Population pharmacokinetic modelling of carbamazepine in epileptic elderly patients: implications for dosage

Бондарева, И. Б.; Jelliffe, Roger W.; Гусев, Е. И.; Guekht, Alla; Melikyan, Elina; Belousov, Yu. B.

doi:10.1111/j.1365-2710.2006.00717.x

Cited by 22 publications

(16 citation statements)

References 28 publications

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“…The estimate of CL/F and the variability between patients from our study are comparable with previous reports from population pharmacokinetic studies of carbamazepine in adults and elderly patients [21–24]. Carbamazepine is primarily metabolized by CYP3A4 yielding an active carbamazepine-10, 11-epoxide.…”

Section: Discussionsupporting

confidence: 87%

Population Pharmacokinetics of Carbamazepine in Elderly Patients

Punyawudho

Ramsay²,

Brundage³

et al. 2012

Therapeutic Drug Monitoring

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Background Carbamazepine is a commonly used antiepileptic drug in elderly patients. This study analyzed prospective data collected as part of a randomized, double-blinded trial of newly diagnosed epilepsy patients. The aims of this study were to determine the pharmacokinetic parameters and their variability of carbamazepine in elderly patients and to quantify the effect of covariates on these parameters. Methods Prospectively collected carbamazepine concentrations from 121 patients aged 60 years or older were used to develop a population pharmacokinetic model. Data were analyzed by a nonlinear mixed effects model (NONMEM). A one-compartment model with first order absorption and elimination was used to characterize the time course of carbamazepine concentration. Model evaluation and the predictive performance of the final model were assessed using the nonparametric bootstrap approach. Results The apparent clearance (CL/F) of carbamazepine in this community-dwelling elderly population was estimated to be 3.59 L/hr with an inter-individual variability of 18.1%. The CL/F increases 23% in patients co-medicated with phenytoin. The volume of distribution (V/F) was estimated to be 102 L with an inter-individual variability of 74.7%. Conclusions Carbamazepine clearance was not associated with body weight or any parameterization of body size, nor was age or race, nor any marker of hepatic or renal function. Patients on concurrent phenytoin therapy can be expected to require a 23% higher dose on average.

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Section: Discussionsupporting

confidence: 87%

Population Pharmacokinetics of Carbamazepine in Elderly Patients

Punyawudho

Ramsay²,

Brundage³

et al. 2012

Therapeutic Drug Monitoring

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“…Indeed, it has been shown that age-related changes in pharmacokinetics of carbamazepine in most elderly patients alter the proportion of epoxide and are associated with lower dose requirements than predicted from median population kinetics. 15 Patients with genetic polymorphisms in microsomal epoxide hydroxylase, the enzyme primarily associated with production of the epoxide metabolite, may benefit from epoxide monitoring to define the metabolic phenotype and optimize dose. 16 Finally, drug-drug interactions may place a patient at risk for inappropriate epoxide concentrations that would justify therapeutic monitoring of the metabolite.…”

Section: Discussionmentioning

confidence: 99%

Estimation of Carbamazepine and Carbamazepine-10,11-Epoxide Concentrations in Plasma Using Mathematical Equations Generated With Two Carbamazepine Immunoassays

et al. 2010

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Carbamazepine is metabolized to an active metabolite known as carbamazepine-10,11-epoxide, or simply the "epoxide" metabolite. The presence of this metabolite can have clinically significant implications in therapeutic drug monitoring of carbamazepine, but accurate quantification of the epoxide metabolite is currently limited to chromatographic techniques. In this study, mathematical equations are proposed for the estimation of carbamazepine and epoxide metabolite concentrations based on values generated by common carbamazepine immunoassays. Three immunoassays were studied: particle-enhanced turbidimetric inhibition immunoassay (PETINIA, Siemens Healthcare Diagnostics, Deerfield, IL), ADVIA Centaur (Siemens Healthcare Diagnostics), and a cloned enzyme donor immunoassay (CEDIA; Roche, Indianapolis, IN). Equations were based on observed cross-reactivity of epoxide with the PETINIA (average, 96.2%; range, 86.6%-105.7%) and epoxide cross-reactivity with the ADVIA Centaur assay (average, 6.5%; range, 5.3%-7.7%). In addition, equations were developed using average cross-reactivity of epoxide with the PETINIA and with the CEDIA. Values determined by calculation correlated well with carbamazepine and epoxide concentrations in supplemented and patient samples, for which values of carbamazepine (2.2-12.0 microg/mL [9-51 micromol/L]) and the epoxide metabolite (0.6-2.4 microg/mL) were also verified by liquid chromatography-tandem mass spectrometry.

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“…Potter and Donnelly suggested that routine monitoring of the epoxide metabolite could be clinically useful (8). In addition to renal patients, elderly patients have demonstrated changes in pharmacokinetics of carbamazepine (10), and patients with genetic polymorphisms in microsomal epoxide hydroxylase, the enzyme primarily attributed with the production of the epoxide metabolite, which may exhibit an abnormal metabolic phenotype and may require epoxide determinations to optimize the dose (11). Moreover, drug-drug interactions may place a patient at risk for inappropriate epoxide concentrations requiring therapeutic monitoring of the metabolite.…”

Section: Discussionmentioning

confidence: 99%

Discordant carbamazepine values between two immunoassays: carbamazepine values determined by ADVIA centaur correlate better with those determined by LC-MS/MS than PETINIA assay

McMillin

Juenke

Johnson

et al. 2011

J. Clin. Lab. Anal.

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Discordant carbamazepine values as determined by two different immunoassays may be due to different cross-reactivities with the active metabolite carbamazepine 10, 11-epoxide and may cause confusion in interpreting carbamazepine serum levels. In this study, we compared carbamazepine values in samples containing carbamazepine and the epoxide metabolite, as determined by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) and by two commercial carbamazepine immunoassays: the PETINIA and the ADVIA Centaur carbamazepine. Clinical specimens were used for the comparative studies wherein we determined carbamazepine concentrations using the PETINIA, ADVIA Centaur, and LC-MS/MS assays. We observed an excellent correlation between carbamazepine concentrations determined by the ADVIA Centaur and LC-MS/MS methods while carbamazepine values were overestimated using the PETINIA assay. When aliquots of drug-free serum were supplemented with clinically relevant concentrations of the carbamazepine epoxide metabolite, we observed negligible cross-reactivity of epoxide with the ADVIA Centaur assay but over 90% cross-reactivity with the PETINIA assay. We conclude that the ADVIA centaur assay accurately measures carbamazepine concentrations in plasma or serum and that the PETINIA assay significantly overestimates true carbamazepine concentration. Such discordance may cause confusion in interpreting serum carbamazepine levels.

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Population pharmacokinetic modelling of carbamazepine in epileptic elderly patients: implications for dosage

Cited by 22 publications

References 28 publications

Population Pharmacokinetics of Carbamazepine in Elderly Patients

Population Pharmacokinetics of Carbamazepine in Elderly Patients

Estimation of Carbamazepine and Carbamazepine-10,11-Epoxide Concentrations in Plasma Using Mathematical Equations Generated With Two Carbamazepine Immunoassays

Discordant carbamazepine values between two immunoassays: carbamazepine values determined by ADVIA centaur correlate better with those determined by LC-MS/MS than PETINIA assay

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