Effect of age and comedication on levetiracetam pharmacokinetics and tolerability.
OBJECTIVE
To compare pharmacokinetics and tolerability of levetiracetam (LEV) in older versus younger adults.


METHODS
As part of the Columbia Antiepileptic Drug Database, we retrospectively studied the pharmacokinetics and tolerability of LEV in patients who had been seen as an outpatient at our center during a 4-year period. We compared apparent clearance (CL) of LEV in the youngest (16-31 years; n=151) and oldest (55-88 years; n=157) quartile of 629 adult outpatients who had taken LEV. We also analyzed the frequency of adverse effects leading to dose change or discontinuation ("intolerability") and specific adverse effects in the younger versus older adults. One-year retention was determined for younger and older adults newly started on LEV at our center.


RESULTS
Mean LEV CL differed significantly between older (46.5 ml/h/kg) and younger adults (78.3 ml/h/kg). On average, older patients had a 40% lower LEV CL than younger patients. Comedication with an enzyme-inducing antiepileptic drug (EIAED; mostly carbamazepine) was associated with a 24% higher clearance of LEV compared to those who were not on EIAEDs. This difference was 37% in a subgroup of patients whose LEV CL was compared while they were on and off EIAEDs. Stepwise linear regression identified younger age and comedication with an EIAED as significant predictors of increased LEV CL. A total of 34.3% of the 629 patients (31.7% of younger vs. 40.7% of older patients; p=0.16) reported intolerability to LEV on at least one occasion. This difference in tolerability reached significance in the group of patients newly started on LEV (26.3% vs. 41.0%; p=0.017). Drowsiness and psychiatric/behavioral side effects were the most common adverse effects associated with LEV use in both age groups. One-year retention was 72% in the older group vs. 54% in the younger group (not significant).


CONCLUSIONS
Older adults have lower CL than younger adults and require a mean 40% lower dose of LEV to achieve the same serum level. Comedication with an EIAED increases LEV CL by 24-37%. Younger adults tolerate LEV better than older adults, but 1-year retention was (nonsignificantly) higher in the older group.
Hirsch
Lawrence J
LJ
Comprehensive Epilepsy Center, Department of Neurology, Neurological Institute, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. ljh3@columbia.edu
Arif
Hiba
H
Buchsbaum
Richard
R
Weintraub
David
D
Lee
Jeansun
J
Chang
Jennifer T
JT
Resor
Stanley R
SR
Bazil
Carl W
CW
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000553:Ambulatory Care; D000927:Anticonvulsants / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004790:Enzyme Induction / Q000187:drug effects; D004827:Epilepsy / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D010889:Piracetam / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012189:Retrospective Studies
D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam