
- CrCl ≥10 mL/minute: No dosage adjustment necessary.
- CrCl <10 mL/minute: Administer every 12 to 16 hours.
- HD (moderately dialyzable [20% to 50%]): Administer dose before dialysis and 50% of dose after dialysis.
- PD: Administer 50% of normal dose.
- CRRT: Administer normal dose and monitor levels.
- Mild to severe impairment: No dosage adjustment necessary (including patients on hemodialysis); however, due to decreased protein binding in renal impairment, monitoring only total valproate concentrations may be misleading.
- Dosing: Renal Impairment
- Oral: No dosage adjustment necessary
- IM, IV: Risk of propylene glycol toxicity. Monitor closely if using for prolonged periods of time or at high doses.
- Mild-to-moderate disease: Use with caution.
- Severe disease or failure: Use is not recommended.
- Dosing: Renal Impairment
- There are no dosage adjustments provided in manufacturer’s labeling; however, patients with renal failure receiving a continuous infusion cannot adequately eliminate the active hydroxylated metabolites (eg, 1-hydroxymidazolam) contributing to prolonged sedation sometimes for days after discontinuation
- Intermittent HD: Supplemental dose not necessary
- CVVH: Unconjugated 1-hydroxymidazolam not effectively removed; 1-hydroxymidazolamglucuronide effectively removed; sieving coefficient = 0.45
- PD: Significant drug removal unlikely
- There are no dosage adjustments provided in the manufacturer’s labeling. Decreased maintenance dosage may be effective in patients with significant renal impairment; has not been adequately studied; use with caution.
- No dosage adjustment necessary.
Lacerda, Glenda Corrêa Borges de. “Treating Seizures In Renal And Hepatic Failure”. J. epilepsy clin. neurophysiol. 14 (2008): 46-50.
Uptodate. Accessed 07/12/2016.