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 s afety on actual patient data. DESIGN: Patients with steady-state PHT p lasma concentrations at least two different PHT doses were identified from three separate sources of patient data. A computerized dosing pro gram calculated pharmacokinetic parameters using Bayesian methodology, then predicted how many patients were likely to reach potentially tox ic 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 mu/mL. The do sing rules then were tested on dose/plasma concentration data from a s eparate group of patients. SETTING: All patients were being treated by neurologists either as outpatients or inpatients. PATIENTS: All patie nts were adults with epilepsy being treated with PHT; none had clinica lly significant renal or hepatic disease. Patients for the computer si mulation were from three sources: (1) patients who had an initial PHT plasma concentration < 1 0 pg/mL and required a dosage increase; (2) p atients admitted to the hospital for PHT intoxication; and (3) patient s who required consultations specifically for PHT dosing. Patients on whom the dosing rules were tested were pan of a prospective, randomize d trial of antiepileptic drug safety and efficacy. MAIN OUTCOME MEASUR ES: Successful dosing rules allowing fewer than ten percent of resulti ng plasma concentrations in the test group to exceed 25 mug/mL. RESULT S: The simulations used 167 actual dose/plasma concentration pairs fro m 45 patients. The resulting dosing rules were: increase the dosage by 100 mg/d if the initial plasma concentration was <7 mug/mL; increase the dosage by 50 mg/d if the initial plasma concentration is 7 to < 12 pg/mL; increase the dosage by 30 mg/d if the initial plasma concentra tion is greater-than-or-equal-to 12 mug/mL. The rules were tested on 1 29 50- or 100-mg dosage increases in 77 patients. All 53 dosage increa ses that were within the dosing rules produced plasma concentrations < 25 mug/mL, whereas 36 percent (27 of 74) of the dosage increases that exceeded the dosing rules produced plasma concentrations >25 mug/mL. C ONCLUSIONS: The proposed dosing rules are a simple method for clinicia ns to estimate PHT dosage changes and appear to be safe and accurate w hen applied retrospectively to actual patient data.