Serum carbamazepine concentrations in elderly patients: a case-matched pharmacokinetic evaluation based on therapeutic drug monitoring data.
OBJECTIVE
To assess the influence of aging on the steady-state pharmacokinetics of carbamazepine (CBZ) in a large population of patients evaluated in a therapeutic drug monitoring (TDM) setting.


METHODS
The database of a large TDM service was used to identify retrospectively steady-state serum CBZ concentrations in 157 elderly patients with epilepsy (65 years and older) treated with CBZ alone or in combination with phenobarbital (PB). CBZ apparent oral clearance (CL/F) values were calculated and compared with those determined in an equal number of controls aged 20 to 50 years, and matched for gender, body weight, and comedication.


RESULTS
Compared with corresponding controls, mean CBZ CL/F values were 23% and 24% lower, respectively, in the groups of elderly patients receiving monotherapy (57.1 +/- 20.6 vs. 74.6 +/- 28.3 ml/h/kg; p < 0.0001) and PB comedication (74.7 +/- 25.5 vs. 98.7 +/- 34.9 ml/h/kg; p < 0.01). Within each age group, patients comedicated with PB showed significantly higher CBZ CL/F values than those on monotherapy. A negative correlation between CL/F and age was found both within the monotherapy and the PB comedicated groups. In addition, CL/F values showed a positive relation with the administered daily dosage, which persisted within subgroups homogeneous for age and comedication. The independent influence of age, CBZ dosage, and comedication on CBZ CL/F was confirmed by multiple regression analysis.


CONCLUSIONS
CBZ CL/F is decreased in an age-dependent manner in elderly patients compared with younger subjects, presumably because a reduction in the rate of CYP3A4-mediated drug metabolism. Elderly patients retain their sensitivity to dose-dependent autoinduction and to heteroinduction by enzyme-inducing AEDs, but their metabolic rates remain considerably below those observed in matched controls. As a result of this, patients in old age will require lower CBZ dosages to achieve serum concentrations comparable with those found in nonelderly adults.
Battino
Dina
D
Carlo Besta National Neurological Institute, Milan, Italy. dbattino@istituto-besta.it
Croci
Danilo
D
Rossini
Alessandro
A
Messina
Sara
S
Mamoli
Daniela
D
Perucca
Emilio
E
D000328:Adult; D000367:Age Factors; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002220:Carbamazepine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016022:Case-Control Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000097:blood* / Q000188:drug therapy; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008875:Middle Aged; D010634:Phenobarbital / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D012016:Reference Values; D012044:Regression Analysis; D012189:Retrospective Studies
D000927:Anticonvulsants; D002220:Carbamazepine; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010634:Phenobarbital