A 4-year-old neutered male Border Collie with idiopathic ...

Ah, a classic challenge in managing canine idiopathic epilepsy. It's commendable that you're monitoring phenobarbital levels and liver enzymes – that's the cornerstone of responsible AED management. Let's walk through this methodically.

First, the fact that your 4-year-old Border Collie is experiencing cluster seizures while on phenobarbital, with a trough level of 15 µg/mL, immediately signals that the current drug concentration is likely insufficient to control his epilepsy. While 15 µg/mL technically falls within the broad therapeutic range of 15-40 µg/mL, it's at the very lowest end. For many dogs, particularly those with cluster seizures or more severe epilepsy, we often aim for the mid to upper end of that range, ideally 25-35 µg/mL, to achieve better seizure control.

Here's my recommended approach:

Increase Phenobarbital Dosage:

Given the current low-end therapeutic level and the presence of cluster seizures, the most direct and often most effective first step is to increase the phenobarbital dosage. I would recommend a 10-25% increase from his current dose. For example, if he is currently on 2.5 mg/kg PO q12h (which is a common starting dose within the 2-3 mg/kg range), you might increase it to 2.8-3.1 mg/kg PO q12h. This gradual increase helps mitigate potential side effects like sedation.
The goal is to gently push his trough level into that 25-35 µg/mL sweet spot, where we often see better efficacy without excessive side effects.

Monitor and Recheck:

After increasing the dose, it takes approximately 10-14 days (5 half-lives) for phenobarbital to reach a new steady state. Therefore, you should recheck his phenobarbital trough level, along with liver enzymes (ALP, ALT, and consider bile acids if you have concerns about true hepatotoxicity), approximately 2 weeks after the dose adjustment.
Continue to meticulously track his seizure diary (frequency, duration, severity, post-ictal period). This clinical data is just as important as the drug levels in assessing efficacy.

Addressing Liver Enzymes:

You mentioned mildly elevated but stable liver enzymes. This is a very common finding with chronic phenobarbital therapy due to hepatic enzyme induction (specifically ALP). As long as the elevations are mild, stable, and liver function (e.g., bile acids) remains normal, this typically indicates enzyme induction rather than true hepatotoxicity. However, continued monitoring is crucial. If ALT becomes significantly elevated or there are clinical signs of liver disease, further investigation (e.g., bile acids, abdominal ultrasound) would be warranted.

Consider Combination Therapy (if needed):

If, after optimizing the phenobarbital dose, cluster seizures persist, or if increasing the phenobarbital dose leads to unacceptable side effects (e.g., profound sedation, severe ataxia, unmanageable PU/PD/polyphagia), then it's time to consider adding a second antiepileptic drug (AED).
My top choice for an add-on in this scenario would typically be levetiracetam. It has an excellent safety profile, minimal drug-drug interactions, and is generally well-tolerated. The dose for standard release levetiracetam is 20-30 mg/kg PO q8h. If using the extended-release formulation, the dose would be 30-60 mg/kg PO q12h (and remember, do not split extended-release tablets).
Another option is zonisamide, typically dosed at 5-10 mg/kg PO q12h. However, be aware that phenobarbital can induce CYP3A4, potentially lowering zonisamide levels, so a higher zonisamide dose might be needed if combined.

Re-evaluate Diagnosis (Refractory Cases):

While this is diagnosed as idiopathic epilepsy, if the seizures become truly refractory despite appropriate phenobarbital levels and the addition of a second AED, it's always prudent to reconsider the initial diagnosis. A diagnostic workup including MRI of the brain and CSF analysis might be indicated to rule out structural causes (e.g., a subtle brain tumor, inflammatory disease) that might not have been evident at the time of initial diagnosis or could have developed since. For a 4-year-old Border Collie, a structural lesion is less likely than in an older dog, but cluster seizures can sometimes be a red flag.

For now, focus on safely and effectively increasing that phenobarbital level. You're doing excellent work by closely monitoring your patient. Keep that seizure diary current and maintain open communication with the owner.