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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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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DOI: https://doi.org/10.1007/BF01061691