Procedures for estimating the variability in dosage requirements of phenytoin to achieve steadystate plasma concentrations of 10–20 mg/liter and for estimating the plasma concentrations produced on a fixed dose are given. Further, a method is proposed for estimating the dosage required to achieve a desired steady-state plasma phenytoin concentration when a steady-state value on a known daily dose has been measured, A method is also described for estimating dosage requirements when two or more plasma concentrations have been measured. These methods are derived from data obtained on administering phenytoin in four to five different dosage regimens until steady state was achieved in each of nine volunteers. The drug was administered orally as a suspension every 8 hr, starting with about 100mg/day. The daily dose was increased in steps, and maintained at each daily dose rate for 6–14 days, or longer. Blood samples were drawn 4 and 8 hr after the last dose on 2 successive days at the end of each step and analyzed for phenytoin concentration. The average of these values was used to estimate the steady-state plasma concentration, Cpss. For each subject the Cpss values were fitted to a rearranged Michaelis-Menten equation Cpss =KmR/(Vm-R). In this equation R is the dosing rate, Vm is the maximum rate of metabolism, and Km is a constant equal to the plasma concentration at which the metabolism rate is one-half maximum. The average values found for Vm and Km were 10.3 mg/kg/day and 11.54 mg/liter, respectively. The individual values of Vm and Km appear to be constant over time, but there is considerable interindividual variability: coefficients of variation are 25% and 50%, respectively.
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Supported in part by grants (GM-16496, GM-01791, and GM-00001) from the National Institutes of Health. Dr. Martin was a recipient of a grant from the Swiss National Research Foundation.
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Martin, E., Tozer, T.N., Sheiner, L.B. et al. The clinical pharmacokinetics of phenytoin. Journal of Pharmacokinetics and Biopharmaceutics 5, 579–596 (1977). https://doi.org/10.1007/BF01059685
- steady state
- dosage requirements
- dosage adjustment
- capacitylimited elimination