Comparison of four basic models of indirect pharmacodynamic responses (original) (raw)

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.

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Abbreviations

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

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Author notes

1. Natalie L. Dayneka
   Present address: Pharmacy Department, Childrens Hospital of Eastern Ontario, Ottawa, Canada
2. Varun Garg
   Present address: Clinical Research & Development, Wyeth-Ayerst Research, P.O. Box 8299, 19101, Philadelphia, Pennsylvania

Authors and Affiliations

1. Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, 14260, Buffalo, New York
   Natalie L. Dayneka, Varun Garg & William J. Jusko
2. Philadelphia College of Pharmacy and Science, 600 South Forty-Third Street, 19104-4495, Philadelphia, Pennsylvania
   Natalie L. Dayneka

Authors

1. Natalie L. Dayneka
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2. Varun Garg
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3. William J. Jusko
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Additional information

Supported in part by Grant No. 24211 from the National Institutes of General Medical Sciences, National Institutes of Health.

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Dayneka, N.L., Garg, V. & Jusko, W.J. Comparison of four basic models of indirect pharmacodynamic responses.Journal of Pharmacokinetics and Biopharmaceutics 21, 457–478 (1993). https://doi.org/10.1007/BF01061691

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• Received: 22 March 1993
• Revised: 15 June 1993
• Published: 15 June 1993
• Issue Date: August 1993
• DOI: https://doi.org/10.1007/BF01061691

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