Assessment of inter-individual variability in predicted phenytoin clearance.
OBJECTIVE
To assess the inter-individual variability in phenytoin (PHT) clearance predicted from in vitro kinetic data.


METHODS
The Simcyp Population-based ADME Simulator was used to predict the clearance of PHT from reported in vitro kinetic data generated in the absence or presence of albumin. Liver intrinsic clearance (CLint.liver) was calculated from pharmacokinetic studies and compared to the time-averaged liver intrinsic clearance (CLint.liver.0–96  hr) of the simulations. Trough PHT concentrations at steady-state were collated from a therapeutic drug monitoring service, and data from the patient cohort were compared with the results from the virtual population.


RESULTS
Simulations of PHT clearance were most accurate when based on ‘albumin-adjusted’ in vitro kinetic data, and they identified inter-individual variability outside the reported range of pharmacokinetic studies in healthy volunteers (CLint.liver = 4.6–22.5 L h−1 vs. CLint.liver.0–96  hr = 2.4–40.1 L h−1). Cumulative frequency plots of trough PHT concentration at steady-state were comparable between the patient cohort and the virtual population.


CONCLUSIONS
Mechanistic modelling and simulation allow inter-individual variability in clearance to be considered during in vitro–in vivo extrapolation, and this approach may offer a superior indication of variability and covariates in the clinic than that provided by small pharmacokinetic studies.
Polasek
Thomas M
TM
Flinders University and Flinders Medical Centre, Flinders Drive, Adelaide, South Australia, Australia. tom.polasek@flinders.edu.au
Polak
Sebastian
S
Doogue
Matthew P
MP
Rostami-Hodjegan
Amin
A
Miners
John O
JO
D000328:Adult; D000418:Albumins; D015331:Cohort Studies; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D007206:Individuality; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010672:Phenytoin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
D000418:Albumins; D010672:Phenytoin