Journal of Pharmacokinetics and Biopharmaceutics

, Volume 21, Issue 4, pp 457–478

Comparison of four basic models of indirect pharmacodynamic responses

Authors

  • Natalie L. Dayneka
    • Department of Pharmaceutics, School of PharmacyState University of New York at Buffalo
    • Philadelphia College of Pharmacy and Science
  • Varun Garg
    • Department of Pharmaceutics, School of PharmacyState University of New York at Buffalo
  • William J. Jusko
    • Department of Pharmaceutics, School of PharmacyState University of New York at Buffalo
Article

DOI: 10.1007/BF01061691

Cite this article as:
Dayneka, N.L., Garg, V. & Jusko, W.J. Journal of Pharmacokinetics and Biopharmaceutics (1993) 21: 457. doi:10.1007/BF01061691

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 sigmoidE max model methylprednisolone

Glossary

C e

Drug concentration at the hypothetical effect site

C p

Plasma concentration of drug

C p(Tmax)

Plasma concentration of drug at the time of maximal response

D

Dose

EC 50

Drug concentration producing 50% of maximum stimulation at effect site

E max

Maximum effect attributed to drug

E o

Baseline effect prior to drug administration

IC 50

Drug concentration producing 50% of maximum inhibition at effect site

K el

First-order rate constant for drug elimination

K eo

First-order rate constant for drug loss from effect site

K in

Zero-order rate constant for production of drug response

K out

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

Copyright information

© Plenum Publishing Corporation 1993