DRUG METABOLISM/DRUG INTERACTION STUDIES IN THE DRUG DEVELOPMENT PROCESS: STUDIES IN VITRO
After entering the body, a drug is eliminated either by excretion or by metabolism to one or more active or inactive metabolites. When elimination occurs primarily by metabolism, the routes of metabolism can significantly affect the drug’s safety and efficacy and the directions for use. When elimination occurs via a single metabolic pathway, individual differences in metabolic rates can lead to large differences in drug and metabolite concentrations in the blood and tissue. In some instances, differences exhibit a bimodal distribution indicative of a genetic polymorphism (e.g., CYP450 2D6, CYP450 2C19, N-acetyl transferase). When a genetic polymorphism affects an important metabolic route of elimination, large dosing adjustments may be necessary to achieve the safe and effective use of the drug. Pharmacogenetics already has influenced therapeutics. For a drug that is primarily metabolized by CYP450 2D6, approximately 7 percent of Caucasians will not be able to metabolize the drug, but the percentage for other racial populations is generally far lower. Similar information is known for other pathways, prominently, CYP450 2C19 and N-acetyl-transferase. Equally important, if not more so, many enzymatic metabolic routes of elimination, including most of those occurring via the CYP450 enzymes, can be inhibited or induced by concomitant drug treatment. As a result, abrupt changes can occur with a co-administered agent in a single
individual. Such interactions can lead to a substantial decrease or increase in the blood and tissue concentrations of a drug or metabolite or cause the accumulation of a toxic substance (e.g., certain antihistamine-antifungal interactions). These types of changes can alter a new drug’s safety and efficacy profile in important ways, particularly a drug with a narrow therapeutic range.
An understanding of metabolic pathways and potential interactions sometimes allows the use of a drug that would produce an unacceptable level of toxicity if blood levels were not predictable. For these reasons, it is important to learn at an early stage of development whether a drug is eliminated primarily by excretion of unchanged drug or by one or more routes of metabolism. If elimination is primarily by metabolism, the principal metabolizing route(s) should be understood. This information will help identify the implications of metabolic differences between and within individuals and the importance of certain drug-drug and other interactions. Having such information also will aid in determining whether the pharmacologic properties of certain metabolites should be explored further.
OBSERVATIONS AND CONCLUSIONS
The following general observations and conclusions underlie the suggestions found here:
*The concentrations of the parent drug and/or its active metabolite(s) circulating in the body are the effectors of desirable and/or adverse drug actions.
*A principal regulator of drug concentration in the body is clearance. Metabolism can be a major determinant of clearance.
*Even for drugs that are not substantially metabolized, the potential effect of that drug on the metabolism of concomitant drugs could be important.
*Large differences in blood levels can occur because of individual differences in metabolism. Some drugs, such as tricyclic antidepressants, exhibit order of magnitude differences in blood concentrations depending on the enzyme status of patients. Drug drug interactions can have similarly large effects when one drug inhibits the metabolism of another. For example, ketoconazole greatly increases concentrations of parent terfenadine, leading to QT prolongation and torsades de pointes.
*Major advances have been made recently in the availability and use of human tissue and recombinant enzymes for studies in vitro of drug metabolism and drug-drug interactions.
*The development of sensitive and specific assays for a drug and its metabolites is critical to the study of drug metabolism and interactions. Development of such assay methods has long been a high priority for drug development programs, and such assays are increasingly available early in development. Once reliable assays are available, the techniques are available for readily assessing drug metabolism and drug-drug interactions in vitro and interpreting the results.
The studies in vitro described here are one set of approaches to developing
information about drug metabolism and drug-drug interactions. Mechanistic and empirical clinical study approaches are available as well to provide further information. As always, a carefully designed mix of approaches is likely to yield optimal results in the shortest time and at the least cost. Metabolic effects and drug-drug interactions should be considered as early as possible as well as later in the drug development process. Appropriately designed pharmacokinetic/phase 1 studies could provide important information about drug metabolism, relevant metabolites, and actual or potential drug interactions. Blood level data obtained during phase 2 and 3 clinical trials, for example, via a pharmacokinetic screen, also could reveal interactions or marked inter-individual differences. Because clinical trial protocols sometimes limit concomitant drug use, some later studies may not be optimally informative about possible drug interactions. Decreasing exclusions of concomitant drug treatment and
measurement of blood levels before and after treatment with a test drug (interaction screen), as well as testing drug blood levels more frequently, could make later phase clinical studies more useful. All of these studies could be more informative if significant metabolites and prodrugs could be identified and their pharmacological properties described.
Identifying metabolic differences in patient groups based on genetic polymorphisms, or on other readily identifiable factors such as age, race, and gender, could help guide the design of dosimetry studies for such populations groups. This kind of information also will provide improved dosing recommendations in product labeling, facilitating the safe and effective use of a drug by allowing prescribers to anticipate necessary dose adjustments. Indeed, in some cases, understanding how to adjust dose to avoid toxicity may allow the marketing of a drug that would have an unacceptable level of toxicity were its toxicity unpredictable and unpreventable.
Also see :
A. Cytochrome P-450, Microsomes, and Related Tools
B. Other Hepatic Enzymes
C. Gastrointestinal Drug Metabolism
D. Interspecies Metabolic Comparisons and Other Uses of Animal Data
For Reading Above Topics refer http://whoguideline.blogspot.com/2010/10/drug-metabolismdrug-interaction-studies.html
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