Abstract
An important goal in therapeutics is the quantitative prediction of drug effects. Although several comprehensive pharmacodynamic models have been proposed, relatively few of these have attempted to assess objectively the application of the models to predict pharmacologic responses. A variable-direction hysteresis minimization approach was proposed recently that allowed the pharmacodynamics of drugs to be modeled using information about drug input. The application and validation of this approach are demonstrated using the pharmacodynamic effect of alfentanil, a short-acting narcotic analgesic agent, in New Zealand White rabbits. A parameter is proposed to assess the ability of the pharmacodynamic model to predict responses.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
L. B. Sheiner, D. R. Stanski, S. Vozeh, R. D. Miller, and J. Ham. Simultaneous modeling of pharmacokinetics and pharmacodynamics: Application to d-tubocurarine. Clin. Pharmacol. Ther. 25:358–371 (1979).
E. Fuseau and L. B. Sheiner. Simultaneous modeling of pharmacokinetics and pharmacodynamics with a nonparametric pharmacodynamic model. Clin. Pharmacol. Ther. 35:733–741 (1984).
P. Veng-Pedersen, J. W. Mandema, and M. Danhof. A system approach to pharmacodynamics. III. an algorithm and computer program COLAPS, for pharmacodynamic modelling. J. Pharm. Sci. 80:488–495 (1991).
P. Veng-Pedersen and N. B. Modi. Pharmacodynamic system analysis of the biophase level predictor and transduction function. J. Pharm. Sci. 81:925–934 (1992).
B. Kay and B. Pleuvry. Human volunteer studies of alfentanyl (R39209), a new short-acting narcotic analgesic. Anaesthesia 35:952–956 (1980).
J. O. Arndt, B. Bednarski, and C. Parasher. Alfentanil's analgesic, respiratory, and cardiovascular actions in relation to dose and plasma concentration in unanesthetized dogs. Anesthesiology 64:345–352 (1986).
H. Askitopoulou, J. G. Whitwam, S. Sapsed, and M. K. Chakrabarti. Dissociation between the effects of fentanyl and alfentanil on spontaneous and reflexly evoked cardiovascular responses in the dog. Br. J. Anaesth. 55:155–161 (1983).
J. H. Brown, B. J. Pleuvry, and B. Kay. Respiratory effects of a new opiate analgesic R 39209, in the rabbit: Comparison with fentanyl. Br. J. Anaesth. 52:1101–1106 (1980).
J. D'aubioul, W. Van Gerven, A. Van de Water, R. Xhonneux, and R. S. Reneman. Cardiovascular and some respiratory effects of high doses of alfentanil in dogs. Eur. J. Pharmacol. 100:79–84 (1984).
B. Kay and D. K. Stephenson. Alfentanil (R39209): Initial experience with a new narcotic analgesic. Anaesthesia 35:1197–1201 (1980).
M. Atef, S. A. H. Youssef, M. A. Shalaby, M. G. A. El-Sayed, and W. A. Amin. Some cardiovascular and respiratory effects of alfentanil in animals. Dtsch. tierärztl. Wschr. 94:333–336 (1987).
C. Zhang, J. Y. Su, and D. Calkins. Effects of alfentanil on isolated cardiac tissues in the rabbit. Anesth. Analg. 71:268–274 (1990).
P. Veng-Pedersen and W. R. Gillespie. A system approach to pharmacodynamics. I. Theoretical framework. J. Pharm. Sci. 77:39–47 (1988).
P. Veng-Pedersen. Linear and nonlinear system approaches in pharmacokinetics: How much do they have to offer? II. The response mapping operator (RMO) approach. J. Pharmacokin. Biopharm. 16:543–571 (1988).
D. Verotta and L. B. Sheiner. Semiparametric analysis of nonsteady-state pharmacodynamic data. J. Pharmacokin. Biopharm. 19:691–712 (1991).
P. Veng-Pedersen. Reparameterization to implementing kinetic constraints in pharmacokinetics. J. Pharm. Sci. 80:978–985 (1991).
R. A. Herman and P. Veng-Pedersen. A note regarding curve fitting with a sum of exponentials. Biopharm. Drug Disp. 9:579–586 (1988).
P. Veng-Pedersen and N. B. Modi. An algorithm for constrained deconvolution based on reparameterization. J. Pharm. Sci. 81:175–180 (1991).
C. J. Hull, H. B. H. Van Beem, K. McLeod, A. Sibbald, and M. J. Watson. A pharmacodynamic model for pancuronium. Br. J. Anaesth. 50:1113–1123 (1978).
D. V. Lindley. Regression linear and the linear functional relationship. J. Roy. Stat. Soc. Suppl. 9:219–244 (1949).
P. Veng-Pedersen. Curve fitting and modelling in pharmacokinetics and some practical experiences with NONLIN and a new program FUNFIT. J. Pharmacokin. Biopharm. 5:513–531 (1977).
P. Veng-Pedersen, J. W. Mandema, and M. Danhof. Biophase equilibration times. J. Pharm. Sci. 80:881–886 (1991).
L. B. Sheiner. Commentary to pharmacokinetic/pharmacodynamic modeling: What it is! J. Pharmacokin. Biopharm. 15:533–555 (1987).
A. Peper, C. A. Grimbergen, J. W. Kraal, and J. H. Engelbart. An approach to the modeling of the tolerance mechanism in the drug effect. I: The drug effect as a disturbance of regulations. J. Theor. Biol. 127:413–426 (1987).
A. Peper, C. A. Grimbergen, J. W. Kraal, and J. H. Engelbart. An approach to the modeling of the tolerance mechanism in the drug effect. II. On the implication of compensatory regulation. J. Theor. Biol. 132:29–41 (1988).
P. Veng-Pedersen and N. B. Modi. A system approach to pharmacodynamics. Input-effect control system analysis of central nervous effect of alfentranil. J. Pharm. Sci. 82:266–272 (1993).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Modi, N.B., Veng-Pedersen, P. Validation of a Variable Direction Hysteresis Minimization Pharmacodynamic Approach: Cardiovascular Effects of Alfentanil. Pharm Res 11, 128–135 (1994). https://doi.org/10.1023/A:1018966232183
Issue Date:
DOI: https://doi.org/10.1023/A:1018966232183