Pharmacokinetics compound choice

Difficulty in supply and synthesis In propriate formulation Insufficient patent and licensing situation Excessive early toxicity Ineffective route or schedule of administration Long-term unpredictable toxicities Delays in execution of clinical trials Inappropriate compound choice Unexpected pharmacokinetics or metabolism... 

Toxicology studies must be performed in at least two animal species. If the toxicity profile of the compound is acceptable, then it joins the hit or lead list of compounds to proceed. The metabolism of the compound must be understood and pharmacokinetic studies must be performed in small and large animals. Efficacy studies must be performed in relevant animal models, especially in chimpanzees when more than one candidate is identified and a choice has to be made before proceeding to studies in humans. The ultimate preclinical steps include various studies testing drug combinations in vitro and in vivo, selection of resistant viruses, viral fitness, pyrophosphorolysis, and others. 

The initial choice of the rat as the primary species for pharmacokinetic studies arose because of their use in pharmacology and toxicology studies. However, there is now such a large database of information about the relative pharmacokinetics of the same compounds in rats and man that, as described below, useful predictions to man can be made. 

The quinoline antibiotics are relatively late arrivals on the antibiotic scene. The parent compound of this class of drugs is nalidixic acid. The downside of this molecule is the rapid development of resistance by pathogenic bacteria. A major step forward was the introduction of a single fluorine atom at a key position, to yield new molecules such as ciprofloxacin, ofloxacin, levofloxacin, andmoxifloxacin. Of these, levofloxacin and moxifloxacin have the best combinations of spectrum of action, potency, and pharmacokinetic properties. In time, they are likely to largely replace the current quinoline antibiotic of choice, ciprofloxacin. Since these molecules work by a different mechanism than do the p-lactams, organisms that become resistant to the latter are generally susceptible to the former. 

Pharmacokinetics may also form the basis of a decision on the choice of compound from a series for development. It is not uncommon for a company to take three or four compounds of a series as far as the first study in man and to choose for development the compound that is most attractive from the pharmacokinetic point of view. Similarly, the development of achiral compounds rather than racemic mixtures is generally preferred and it may be necessary to establish whether stereoselective metabolism occurs in man and, if so, which enantiomer has the more desirable profile. 

The acidic NSAIDs include the salicylates and an increasing number of other compounds. The latter agents, as a group, share many common properties they may have toxicities, are highly protein bound and have the potential for interacting with other protein-bound drugs. The choice of a particular agent often depends on the reaction of the patient. Table 36.3 illustrates pharmacokinetic properties of selected NSAIDs. 

In addition to the principal studies, supporting studies are used in evaluating chemical toxicity. These studies provide supportive, rather than definitive, information and can include data from a variety of sources. For example, studies of different durations or in different species may confirm the choice of the critical response. Metabolic and other pharmacokinetic studies can provide insights into the mechanism of action of a chemical. By comparing the metabolism of the chemical in the laboratory animal and in humans, EPA might be able to estimate equitoxic doses. In vitro studies can provide insights into the chemical s potential for biological activity. The known toxicity of a structurally related compound and the use of structure-activity relationships can also provide clues to the chemical s possible toxicity. 

Most peptides and proteins are water-soluble, and therefore D-PBS or saline can be used as a vehicle. Often, however, limited information is available about the solubility properties of novel small molecules, and the choice of a non-toxic vehicle is more difficult. For example, 200 pi of a 5% ethanol solution is equivalent to one beer in humans and may affect behavior. A solution of 20% cyclodextrin has no known side effects in vivo, but in rare cases, some compounds are trapped in the solution and therefore mice have no exposure to the compound. Some vehicles used for in vitro studies can be toxic in live mice. Some vehicles such as methylcellulose have no side effect when given p.o., but are toxic if administered i.v. Access to information about the pharmacokinetics properties of a test compound can help in the choice of a vehicle. 

Megestrol acetate (A) is an oral contraceptive. What pharmacokinetic parameters should be determined for other potential oral contraceptives in order to compare their actions with compound A Give reasons for your choice. 

The choice of the concentration of the drug to be tested should consider therapeutic levels that could be attained with clinically employed doses. In the case of a compound under pre-clinical evaluation for a potential antitumor activity, a concentration limit of 100 pg/ml is recommended. Pharmacokinetic data are available for various anti-neoplastic clinically used drugs, with information about their maximum plasma concentration, concentration versus time, and pharmaceutical half-life in plasma. When these data are not available, an approximation of plasma levels could be obtained by calculating the theoretical concentration obtained when the administered dose is uniformly distributed throughout the body fluid. 

LC-MS/MS is the current method of choice for the analysis of small molecules in biological fluids (i.e., perfusate plasma, urine, bile) from organ-perfusion studies. The speed, high specificity, and sensitivity of this analysis format are widely applicable to compounds with diverse structure. Simultaneous dosing of a number of compounds followed by analysis of multiple analytes with LC-MS/MS (A-in-1) has been developed and shown to be an effective approach to improve the throughput of pharmacokinetics (PK) and metabolite screening [18,19]. 

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