Pharmacokinetic-pharmacodynamic modeling of the influence of chronic phenytoin therapy on the rocuronium bromide response in patients undergoing brain surgery.
BACKGROUND
Antiepileptic drugs decrease the intensity of the effect of neuromuscular blocking agents. The objective of this study was to evaluate the influence of chronic phenytoin therapy (CPT) on the pharmacokinetics (PK) and pharmacodynamics (PD) of rocuronium.


METHODS
A total of 21 patients undergoing intracranial surgery were enrolled in the study. Ten of these were under CPT. Rocuronium was administered intravenously. Arterial blood samples were drawn, and the T1% (percentage change from the response to the supramaximal stimulus) derived from electromyogram was continuously recorded. NONMEM: software was used to construct, evaluate and validate the PKPD models.


RESULTS
The PKPD of rocuronium was described using a three-compartment PK model and effect compartment model. The CPT therapy was found to increase the total plasma clearance from 0.26 to 0.75 L min(-1). The PD model parameter estimates were k(e0)= 0.073 min(-1), IC(50) (the steady-state plasma concentration eliciting half of the maximum response) = 836 ng mL(-1) and gamma = 3.13.


CONCLUSIONS
Chronic phenytoin therapy increases the clearance of rocuronium from 0.26 to 0.75 L min(-1) but has no effect on the k(e0), IC(50) or gamma parameters.
Anesthesiology Department, Hospital Clinic, University of Barcelona, Barcelona, Spain.
Juan
J
Fernández-Candil
Pedro L
PL
Gambús
Iñaki F
IF
Trocóniz
Ricard
R
Valero
Enrique
E
Carrero
Lorea
L
Bueno
Neus
N
Fábregas
D000328:Adult; D000368:Aged; D000732:Androstanols / Q000493:pharmacokinetics / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology*; D004347:Drug Interactions; D004576:Electromyography; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009467:Neuromuscular Depolarizing Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019635:Neurosurgical Procedures; D010672:Phenytoin / Q000494:pharmacology*; D000077123:Rocuronium; D012984:Software; D055815:Young Adult
D000732:Androstanols; D000927:Anticonvulsants; D009467:Neuromuscular Depolarizing Agents; D010672:Phenytoin; D000077123:Rocuronium