The ‘apparent clearance’ of free phenytoin in elderly vs. younger adults

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The clearance of many drugs is reduced in the elderly, but the data regarding phenytoin are conflicting. Most studies have estimated phenytoin metabolic clearance using total drug concentrations (bound plus unbound), which may be confounded by protein binding effects. Free phenytoin concentrations are independent of protein binding and should more accurately reflect true metabolic clearance changes in elderly patients. WHAT THIS STUDY ADDS• The two studies reported in this paper suggest a trend towards reduced free phenytoin 'apparent clearance' in the elderly, although statistically significant results were not found. Other published studies have largely found similar trends, suggesting an age effect. AIMSTo test the hypothesis that the 'apparent clearance' of free phenytoin is reduced in elderly patients. METHODSTwo separate studies were conducted comparing free phenytoin 'apparent clearance' in elderly vs. younger adults. The first study was a retrospective analysis of free phenytoin concentrations measured at Christchurch Hospital from 1997 to 2006. In the second study free phenytoin concentrations were measured prospectively in ambulatory subjects who were taking phenytoin regularly. RESULTSIn the retrospective study (n = 29), free phenytoin 'apparent clearance' was 0.27 Ϯ 0.04 l kg -1 day -1 (95% CI 0.19, 0.34) in the elderly cohort vs. 0.37 Ϯ 0.06 l kg -1 day -1 (95% CI 0.22, 0.52) in younger adults, but the difference was not statistically significant. In the prospective study, free phenytoin 'apparent clearance' showed a non-significant trend to being reduced in the elderly patients (0.12 Ϯ 0.02 l kg -1 day CONCLUSIONSThis research does not prove the hypothesis that the 'apparent clearance' of free phenytoin is reduced in the elderly. However, the trends found in these two studies are supported by trends in the same direction in other published studies, suggesting an age effect.

Understanding the time course of pharmacological effect: a PKPD approach

“…As a result, it is widely employed clinically (see examples [18][19][20]). An example of a typical steady-state PKPD model is given by: …”

“…The steady-state condition provides a powerful framework from which to describe the magnitude of drug effect. As a result, it is widely employed clinically (see examples [18][19][20]). An example of a typical steady-state PKPD model is given by: In this setting, the assumption is made that the steadystate average concentration is sufficient to describe the important pharmacokinetic characteristics of the drug.…”

Association of CYP2C9 polymorphisms with phenytoin toxicity in Indian patients

“…This is in contrast to previous studies which showed reduced phenytoin clearance in older individuals leading to higher plasma levels and toxicity. [26,27] We also found that males had 6 times higher odds of developing toxicity relative to females. Kesavan et al [20] did not find any association between gender and neurological toxicity as also by others.…”

Interference in Immunoassays Used for Monitoring Anticonvulsants and the Usefulness of Monitoring Free Anticonvulsants

“…An apparent clearance of free phenytoin tends to decrease in the elderly compared with younger people (53) . An apparent clearance of free phenytoin tends to decrease in the elderly compared with younger people (53) .…”