Individualization of phenytoin dosage regimens

Abstract

Two methods for arriving at optimum, individual phenytoin dosage regimens have been evaluated in 12 patients. (1) Individual Michaelis-Menten pharmacokinetic parameters for phenytoin were estimated from two reliable steady-state phenytoin serum concentrations resulting from different daily doses: The observed steady-state phenytoin serum levels obtained after 3 to 8 wk of compliance with dosage regimens calculated from the individual pharmacokinetic parameters agreed well with predicted levels (r = 0.824, p less than 0.02). The average deviation between observed and predicted levels was 0.04 mug/ml (range, +/- 3.2 mug/ml). (2) A previously published nomogram for making adjustments in phenytoin dosage regimens: The serum phenytoin concentration actually expected from the dose indicated by the nomogram was calculated using individual pharmacokinetic parameters. The daily dose for one patient would have exceeded his estimated maximal rate of metabolism. The correlation between calculated and predicted phenytoin serum levels in the other 11 patients was weak but significant (r= 0.360, p less than 0.05). The average deviation was --3 mug/ml (range, 3.9 to --11.3 mug/ml). It was concluded that the use of individual pharmacokinetic parameters is practical and is also superior to the nomogram.

Use of Three Probes to Assess the Influence of Sex on Hepatic Drug Metabolism

“…However, given that CLuinl is the ratio of Vmax/Km where Km is referenced to unbound drug [13], and allowing Km to be set at 0.57 mg/1 (population Km referenced to total PHT concentrations [17] multiplied by a nominal free fraction of 0.1) and Vmax at 0.247 mg/kg/h [17], one can estimate a CLuin[ of 433 ml/h/kg to which our value (all subjects) of 483 (± 178) compares favora bly. Likewise, estimating CLU jnl from the data of Ludden et al [18] by referencing Km to unbound PHT, assuming a nominal free fraction of 0.1, and omitting the data of their patient J (CLuint s 2,720 ml/h/kg), a mean value of 473 mi/kg/h is obtained which ap proximates our value. Thus, our single-sam ple estimates of PHT kinetic parameters (Vmax/Km) based on salivary PHT concentra tions are in line with Vmax/Km values refer enced to unbound PHT which have been estimated from steady-state PHT measure ments in plasma.…”

Predictability of Phenytoin Serum Levels by Nomograms and Clinicians

“…If a dose adjust ment is needed, physicians who do not have much experience with phenytoin therapy may use either of the two nomograms tested in this study, bearing in mind the large confidence interval of the prediction error and the fact that both nomograms will on the average underesti mate the rise in the phenytoin serum concentra tion by 2 -3 mg/1. If more than one steady state serum concentration measurement is available either the method proposed independently by Ludden et al (11) and Martin et al (14) or the graphical procedure described by Eisentltal and Cornisli-Bowden (2) and proposed for clinical use by Mullen (15) can be employed to esti mate the patient's individual pharmacokinetic parameters. Although presently available results indicate that a reasonably good prediction of phenytoin serum concentration can be obtained by both methods, a prospective evaluation in a sufficiently large sample of patients is needed to confirm their clinical usefulness and safety.…”

“…However, the dose-dependent pharmacokinetics of the drug make the choice of the appropriate dose a difficult therapeutic task even if a serum con centration value is available. Several dosing aids have therefore been developed to help the physician to adjust the dose in a patient in whom one or more steady state serum concen trations are known (11,14,17,18).…”

Relative Bioavailability of Two Different Phenytoin Preparations

“…where the factor F-D is used as an estimate of elimination rate [11]; F = fraction of drug absorbed; D = dose (mg/kg/day); C = serum concentration (pg/ml); Km = MichaelisMenten constant (pg/ml); Vraax = Michaelis-Menten constant (mg/kg/day). The equation can be rearranged as:…”