The therapeutic agent of choice for management of epileptic seizures in dogs is phenobarbitone. The published "therapeutic range" reflects the serum concentration determined to provide optimal seizure control while minimising adverse side effects. However, phenobarbitone induces hepatic microsomal enzyme systems which increase metabolism and decrease the half life. Thus oral dosing may have to be increased to maintain serum concentrations.

The aims of this study were to 1) determine the proportion of dogs with serum phenobarbitone concentrations in the recommended therapeutic range (65-194 µmol/L) at the time of first monitoring (range: 1 to 16 weeks after starting therapy) and, 2) investigate the effect of therapy duration on the serum phenobarbitone concentration achieved, relative to dose.

Retrospective analysis was performed on data from dogs enlisted in the Vétoquinol UK phenobarbitone monitoring voucher scheme (n=1554). Data recorded included weight, total daily phenobarbitone dose, therapy duration and serum phenobarbitone concentration. For aim-2 therapy durations were split into <2 weeks, 2-4 weeks, 4-12 weeks, 12 weeks to 1 year, and >1 year. The ratio of serum concentration to total daily dose was calculated for each group and compared, using the unpaired t-test with Welch's correction, to the <2 week therapy duration group.

Results Aim-1

In dogs starting phenobarbitone therapy at the manufacturer's recommended dose (2-5 mg/kg per day, divided BID; n=220) 90 reached therapeutic serum concentrations at first monitoring. In dogs started below this level (n=16) only one animal reached therapeutic levels (OR=0.10, p-value=0.025). If dogs were started at 5-8 mg/kg per day 40 out of 50 reached therapeutic levels (OR=5.8, p-value < 0.001). Ten dogs were started at levels above this range.

Results Aim-2

The ratio of serum phenobarbitone concentration to total daily dose decreased significantly with increased therapy duration. At therapy duration of <2-weeks the ratio was 18.31 (n=106), at 2-4 weeks 16.94 (n=214, p-value=0.17), at 4-12 weeks 16.46 (n=310, p-value=0.05), at 12-weeks to 1-year 15.96 (n=315, p-value=0.01), and at >1-year 16.29 (n=609, p-value=0.02).

In conclusion, routine monitoring of serum phenobarbitone concentrations in dogs starting on phenobarbitone therapy is recommended as only 41% started on recommended doses reach therapeutic levels at first monitoring. Furthermore, significant reduction in serum phenobarbitone concentration relative to total daily dose occurs with increasing duration of therapy, confirming a requirement for regular monitoring.

Acknowledgements

We are grateful to Vétoquinol UK for access to the voucher scheme data.