Tolerance development antiepileptics

Phase I. Initial safety trials on a new medicine, usually conducted in normal male volunteers. An attempt is made to establish the dose range tolerated by volunteers for single and for multiple doses. Phase I trials are sometimes conducted in severely ill patients (e.g., in the field of cancer) or in less ill patients when pharmacokinetic issues are addressed (e.g., metabolism of a new antiepileptic medicine in stable epileptic patients whose microsomal liver enzymes have been induced by other antiepileptic medicines). Pharmacokinetic trials are usually considered Phase I trials regardless of when they are conducted during a medicine s development. 

Side effects. Because clobazam has been widely used as an anxiolytic, its side effects are well known and essentially similar to those of the other benzodiazepines. Thus sedation, dizziness, ataxia, blurred vision and diplopia are the most commonly reported in epileptic patients. One of the most problematic features of clobazam is its tendency to produce tolerance, an effect which may occur more frequently with clobazam than with the other widely used benzodiazepine, clonazepam. It has been estimated that at least 50% of patients develop tolerance. Tolerance to the sedative effects of the drug develop more rapidly than those to the antiepileptic effect. Clobazam should be considered as adjunctive therapy whenever treatment with a single first-line drug has proven to be ineffective. 

Cross-sensitivity among aromatic antiepileptic drugs occurs in about 50% of patients with a hypersensitivity reaction. It has previously been described on first exposure to each of the offending drugs (57). However, this patient developed an allergic rash on his second exposure to phenytoin, having previously tolerated it for 6 months. This suggests that carbamazepine may have altered his response to phenytoin. 

Levetiracetam and phenytoin have been retrospectively compared in the prophylaxis of early and late postoperative seizures in 315 patients [182 ]. Levetiracetam (n = 105) was at least as effective as phenytoin ( = 210) and significantly better tolerated. Adverse effects that prompted a change in antiepileptic drug therapy occurred in one patient taking levetiracetam, who had visual hallucinations, compared with 38 patients taking phenytoin (18%). In patients who were followed for at least 1 year and developed epilepsy, levetiracetam also had a higher retention rate. 

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