Monitoring zonisamide therapy; recommended for all patients to ensure appropriate dosing
Zonisamide (Zonegran) is approved as adjunctive therapy for partial seizures refractory to therapy with traditional anticonvulsants. Zonisamide is the pharmacologically active agent; metabolites are not active. Essentially 100% of the zonisamide dose is absorbed. Zonisamide binds to erythrocytes; approximately 88% of circulating zonisamide is bound in erythrocytes. Because the erythrocyte-bound zonisamide is inactive, and binding varies with blood concentration, the relationship between serum level and dose is not linear. Time to peak zonisamide concentration is 2 to 4 hours; time to peak is delayed by co-administration with food to 4 to 6 hours. Zonisamide is metabolized by N-acetyl transferase (NAT1), cytochrome P4503A4 (CyP3A4), and uridine diphosphate glucuronidation (UDPG). Zonisamide is eliminated in the urine predominantly as the parent drug (35%), N-acetyl zonisamide (15%), and as the glucuronide ester of reduced zonisamide (50%). Co-administration of drugs that affect NAT1, CyP3A4, and UDPG activity, such as phenytoin and carbamazepine, will decrease zonisamide concentration.
A typical zonisamide dose administered to an adult is 400 to 600 mg/day, administered in 2 divided doses. The apparent volume of distribution of zonisamide is 1.5 L/kg. Approximately 40% of the zonisamide circulating in the serum is bound to proteins. Zonisamide protein binding is unaffected by other common anticonvulsant drugs. The elimination half-life from plasma is 50 to 60 hours; the elimination half-life from erythrocytes is >100 hours. Since zonisamide is cleared predominantly by the kidney, the daily dosage of zonisamide given to patients with creatinine clearance <20 mL/min should be reduced.(1,2)
Serum level monitoring is recommended for all patients to ensure appropriate dosing because: 1) patient response correlates with serum level, 2) serum level does not correlate with dose because of concentration-dependent erythrocyte binding, 3) elimination is affected by co-administration of drugs that affect NAT1, CyP3A4, and UDPG, and 4) renal function affects elimination.
The most common toxicity associated with excessive serum level is drowsiness. Adverse effects not related to serum level include rash, increased serum creatinine and alkaline phosphatase, kidney stone formation, and bruising.
Steady-state zonisamide concentration in a trough specimen drawn just before next dose correlates with patient response, but not with dose. Optimal response to zonisamide occurs when trough zonisamide concentration is in the range of 10 to 40 mcg/mL. Peak serum concentration for zonisamide occurs 2 to 6 hours after dose, and time to peak is affected by food intake.
Because carbamazepine activates glucuronidation, patients taking carbamazepine concomitantly with zonisamide have significantly lower zonisamide concentrations compared to patients on the same dose not receiving carbamazepine.
Rufinamide is a known interference of this assay. Patients who are coadministered zonisamide and rufinamide may have falsely elevated and uninterpretable zonisamide concentrations reported by this assay.
Serum zonisamide will be increased with hemolysis.
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Perucca E: The clinical pharmacokinetics of the new antiepileptic drugs. Epilepsia 1999;40(Suppl 9):S7-S13
2. Marson AG, Hutton JL, Leach JP, et al: Levetiracetam, oxcarbazepine, remacemide and zonisamide for drug resistant localization-related epilepsy: a systematic review. Epilepsy Res 2001 Sep;46(3):259-270
3. Benedetti MS: Enzyme introduction and inhibition by new antiepileptic drugs: a review of human studies. Fundam Clin Pharmacol 2000 Jul-Aug;14(4):301-319
4. Kawada K, Itoh A, Kusaka T, et al: Pharmacokinetics of zonisamide in perinatal period. Brain Dev 2002 Mar;24(2):95-97