Pharmacodynamic studies

Although in many cases an enantiopure drug can be safer than the racemate, the advantages are clear. The final formulation of the drug product could be reduced inhalf, potential side effects could be minimized, and the resulting pharmokinetic and pharmacodynamic studies could clearly determine the efficacy of the active pharmaceutical ingredient (API) [21]. 

Osborn BL, Olsen HS, NardeUi B, Murray JH, Zhou JX, Garcia A, Moody G, Zaritskaya LS, Sung C (2002) Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-alpha fusion protein in cynomolgus monkeys. J Pharmacol Exp Ther 303 540-548 Ozes ON, Reiter Z, Klein S, Blatt LM, Taylor MW (1992) A comparison of interferon-Conl with natural recombinant interferons-alpha antiviral, antiproliferative, and natural kiUer-inducing activities. J Interferon Res 12 55-59... 

Clin Pharmacol Ther 1991 50 573-579. Ratain MJ, Rosner G, Allen SL et al. Population pharmacodynamic study of amonafide a Cancer and Leukemia Group B study J Clin Oncol 1995 13 741-747. 

Rojo F, Tabernero J, Albanell J, et al. Pharmacodynamic studies of gefitinib in tumor biopsy specimens from patients with advanced gastric carcinoma. J. Clin. Oncol. 2006 24 4309-4316. 

Pharmacodynamic studies deal more specifically with how the drug brings about its characteristic effects. Emphasis in such studies is often placed upon how a drug interacts with a cell/organ type, the effects and side effects it induces, and observed dose-response curves. 

Bioavailability and bioequivalence are also usually assessed in animals. Such studies are undertaken as part of pharmacokinetic and/or pharmacodynamic studies. Bioavailability relates to the proportion of a drug that actually reaches its site of action after administration. As most biopharmaceuticals are delivered parenterally (e.g. by injection), their bioavailability is virtually 100 per cent. On the other hand, administration of biopharmaceuticals by mouth would, in most instances, yield a bioavailability at or near 0 per cent. Bioavailability studies would be rendered more complex if, for example, a therapeutic peptide was being administered intranasally. 

A prerequisite to pharmacokinetic/pharmacodynamic studies is the availability of a sufficiently selective and sensitive assay. The assay must be capable of detecting and accurately quantifying the therapeutic protein in the presence of a complex soup of contaminant molecules characteristic of tissue extracts/body fluids. As described in Chapter 7, specific proteins are usually detected and quantified either via immunoassay or bioassay. Additional analytical approaches occasionally used include liquid chromatography (e.g. HPLC) or the use of radioactively labelled protein. 

Primary pharmacodynamic studies investigate the mode of action or effects of a substance in relation to its desired therapeutic target. 

Aymard, G., Berlin, L, de Brettes, B., and Diquet, B., Pharmacokinetic-pharmacodynamic study of apomorphine s effect on growth hormone secretion in healthy subjects, Fundam. Clin. Pharmacol., 17, 473-481, 2003. 

Tod, M., Minozzi, C., Beaucaire, G., Ponsonnet, D., Gougnard, J., and Petitjean, O., Isepamicin in intensive care unit patients with nosocomial pneumonia population pharmacokinetic-pharmacodynamic study, /. Antimicrob. Chemother., 44, 99-108,1999. 

If these conclusions are valid they have important implications for the design of tests to evaluate relative toxicity and also for structure/activity theories for example if the relationship between polarity and toxicity is strongly influenced by decay processes then it is important that these are given appropriate consideration in designing candidate compounds. The analysis presented above also gives a strong support for further pharmacodynamic studies of pesticide action... 

Greenhill, L., Swanson, J., Steinhoff K, Tullock S, Clausen S, Zhang Y (2002 b), A pharmacokinetic/pharmacodynamic study comparing a single morning dose of Adderall to twice daily dosing in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc (in press). Psychiatry. 

Pharmacokinetic and pharmacodynamic studies lead to a greater understanding of chemical interactions at the molecular level and may identify specific receptors for drug activity. With more specific knowledge of how a drug works, it may become easier to more accurately establish what effects are actually caused by a particular drug. Thus, studies in these two areas of pharmacology will always be necessary. 

This section deals with the question of whether there are quantitatively detectable and interpretable correlations between the dose of an administered drug, or the concentration of a drug and its metabolites measured in the blood or plasma (blood or plasma level), and the therapeutic action or side effects observed. Investigations relating to questions of this type are called PK PD (pharmacokinetic pharmacodynamic) studies. The PK PD analysis is a bidirectional approach pharmacokinetics represent what the body does with a drug, and pharmacodynamics describes what a drug does to the body. The PK PD analyses are key elements of early drug development, and PK PD trials are able to answer specific disease-related efficacy and safety questions. 

Pharmacotherapeutics deals with the use of drugs in the prevention and treatment of diseases and it utilizes or depends upon the information of drug obtained by pharmacodynamic studies. 

The second generation H -receptor antagonist cetirizine is a reacemate consisting of equal quantities of 2 enantiomers, levocetirizine [(R)-enantiomer] and dextrocetirizine [(S)-enantiomer]. In vitro and human pharmacodynamic studies have provided evidence that levocetirizine is the more active enantiomer, accounting for most or all clinical antihistaminic activity of racemic cetirizine this activity of levocetirizine is seen at half the dose of cetirizine. 

Galluppi, G.R., M.C. Rogge, L.K. Roskos, L.J. Lesko, M.D. Green, D.W. Feigal, Jr., and C.C. Peck, Integration of pharmacokinetic and pharmacodynamic studies in the discovery, development, and review of protein therapeutic agents a conference report. Clin Pharmacol Ther, 2001. 69(6) 387-99. 

Ziprasidone s pharmacokinetics permit rapid and predictable dose adjustment, with metabolites that are considered to be clinically inactive ( 134). The results of PET pharmacokinetic and pharmacodynamic studies indicate that a twice daily dosage regimen is appropriate. 

Adalimumab is a completely human IgGi approved for use in rheumatoid arthritis. Like the other anti-TNF- biologicals, adalimumab blocks the interaction of TNF- with TNF receptors on cell surfaces it does not bind TNF-3. Pharmacodynamic studies showed that administration of adalimumab reduced levels of C-reactive protein, erythrocyte sedimentation rate, serum IL-6, and matrix metalloproteinases MMP-1 and MMP-3. In vitro, adalimumab lyses cells expressing TNF- in the presence of complement. Patients may self-administer single doses of the antibody subcutaneously, every other week. Adalimumab has a serum half-life of 2 weeks, which is increased by 29-44% in patients who are also taking methotrexate. 

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