The Case for Preclinical Pharmacodynamics
Pharmacodynamics concerns the relationship between drug concentration and intensity of pharmacologic effect. It includes the exploration and assessment of relevant variables such as pharmacologically active metabolites, pharmacodynamic drug interactions and effects of genetics and underlying diseases. Available (though limited) information indicates that drug concentrations required to produce a defined intensity of pharmacologic action are quite similar in man and animals. For such interspecies comparisons, consideration must be given to possible differences in drug-protein binding, active metabolites, kinetics of equilibration of drug between plasma and biophase, and definition of the pharmacologic endpoint. It is now evident that many unanticipated, pharmacodynamically relevant clinical risk factors, including some that have caused a substantial number of deaths, could have been recognized in preclinical pharmacodynamic studies. Examples based on studies in the author’s laboratory include potentiation of barbiturates in renal failure, increased response to benzodiazepines in severe liver disease, increased neurotoxicity of theophylline in renal failure, increased potency of general anesthetics in hemorrhagic hypovolemia, and the steep responder syndrome in warfarin therapy. Preclinical pharmacodynamics provides a means for identifying, in advance of clinical use, potential risk factors and conditions under which drugs may be subject to profound changes in their concentration-effect relationships.
KeywordsUnbind Drug Pharmacodynamic Model Drug Development Process Pearl Harbor Interspecies Comparison
Unable to display preview. Download preview PDF.
- Aitken, M. L., and T. R. Martin (1985). Life-threatening complications of theophylline toxicity are not predicted by serum theophylline levels. Amer. Rev. Resp. Dis., 131 A68.Google Scholar
- Bakti, G., H. U. Fisch, G. Karlaganis, C. Minder, and J. Bircher (1987). Mechanism of the excessive sedative response of cirrhotics to benzodiazepines: model experiments with triazolam. Hepatology 7, 629–638.Google Scholar
- Gianni, L., L. Vigano, A. Surbone, D. Ballinari, P. Casali, C. Tarella, and J. M. Collins (1990). Pharmacology and clinical toxicity of 4’-iodo-4’- deoxydoxorubicin: An example of successful application of pharmacokinetics to dose escalation in phase I trials. J. Natl. Cancer Inst. 82, 469–477.Google Scholar
- Hisaoka, M., and G. Levy (1985). Kinetics of drug action in disease states. XIII. Effect of dialyzable component(s) of uremic blood on phenobarbital concentrations in rats at onset of loss of righting reflex. J. Pharmacol. Exp. Ther., 234 180–183.Google Scholar
- Klockowski, P., and G. Levy (1988). Kinetics of drug action in disease states. XXIII. Effect of acute hypovolemia on the pharmacodynamics of phenobarbital in rats. J. Pharm. Sci. 77,365–366.Google Scholar
- Levy, G. (1985). Variability in animal and human pharmacodynamic studies. In M. Rowland, L. B. Sheiner, and J.-L. Steimer (Eds.), Variability in Drug Therapy: Description, Estimation, and Control Raven Press, New York, pp. 125–138.Google Scholar
- Ramzan, I. M., and G. Levy (1987). Kinetics of drug action. XV]:II. Effect of experimental renal failure on the pharmacodynamics of theophylline-induced seizures in rats. J. Pharmacol. Exp. Ther., 240 584–588.Google Scholar
- Routledge, P. A., P. H. Chapman, D. M. Davies, and M. D. Rawlins (1979). Pharmacokinetics and pharmacodynamics of warfarin at steady state. Br. J. Clin. Pharmacol. 8, 243–247.Google Scholar
- Yacobi, A., and G. Levy (1977). Comparative pharmacokinetics of coumarin anticoagulants XXVIII: predictive identification of rats with relatively steep serum warfarin concentration-anticoagulant response characteristics. J. Pharm. Sci. 66, 145.Google Scholar
- Yacobi, A., L. B. Wingard, Jr., and G. Levy (1974). Comparative pharmacokinetics of coumarin anticoagulants X: relationship between distribution, elimination, and anticoagulant action of warfarin. J. Pharm. Sci. 63, 868–872.Google Scholar