Enzyme-inducing anticonvulsants increase plasma clearance of dexmedetomidine: a pharmacokinetic and pharmacodynamic study.
BACKGROUND
Dexmedetomidine is useful during mapping of epileptic foci as it facilitates electrocorticography unlike most other anesthetic agents. Patients with seizure disorders taking enzyme-inducing anticonvulsants appear to be resistant to its sedative effects. The objective of the study was to compare the pharmacokinetic and pharmacodynamic profile of dexmedetomidine in healthy volunteers with volunteers with seizure disorders receiving enzyme-inducing anticonvulsant medications.


METHODS
Dexmedetomidine was administered using a step-wise, computer-controlled infusion to healthy volunteers (n = 8) and volunteers with seizure disorders (n = 8) taking phenytoin or carbamazapine. Sedation and dexmedetomidine plasma levels were assessed at baseline, during the infusion steps, and after discontinuation of the infusion. Sedation was assessed by using the Observer's Assessment of Alertness/Sedation Scale, Ramsay Sedation Scale, and Visual Analog Scale and processed electroencephalography (entropy) monitoring. Pharmacokinetic analysis was performed on both groups, and differences between groups were determined using the standard two-stage approach.


RESULTS
A two-compartment model was fit to dexmedetomidine concentration-time data. Dexmedetomidine plasma clearance was 43% higher in the seizure group compared with the control group (42.7 vs. 29.9 l/h; P = 0.007). In contrast, distributional clearance and the volume of distribution of the central and peripheral compartments were similar between the groups. No difference in sedation was detected between the two groups during a controlled range of target plasma concentrations.


CONCLUSIONS
This study demonstrates that subjects with seizure disorders taking enzyme-inducing anticonvulsant medications have an increased plasma clearance of dexmedetomidine as compared with healthy control subjects.
From the Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada (A.M.F.); Drug Metabolism and Pharmacokinetics, Genentech Inc., San Francisco, California (H.W.); Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada (K.W.R.); and Department of Neurology (T.S., P.A.G.), Department of Anesthesia and Perioperative Care (S.V., P.O.T.), University of California San Francisco, San Francisco, California.
Alana M
AM
Flexman
Harvey
H
Wong
K Wayne
KW
Riggs
Tina
T
Shih
Paul A
PA
Garcia
Susana
S
Vacas
Pekka O
PO
Talke
D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood*; D020927:Dexmedetomidine / Q000008:administration & dosage / Q000097:blood*; D004347:Drug Interactions / Q000502:physiology; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D055815:Young Adult
D000927:Anticonvulsants; D020927:Dexmedetomidine