Jacqueline A Hannam (1, 2), Iñaki F Trocóniz (1), Xavier Borrat (3), Pedro L Gambús (3)
(1) Pharmacometrics and Systems Pharmacology, School of Pharmacy, Universidad de Navarra, Pamplona, Spain, (2) Department of Anaesthesiology, School of Medicine, University of Auckland, Auckland, New Zealand, (3) Systems Pharmacology Effect Control and Modeling Research Group, Department of Anesthesia, Hospital CLINIC de Barcelona, Barcelona, Spain.
Objectives: Propofol and remifentanil are commonly combined for sedation and may act synergistically on the respiratory system. Most models describing respiratory effects for anesthetic drugs are developed in controlled study conditions or health volunteers. We aimed to develop a model for propofol-remifentanil effects on respiratory depression in patients undergoing noxious procedures, in a clinical setting.
Methods: Data were available for 136 patients undergoing endoscopy with sedation using propofol with remifentanil. Participants were randomized to receive a fixed, targeted controlled infusion (TCI) of propofol 2.0 µg/ml, propofol 3.0 µg/ml, remifentanil 1.0 ng/ml or remifentanil 2.0 ng/ml. TCI targets of the second drug (remifentanil or propofol) were determined for each participant using the Dixon up-down method.1 Predicted plasma concentrations were related to measured transcutaneous arterial pressure of carbon dioxide (PaCO2) using an indirect model with rebound mechanism.2 Data were analyzed using NONMEM 7.2. Covariate relationships were investigated for age, noxious stimuli (endoscopy tube insertion) and A118G genotype for the µ-opioid receptor (OPRM1).
Results: Participants had a median (range) age of 64.0 (25.0-88.0) years, weight of 70.0 (35.0-98.0) kg and height of 164.0 (147.0-190.0) cm. Seven percent were recessive homozygous for OPRM1 polymorphism. Remifentanil inhibited arterial pressure of carbon dioxide (PaCO2) removal with an IC50 of 1.13 ng/ml and ke0 of 0.28 min-1. Propofol affected system modulation with an IC50 of 4.97 µg/ml (no effect-site compartment). Propofol IC50 and remifentanil ke0 were reduced with increasing age. Noxious stimuli and genotype were not significant covariates. Iso-effect concentration pairs at steady state conditions, identified using simulation, suggested synergistic drug effects.
Conclusions: An indirect effect model with rebound mechanism can describe remifentanil and propofol induced changes in PaCO2 in patients undergoing noxious procedures. The model may be useful for identifying optimal dosing schedules for these drugs in combination that provide adequate sedation but avoid respiratory depression.
References:
[1] Dixon WJ: Staircase bioassay: the up-and-down method. Neurosci Biobehav Rev 1991; 15: 47-50
[2]. Dayneka NL, Garg V, Jusko WJ: Comparison of four basic models of indirect pharmacodynamic responses. J Pharmacokinet Biopharm 1993; 21: 457-78
Reference: PAGE 24 (2015) Abstr 3435 [www.page-meeting.org/?abstract=3435]
Poster: Drug/Disease modeling - CNS