Comparison of four basic models of indirect pharmacodynamic responses

  • Natalie L. Dayneka
  • Varun Garg
  • William J. Jusko
Article

Abstract

Four basic models for characterizing indirect pharmacodynamic responses after drug administration have been developed and compared. The models are based on drug effects (inhibition or stimulation) on the factors controlling either the input or the dissipation of drug response. Pharmacokinetic parameters of methylprednisolone were used to generate plasma concentration and response-time profiles using computer simulations. It was found that the responses produced showed a slow onset and a slow return to baseline. The time of maximal response was dependent on the model and dose. In each case, hysteresis plots showed that drug concentrations preceded the response. When the responses were fitted with pharmacodynamic models based on distribution to a hypothetical effect compartment, the resulting parameters were dose-dependent and inferred biological implausibility. Indirect response models must be treated as distinct from conventional pharmacodynamic models which assume direct action of drugs. The assumptions, equations, and data patterns for the four basic indirect response models provide a starting point for evaluation of pharmacologie effects where the site of action precedes or follows the measured response variable.

Key words

pharmacodynamics indirect response effect compartment model sigmoidEmax model methylprednisolone 

Glossary

Ce

Drug concentration at the hypothetical effect site

Cp

Plasma concentration of drug

Cp(Tmax)

Plasma concentration of drug at the time of maximal response

D

Dose

EC50

Drug concentration producing 50% of maximum stimulation at effect site

Emax

Maximum effect attributed to drug

Eo

Baseline effect prior to drug administration

IC50

Drug concentration producing 50% of maximum inhibition at effect site

Kel

First-order rate constant for drug elimination

Keo

First-order rate constant for drug loss from effect site

Kin

Zero-order rate constant for production of drug response

Kout

First-order rate constant for loss of drug response

n

Sigmoidicity factor of the sigmoid Emax equation

R

Response variable

Rmax

Maximal (or minimal) response

Ro

Initial response (time zero) prior to drug administration

t

time after drug administration

T

Infusion time

Tmax

Time to reach maximum effect following drug administration

V

Volume of distribution

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Copyright information

© Plenum Publishing Corporation 1993

Authors and Affiliations

  • Natalie L. Dayneka
    • 1
    • 2
  • Varun Garg
    • 1
  • William J. Jusko
    • 1
  1. 1.Department of Pharmaceutics, School of PharmacyState University of New York at BuffaloBuffalo
  2. 2.Philadelphia College of Pharmacy and SciencePhiladelphia
  3. 3.Pharmacy DepartmentChildrens Hospital of Eastern OntarioOttawaCanada
  4. 4.Clinical Research & DevelopmentWyeth-Ayerst ResearchPhiladelphia

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