Abstracts

Rationale: Tolerance is a diminished response to a drug following repeated administration, necessitating a dosage increase to maintain an effect. While it is widely believed that some patients develop pharmacologic tolerance to the anti-seizure effects of benzodiazepines, there is a paucity of clinical data to support this. Whether tolerance actually occurs in patients is a clinically important question, particularly for the chronic treatment of epilepsy. Clobazam is a 1,5-benzodiazepine indicated in the US for the adjunctive treatment of seizures associated with Lennox–Gastaut Syndrome (LGS) in patients ≥2 years of age. This post hoc analysis evaluated the potential development of tolerance in a long-term open-label study of adjunctive clobazam in patients with LGS.Methods: Patients who completed a phase 2 study (OV-1002, NCT00162981) or a phase 3 study (OV-1012, NCT00518713) were eligible to enroll in an open-label extension (OLE) trial (OV-1004, NCT01160770). The OLE study continued until clobazam was commercially available in the US or for a maximum of 2 years outside the US. Enrolled patients (N=267) were started at 0.5 mg/kg/day clobazam, not to exceed 40 mg/day. This was to be maintained for 48 hours, and thereafter, dosages could be adjusted based on efficacy and tolerability, up to 2.0 mg/kg/day (maximum allowable dosage: 80 mg/day), at the discretion of the investigator. Post hoc analyses were conducted to determine mean dosages over the first 2 years of the OLE trial based on responder rates in lead-in study OV-1012 (100% reduction in drop seizures, ≥75%, 50%–<75%, 25%–<50%, <25%). Mean weekly drop seizure rates over 24 months were examined in patients with 100% and ≥75% reduction in drop seizures during the lead-in study. Individual patient listings were reviewed for dosage increases ≥40% and seizure rates.Results: A total of 200 patients were included in post hoc analyses. There was no significant change in dosage over 24 months for patients free of drop seizures (Figure 1). All other drop-seizure responder groups (ie, ≥75%, 50%–<75%, 25%–<50%, <25%) had significant increases in dosage over time (Figure 1). Most increases were seen in the first 6 months; thereafter dosages remained relatively stable for the next 18 months. Weekly drop seizure rates for the ≥75% responder group demonstrated a consistent response over time (Figure 2). Review of individual patient dosages and seizure rates indicated low prevalence of clobazam tolerance.Conclusions: Our findings, based upon 2 years of observation, suggest that the vast majority of patients do not develop tolerance to the anti-seizure actions of clobazam. Dosage increases observed during the first 12 months seem to reflect best practices in an effort to achieve the clinical goal of seizure freedom. It is possible that the clinical development of tolerance to clobazam has been overstated. Funded by Lundbeck, LLC