Pharmacodynamics 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. 

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. 

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. 

After intravenous administration of I—1.3 mg/rrf of bortezomib in patients without renal or hepatic impairment, there is a rapid distribution phase (<10 minutes), followed by a longer elimination phase of 5—15 hours. Plasma protein binding averaged 83%. The mean terminal elimination in preclinical studies was 5.4 hours, with an average clearance of 66 Uh. Peak pharmacodynamic activity (proteasome inhibition) occurred at I hour with a mean of 61% inhibition and a tyi of 24 hours. Inhibition of the 20S subunit was 10—30% at 96 hours. Proteasome inhibition is highly concentration dependent. 

Preclinical studies provide a plausible pharmacodynamic rationale for the addition of... 

The applicant should provide justification for using the racemate. Where the interconversion of the enantiomers in vivo is more rapid than the distribution and elimination rates, then use of the racemate is justified. In cases where there is no such interconversion or it is slow, then differential pharmacological effects and fate of the enantiomers may be apparent. Use of the racemate may also be justified if any toxicity is associated with the pharmacological action and the therapeutic index is the same for both isomers. For preclinical assessment, pharmacodynamic, pharmacokinetic (using enantiospecific analytical methods) and appropriate toxicological studies of the individual enantiomers and the racemate will be needed. Clinical studies on human pharmacodynamics and tolerance, human pharmacokinetics and pharma-cotherapeutics will be required for the racemate and for the enantiomers as appropriate. 

Phase I studies evaluate the pharmacokinetics and safety of the drug in a small number (tens) of healthy volunteers. Phase I studies are sometimes conducted in a small patient population (Proof of Concept studies) with a specific objective such as the validation of the relevance of preclinical models in man. The purpose of these studies may be the rapid elimination of potential failures from the pipeline, definition of biological markers for efficacy or toxicity, or demonstration of early evidence of efficacy. These studies have a potential go/no-go decision criteria such as safety, tolerability, bioavailability/PK, pharmacodynamics, and efficacy. Dosage forms used in Phase I or Proof of Concept studies must be developed with the objectives of the clinical study in mind. 

A comprehensive knowledge of all the preclin-ical information about a compound is an essential requirement for the safe conduct of the first study in man. Toxicology, metabolism, pharmacokinetics and pharmacodynamics are all important despite their limited predictive power for man. As explained above, the study design must take the findings into account. 

Before a drug may be tested on humans, it must first be tested on animals. Tests on humans are called clinical trials, and animal trials are often referred to as preclinical trials. Preclinical trials differ from the animal tests mentioned earlier in this chapter. The previously discussed animal tests help the drug discovery team determine and optimize the pharmacodynamic and pharmacokinetic behavior of a hit or lead. Preclinical trials, in contrast, are standardized, industrywide tests. The preclinical tests have technical names such as Segment II Reproductive Study in Rabbits or 6-Month Toxicity Study in Rats. The specific names suggest the exact nature of each study. Each trial seeks to answer predefined safety questions concerning a drug candidate. Preclinical trials do not address the therapeutic effectiveness of the drug candidate in any way. Preclinical trials examine exclusively safety issues. 

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

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