Guess what? Another study evaluating zonisamide was published recently (this one out of Japan: Saito et al. JVIM 2024). A historical paucity of data about zonisamide has made me hesitant to use this antiepileptic drug (AED) so I’m pleased that times are a changing!
On to the important stuff… This was a prospective multicenter, open-label uncontrolled study in 56 dogs. Several dogs dropped out, so the end result was that 53 dogs were assessed for efficacy and 56 dogs were included for evaluation of tolerability.
Results
To determine an appropriate dose and the target plasma concentrations, many researchers will calculate the mean drug dose and concentration for 50%, 90% and 100% of the responders. They found the following:
50%: dose range was 2.7-4.9 mg/kg PO q12h; no mean trough plasma concentration provided.
90%: mean dose 4.8 mg/kg PO q12h; mean trough plasma concentration 18.9 ug/ml
100%: mean dose 5.5 mg/kg PO q12h; mean trough plasma concentration 21.9 ug/ml
Putting all of this together, the starting dose recommendation by the authors was 2.5-5.5 mg/kg PO q12h for most dogs (reduce this for dogs with renal disease). The recommended therapeutic range is 10-40 ug/ml. However, there are a couple of things to be aware of when using this therapeutic range. First, the study design stated that the dose would be increased incrementally every 1-2 weeks for dogs with persistent seizures until adverse effects were noted OR they reached 15 mg/kg dosing. They did not exceed 15 mg/kg which could affect what is considered an appropriate therapeutic range. Secondly, the dose did not predict the serum concentration, suggesting non-linear PK. What this means is that if you start a dog on zonisamide at 5 mg/kg PO q12h, you cannot necessarily predict the plasma drug concentration. Phenobarbital in cats has predictable PK, but it doesn’t in dogs, for example. Because of this, it’s not completely clear what an “acceptable” starting dose may be for a given individual. How do you decide? It is recommended that you start with the given dose, measure drug concentrations and evaluate adverse effects. If the animal is displaying unwanted adverse effects, the dose is probably too high (regardless of drug concentration). If the animal is continuing to have seizures at an undesirable frequency, without adverse effects, the dose is likely too low. We know that adverse effects happen at higher concentrations AND that organ disease is more likely to occur at higher drug concentrations so do be cautious above 40 ug/ml plasma concentration.
Adverse effects noted in this study were minimal. They reported at least 1 adverse effect in 7 of the 56 dogs. Several dogs were withdrawn from the study due to perceived poor efficacy and adverse effects as well. Adverse effects noted include reduced activity, reduced appetite, vomiting, pelvic limb weakness, soft stools and constipation. All were mild and transient. No elevation in liver values were noted. Remember that this drug is a sulfa derivative so a patient with known sulfa sensitivity should avoid zonisamide. No renal disease or renal tubular acidosis was noted however it has been reported in other dogs receiving zonisamide.
Seizure control was obtained in 76% of the 53 dogs. A further 55% of dogs obtained seizure freedom. These results are better than the prior study evaluating zonisamide in which about 60% of the dogs were reported to obtain seizure control. The improved results are possibly due to different dosing, or a different genetic epileptic population.
Take home message:
Zonisamide is a viable alternative for dogs either as a primary or as an add-on AED. Start at 2.5 – 5.5 mg/kg PO q12h and measure plasma drug concentrations (yay!!) at 2 weeks.
Thanks for reading! I hope you have a great week. Remember to check FB for last minute updates to my schedule through out the summer. Happy Father’s day to all of the dads, dads-to-be and pet-dads out there!