Pharmacokinetics preclinical studies

AstraZeneca is developing a series of selective non-peptidic 5 opioid receptor agonists for the treatment of neuropathic pain. The compounds (e.g. cpd., 1) are in preclinical studies. In vivo, they are effective analgesics with negligible tolerance and dependence. They have parenteral and oral activity with suitable pharmacokinetics and pharmacodynamics. 

Due to its high selectivity and potency at H3 receptors (/ )-a-methylhistamine (12) is nowadays used as the standard agonist in pharmacological assays related to this receptor. With regard to its pharmacodynamic properties, which were substantiated in preclinical studies [40], (R)-a-methylhistamine (12) meets all criteria of a potential drug substance. However, in contrast to its pharmacodynamic potential (ft)-a-methyl-histamine (12) suffers from its pharmacokinetic drawbacks which limit its use in both pharmacological and conceivable clinical studies. 

Link between formulations and dosage forms used in preclinical, clinical, pharmacokinetic/pharmacodynamic studies, and formulations planned for the NDA or BLA... 

Pharmacokinetic studies are often used to establish the extent of exposure to a biopharmaceutical in a preclinical study. This information not only validates dosing but also provides a means of extrapolating exposure across species. It... 

There must be considerable overlap here between the basic pharmacodynamic and pharmacological experimentation, which has shown why the intended product may be of therapeutic value and the mechanisms of that desired activity, and the range of investigations that it is necessary and worthwhile to apply in the types of preclinical studies usually labeled as toxicology, here including pharmacokinetics. 

Using the PPK approach in the development of a new drag has the advantage that the relevant pharmacokinetic parameters for a reasonably large population can be obtained from only a few blood samples per subject. The PPK approach is the method of choice in all situations when only sparse and unbalanced data can be obtained. This situation exists when the PK needs to be studied in elderly, critically ill and pediatric patients, but also very often in preclinical studies investigating the effects of the drug in animals. 

Several preclinical studies, originally designed to support the above clinical trials, have been carried out. From these it was determined that m-THPC is not metabolized in vivo and virtually all the drag is eliminated via the liver. Pharmacokinetic data derived from animal studies with m-THPC led to the prediction that this substance would show rapid clearance from plasma in humans. Surprisingly, however, this was only observed in the animal models (dog, rabbit, rat), not in the human populations. This dichotomy stands as a cogent reminder that caution must always be exercised in translating animal-model data into human-dosing decisions [225]. 

Allometric scaling may be used to answer a variety of questions relevant to the design of preclinical studies of intraperitoneal pharmacokinetics. Figure 30.3 shows the variation of PA, which is approximately equivalent to peritoneal clearance if Cpc Cpi, for urea and inulin in rats, rabbits, dogs, and humans (14). The slope of the urea line is 0.74 while the slope of the inulin line is 0.62. The average of these is 0.68, or approximately two-thirds as might be expected for peritoneal surface area. This would imply that the intrinsic membrane permeability, P, is similar among... 

Working, P.K. Cossum, W.A. Clinical and preclinical studies with recombinant human proteins effect of antibody production. In Pharmacokinetics and Pharmacodynamics Peptides, Peptoids and Proteins Garzone, P.D., Colburn, W.A., Mokotoff, M., Eds. Harvey Whitney Books New York, 1991 201-233, Ch. 13. 

The paradigm in drug development is sequentially divided into several phases starting with preclinical assessment. After selection of a drug candidate based on preclinical studies, clinical Phase 1 studies are initiated to characterize the safety, tolerability, biomarker, and pharmacokinetic profiles of the candidate, typically in healthy subjects. Phase 2 studies test the drug efficacy hypothesis in patients and explore dose range, and Phase 3 studies aim to demonstrate efficacy in the intended patient population in a statistically robust manner. 

Ette, E.I. Kelman, A.W. Howie, C.A. Whiting, B. Influence of interanimal variability on the estimation of population pharmacokinetic parameters in preclinical studies. Clin. Res. Reg. Affairs. 1994, 11, 121-139. 

A number of excellent review articles exist, including several that explain MR spectroscopy and detail the impact of MR spectroscopy in drug design and in preclinical studies, and others that provide overviews of human in vivo metabolism and pharmacokinetics measured by 19F MR in fluoropyrimidine compounds as well as in psychotropic compounds [1, 3-5, 7-10, 59, 60-63], In keeping with other facets of drug development, the number of 19F MR clinical investigations is much smaller than the number of animal model, specimen, cell line, or solution experiments. 

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