Clinical rules for phenytoin dosing

OBJECTIVE: To develop simple clinical rules for dosing phenytoin (PHT) using computer simulations, then to test the rules for accuracy and safety on actual patient data. DESIGN: Patients with steady-state PHT plasma concentrations at least two different PHT doses were identified from three separate sources of patient data. A computerized dosing program calculated pharmacokinetic parameters using Bayesian methodology, then predicted how many patients were likely to reach potentially toxic PHT plasma concentrations when their daily dosage was increased by 30, 50, or 100 mg. Dosing rules were developed to allow fewer than ten percent of resultant plasma concentrations to exceed 25 micrograms/mL. The dosing rules then were tested on dose/plasma concentration data from a separate group of patients. SETTING: All patients were being treated by neurologists either as outpatients or inpatients. PATIENTS: All patients were adults with epilepsy being treated with PHT; none had clinically significant renal or hepatic disease. Patients for the computer simulation were from three sources: (1) patients who had an initial PHT plasma concentration < 10 micrograms/mL and required a dosage increase; (2) patients admitted to the hospital for PHT intoxication; and (3) patients who required consultations specifically for PHT dosing. Patients on whom the dosing rules were tested were part of a prospective, randomized trial of antiepileptic drug safety and efficacy. MAIN OUTCOME MEASURES: Successful dosing rules allowing fewer than ten percent of resulting plasma concentrations in the test group to exceed 25 micrograms/mL. RESULTS: The simulations used 167 actual dose/plasma concentration pairs from 45 patients. The resulting dosing rules were: increase the dosage by 100 mg/d if the initial plasma concentration was < 7 micrograms/mL; increase the dosage by 50 mg/d if the initial plasma concentration is 7 to < 12 micrograms/mL; increase the dosage by 30 mg/d if the initial plasma concentration is > or = 12 micrograms/mL. The rules were tested on 129 50- or 100-mg dosage increases in 77 patients. All 53 dosage increases that were within the dosing rules produced plasma concentrations < 25 micrograms/mL, whereas 36 percent (27 of 74) of the dosage increases that exceeded the dosing rules produced plasma concentrations > 25 micrograms/mL. CONCLUSIONS: The proposed dosing rules are a simple method for clinicians to estimate PHT dosage changes and appear to be safe and accurate when applied retrospectively to actual patient data.

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