Therapeutics, pharmacodynamic basis

The 2nd edition of Pharmacodynamic Basis of Herbal Medicine has separated facts from myths and has attempted to provide detailed molecular mechanisms on how herbal plants bring about their beneficial therapeutic effects. 

Ross, E.M., Pharmacodynamics mechanisms of drug action and the relationship between drug concentration and effect, in Goodman and Gilman s The Pharmacological Basis of Therapeutics, 9th ed., Hardman, J.G. and Limbird, L.E., Eds., McGraw-Hill, New York, 1996, chap. 2. 

Establish a dose-response pharmacodynamic profile by using initial doses projected to be therapeutic in humans. The dose required is predicted on the basis of blood levels found in animal screens. 

Shaw LM, Korecka M, De Nofrio D, Brayman KL. (2001) Pharmacokinetic, pharmacodynamic and outcome investigations as the basis for mycophenolic acid therapeutic drug monitoring in renal and heart transplant patients. Clin Biochem 34 17-22. 

Pharmacodynamic tolerance, probably on the basis of down-regulation of receptors, develops more rapidly to the effects of barbiturates on mood and sedation than to the anticonvulsant and lethal action. This results in a marked decrease in therapeutic index and the ratio of LD50 and ED50 can approach 1. Furthermore, barbiturates induce P450 enzymes and thus increase their own metabolism resulting in time dependent pharmacokinetic behavior. 

Pharmacodynamics data are of more relevance for CTAs than for MAAs, as there will be clinical pharmacology data for the latter. The nonclinical pharmacodynamics data form the basis for the assumption that a compound might be of therapeutic use and a clear understanding of the mechanism of action underlies and informs the entire development program. 

The mid and low doses for a carcinogenicity study are to provide information for assessing the relevance of the study findings to humans. The low dose should be equal to, or a multiple of, the maximum dose proposed for human testing. The rationale for the selection of the low and mid dose needs to be provided on the basis of pharmacokinetic linearity and saturation of metabolic pathways, human exposure and therapeutic dose, pharmacodynamic response in the test species, alteration in the normal physiology of the test species, mechanistic information and the potential for threshold effects, and the unpredictability of toxicity progression observed in other toxicology studies. 

Ross, E.M. (1990). Pharmacodynamics Mechanism of drug action and relationship between drug concentration and effect. In Pharmacological Basis of Therapeutics. A.G.Gilman, T.W.Rall, A.S.Nies, and P.Taylor, eds (New York Pergamon Press), pp. 33 48. 

How best to serve therapeutics for racemic mixtures of drugs in development or being considered for clinical development It seems a desirable objective to characterize the pharmacokinetics and pharmacodynamics of pure isomers of drug candidates and to select a pure isomer on the basis of these studies for further development. This tactic would prevent the various difficulties as summarized earlier in this chapter when attempts are made to characterize the disposition, efficacy, and toxicity of drug candidates. The sponsor of a drug candidate should have the opportunity to request an exception from such a policy, and a number of situations can be envisioned in which such a request should be viewed favorably. They are the following ... 

Benet, L.Z. and Shiner, L.B. 1985. Pharmacodynamics the dynamics of drug absorption, distribution and elimination. In The Pharmacological Basis of Therapeutics, 7th Ed., A. Goodman-Gilman, L.S. Goodman, T.W. Rail, and F. Murad (eds.). New York MacMillan Publishers. 

---