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Unit Code 83685:
Zonisamide, Serum

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Useful For

Monitoring zonisamide therapy; recommended for all patients to

ensure appropriate dosing

 

Assessing compliance

Clinical Information

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 2-4 hours; time to peak is

delayed by co-administration with food to 4-6 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 400-600

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 50-60

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.

Reference Values

10-40 ug/mL

Interpretation

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 10-40 ug/mL.

Peak plasma concentration for zonisamide occurs 2-6 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.

Cautions

Hemolysis will significantly affect the serum zonisamide concentration.

Serum zonisamide will be increased with hemolysis.

Clinical Reference

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

Key