ISSN:
1573-8744
Keywords:
pharmacokinetic modeling
;
pharmacodynamic modeling
;
effect compartment model
;
receptor onset/offset rate
;
protein binding
;
tissue binding
;
neuromuscular blocking agents
;
onset time
;
potency
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract An extended pharmacokinetic/pharmacodynamic (PK/PD) model is presented, in which the effect of binding of the drug to plasma proteins and to tissue binding sites in a peripheral compartment, and nonspecific and receptor binding in the effect compartment are taken into account. It represents an extension of the classical Sheiner model, and the model proposed by Donati and Meistelman. The present model is characterized by the following parameters:ku e (exit rate constant of unbound drug from the effect compartment),Pu e (ratio of the unbound clearances to and from the effect compartment),fu e (fraction of drug in effect compartment that is not bound to nonspecific binding sites),K d (equilibrium dissociation constant of drug-receptor binding), andR wt (concentration of receptor binding sites in effect compartment). The rate of association and dissociation of the drug-receptor complex can be incorporated in the model. The influence of the pharmacokinetic parameters (V 1,V 2,fu,fu 2,CLu 10,CLu 20,CLu 12,CLu 21) and the PK/PD model parameters (ku e,Pu e,fu e,K d,R wt) on various dynamic parameters is analyzed. These include potency (single dose needed to produce 90% effect,ED 90), constant infusion dosing rate needed to maintain a constant effect of 90%, time to maximum effect (onset time), and duration to 90% recovery. The neuromuscular blocking agent vecuronium is used as an example. It is shown that both potency and time course of action are strongly dependent on the ratioV t/fu,CLu 10,ku e,Pu e (at equipotent doses the time course is not affected byPu e),fu e,K d, andR wt (only ifR wt is high), whereas they are less affected by the ratioV 2/fu 2,CLu 20,CLu 12, andCLu 21. In general, the model parameters affect theED 90 and the time course of action in the same direction, e.g., an increase ofV 1 results in an increase ofED 90 and an increase of onset time and duration. However, the unbound clearanceCLu 10, the intercompartmental unbound clearanceCLu 12 and the receptor affinityK d have an opposite effect onED 90 and the time course parameters, e.g., an increase ofCLu 10 results in an increase ofED 90 and a decrease of onset time and duration. This effect may be responsible for the inverse relationship between onset time and potency of neuromuscular blocking drugs observed in animal experiments and clinical studies. We demonstrate that PK/PD analysis using the traditional effect compartment model (Sheiner model) results in an apparent value ofk c), which is a function ofku e,fu e,K d,R wt, as well as the unbound drug concentration in the effect compartmentCu e. On the other hand, the model proposed by Donati and Meistelman gives correct values ofk c0 (equal to the productfu e·ku e), but the receptor affinityK d and the receptor densityR wt obtained by this method are apparent values, which depend onfu,fu e, andPu e.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF02353510
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