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The objective of this study was to compare the efficacy and safety of a chronotherapeutic dosing schedule of phenytoin and carbamazepine versus a conventional dosing schedule for the treatment of tonic-clonic epileptic patients. Of 148 epileptic subjects found to have subtherapeutic trough drug levels (subtherapeutic group, STG), 103 subjects who completed the study were randomized to either STG I (n=51) for treatment by the conventional dosing schedule (tablet phenytoin 100-400 mg/day OD or BD, tablet carbamazepine 200-800 mg BD, or both, equally divided doses with no fixed time of drug intake), with a dose increment but no change in usual time of drug administration allowed; or to STG II (n=52), with no dose increment permitted but a shift in all or most (two-thirds or three-fourths) of the daily dose of one or both medications to 20:00 h. The 62 patients who experienced drug toxicity reactions (toxicity group, TG) and who had serum drug levels in the toxic range were assigned to TG I for dose reduction or TG II for dose reduction and drug administration at 20:00 h. Those 16 subjects in STG I and 47 subjects in STG II who initially evidenced subtherapeutic trough drug concentrations exhibited therapeutic drug levels by the end of four weeks of treatment (p<0.01). A significantly greater number of TG II, as compared to TG I, subjects who experienced toxic reactions showed improved drug tolerance. There were no poor responders and more good responders (control of epilepsy for one year) in STG II compared to STG I subjects. The findings of this study indicate that a chronotherapeutic dosing schedule of phenytoin and carbamazepine involving the administration of most or all the daily dose of medication(s) at 20:00 h can improve the response of diurnally active epileptic patients not responding to standard doses, achieve therapeutic drug levels, and reduce toxic manifestations in subjects having drug concentrations beyond the therapeutic range.

The role of the time of administration of phenytoin on its serum levels and pharmacodynamic parameters was studied in two comparable groups of patients of grand mal—epilepsy stabilized on serum phenytoin therapy. In these patients, phenytoin was advised to be taken as a single daily dose either at 08.00 (Group M) or 20.00 (Group E) every day. A serum phenytoin level profile over 24 hours was obtained and all patients were clinically followed up for six months. Maximum serum concentration (C-max) of phenytoin was achieved significantly faster (p < 0.001) in patients of Group E. The total number of serum samples having toxic concentrations and also the incidence and severity of toxic effects of phenytoin was less in Group E. The study suggests that bedtime administration of phenytoin in patients of grand mal—epilepsy may lead to faster absorption of the drug and less side effects as compared with drug administration in the morning. [ABSTRACT FROM AUTHOR]