Peripheral link model as an alternative for pharmacokinetic-pharmacodynamic modeling of drugs having a very short elimination half-life

Attempts to obtain estimates of pharmacokinetic-pharmacodynamic (PK-PD) parameters for mivacurium with traditional central link models were unsuccessful in many patients. We hypothesized that a link model with the peripheral compartment would be more appropriate for mivacurium in view of its extreme...

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Bibliographic Details
Published inJournal of pharmacokinetics and pharmacodynamics Vol. 28; no. 1; pp. 7 - 25
Main Authors Laurin, J, Donati, F, Nekka, F, Varin, F
Format Journal Article
LanguageEnglish
Published United States Springer Nature B.V 01.02.2001
Subjects
Adolescent
Adult
Anesthesia
Atracurium - pharmacokinetics
Atracurium - pharmacology
Body Fluid Compartments
Computer Simulation
Dose-Response Relationship, Drug
Half-Life
Humans
Isoquinolines - pharmacokinetics
Isoquinolines - pharmacology
Mathematical Computing
Models, Biological
Neuromuscular Nondepolarizing Agents - pharmacokinetics
Neuromuscular Nondepolarizing Agents - pharmacology
Studies
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Summary:Attempts to obtain estimates of pharmacokinetic-pharmacodynamic (PK-PD) parameters for mivacurium with traditional central link models were unsuccessful in many patients. We hypothesized that a link model with the peripheral compartment would be more appropriate for mivacurium in view of its extremely rapid plasma clearance and its potential elimination by tissue pseudocholinesterases. For validation purposes, the peripheral link model was applied to other neuromuscular blocking agents (NMBA), i.e., atracurium and doxacurium which have respectively an intermediate and a long elimination half-life. Assuming peripheral elimination in PK-PD modeling was investigated but found to have no impact on the estimation of PK-PD parameters. Our results indicate that, for drugs having intermediate and long elimination half-lives, EC50 values are similar with either the central or peripheral link model. For mivacurium, a peripheral link model enables PK-PD modeling in all subjects, with more precision in the PK-PD parameter estimates and a better fitting of the effect data when compared to the central link model. For these reasons, a peripheral link model should be preferred for mivacurium.
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ISSN:1567-567X
1573-8744
DOI:10.1023/A:1011513618081