Dose-dependency of pharmacokinetic/pharmacodynamic parameters after intravenous bolus doses of cisatracurium

• Published in: British journal of anaesthesia : BJA Vol. 101; no. 6; pp. 788 - 797
• Main Authors: Chen, C., Yamaguchi, N., Varin, F.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.12.2008; Oxford University Press
• Subjects: Anesthesia; Anesthesia, General - methods; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Atracurium - administration & dosage; Atracurium - analogs & derivatives; Atracurium - blood; Atracurium - pharmacology; Biological and medical sciences; Chromatography, High Pressure Liquid - methods; cisatracurium; Cross-Over Studies; Dogs; dose-dependency; Dose-Response Relationship, Drug; early; Electric Stimulation - methods; Infusions, Intravenous; Male; Medical sciences; Neuromuscular Blockade; Neuromuscular Junction - drug effects; Neuromuscular Nondepolarizing Agents - administration & dosage; Neuromuscular Nondepolarizing Agents - blood; Neuromuscular Nondepolarizing Agents - pharmacology; pharmacodynamics; pharmacodynamics, cisatracurium; pharmacokinetics; pharmacokinetics, cisatracurium; pharmacokinetics, dose-dependency; pharmacokinetics, early; pharmacokinetics, cisatracurium; pharmacokinetics, dose-dependency; pharmacodynamics, cisatracurium; pharmacokinetics, early; Intravenous administration; pharmacodynamics; Anesthesia; Pharmacokinetics; dose-dependency; pharmacokinetics; cisatracurium; pharmacokinetics; early
• ISSN: 0007-0912; 1471-6771
• DOI: 10.1093/bja/aen308

Pharmacokinetic/pharmacodynamic (PK/PD) parameters of neuromuscular blocking agents (NMBAs) are generally assumed to be dose-independent. To our knowledge, there are very few clinical reports where the PK/PD parameters of a NMBA were derived separately for each dose group during a formal dose-ranging study. The primary objective of this study was to challenge a potential dose-dependency of cisatracurium PK/PD parameters by conducting a well-controlled experimental study. Eight dogs were anaesthetized with pentobarbital and mechanically ventilated. Two doses of cisatracurium (1.5×ED95 and 6×ED95) were administered in a randomized cross-over design after an appropriate washout period. Neuromuscular function was monitored using train-of-four (TOF) stimulation. Arterial blood was sampled continuously for the first minute after cisatracurium injection and at frequent intervals thereafter. Cisatracurium plasma concentrations were determined by high performance liquid chromatography analysis. PK/PD modelling of individual data sets was performed with NONMEM using a non-parametric approach and a descriptive sigmoid Emax model. Cisatracurium PKs were linear over the dose range studied. Using non-parametric PK/PD analysis, mean values for plasma–effect compartment equilibration delay (ke0) were 0.0600 vs 0.1278 min−1 (P<0.05) and sensitivity (EC50) were 323 vs 235 ng ml−1 (P<0.05) for the high and low doses, respectively. A dose-dependent effect on the PK/PD parameters of cisatracurium has important clinical implications as an accurate estimate of the EC50 is desirable. PK/PD parameters derived after intubating bolus doses of cisatracurium would be more reliable.