Use of simulation to develop multiple-dose regimens for drugs exhibiting nonlinear elimination kinetics

A mathematical model and resulting computer program for simulating blood-level versus time profiles of drugs exhibiting saturable elimination processes are described and evaluated. The iterative digital-analog simulator (IDAS) program consists of two sections--a simulation (SIM) module and an iteration control (IC) module. The SIM module predicts minimum and maximum serum drug levels based on a dose and a dosing interval. The IC module takes the minimum and maximum serum levels from the SIM module and produces a new dose (for a new maximum serum level) and a new dosing interval (for a new minimum serum level). The new dosing information is fed back into the SIM module and the iteration process is repeated until the predicted minimum and maximum levels converge on desired levels set by the user of the program. The model and program were tested by comparing simulation results with actual patient data for phenytoin (seven patients) and theophylline (three patients). The ability of the program to converge on correct doses and dosing intervals was evaluated under a variety of given conditions. The mean difference between actual and simulated profiles was 0.286 mg/liter and 1.5 mg/liter for phenytoin and theophylline, respectively. IDAS produced dose and dosing interval estimates within desired precision given a variety of initial input data. The results encourage prospective clinical investigation of the reliability and validity of the method.