TIMING OF METABOLISM STUDIES
RELATED APPLICATIONS AND CONSIDERATIONS
TIMING OF METABOLISM STUDIES
A question frequently raised is when during drug development should studies in vitro be conducted. Sponsors are reluctant to allocate resources during the investigation of a drug that has not yet demonstrated a suggestion of clinical activity. This is a reasonable concern, and where possible, it is reasonable to identify some useful activity in short-term clinical studies before embarking on a major metabolic evaluation. Nevertheless, an early understanding of how a compound is metabolized could influence selection among several pharmacologically similar agents and could lead to dose regimens that would be more likely to detect a positive clinical effect. When attempting to determine the most appropriate time to conduct metabolism studies in vitro, it is helpful to reconsider the reasons for conducting such studies.
Two of the major clinical reasons, as previously mentioned, are (1) to identify all of the major metabolic pathways that affect the drug and its metabolites and (2) to anticipate the effects of the drug on the metabolism of other drugs. With these objectives in mind, an understanding of the metabolic profile of a drug in vitro would be useful prior to the initiation of phase 2 studies and is especially important before phase 3 trials, when a broader population will be studied.
This knowledge would permit the efficient design of clinical dose/response, interaction, and special population studies and also would enable adequate attention to be given to patient variability and potential interactions in phase 2 and 3 studies. Of course, drugs have been eveloped successfully even when the evaluation of metabolic routes of elimination occurred during the later phases of drug development or were not explored at all. Today, however, it is difficult to justify marketing a drug without knowing how it is metabolized or how it could influence, or be influenced by, the drugs being taken with it. Therefore, sponsors are encouraged to conduct appropriate metabolic studies prior to commencement of phase 3 trials.
The following text is an example of class labeling based on studies in vitro:
Although clinical studies have not been conducted, on the basis of this drug's metabolism by CYP450 3A4, ketoconazole, itraconazole, erythromycin, and grapefruit juice are likely to inhibit its metabolism. Furthermore, rifampin, dexamethasone, and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce this drug's metabolism. Thus, if a patient has been titrated to a stable dosage on this drug, and then begins a course of treatment with one of these inducers or inhibitors, it's
reasonable to expect that a dose adjustment may be necessary to prevent toxicity or therapeutic failure.
The example below demonstrates where the class effects would be inserted and also where information on the drug's inhibitory effects would be stated:
This drug is metabolized by CYP450 3A4 (CURRENT STATMENT). At clinical doses, the drug itself does not inhibit the metabolism of other 3A4 substrates, but does inhibit the metabolism of substrates metabolized via the CYP450 2D6 pathway.
Given the tendency to include many potential interactions, it is sometimes unclear if anything is noninteracting. In such a circumstance, labeling statements that denote both positive and negative expectations may be helpful. For example:
This drug is a substrate for CYP450 1A2. Although inhibition of its metabolism by ciprofloxacin is observed, quinidine, erythromycin, ketoconazole, and itraconazole are not inhibitors.
Each year, large numbers of new drug-drug interactions are discovered, precluding the possibility that any prescriber could memorize them all. Based on the increasing amount of valuable information that is available, it is now possible to label for class effects for various enzymes, and the ability to extrapolate from partial data is growing. Standardized approaches to labeling are likely to emerge and be helpful, in a manner analogous to the class labeling used for certain categories of drugs. For example, certain powerful inhibitors (quinidine for CYP450 2D6, ketoconazole for CYP450 3A4) are likely to affect all drugs metabolized by these pathways. For this reason, if a new drug is found to be a substrate for certain CYP450 enzymes, then certain interactions may be anticipated, even though specific data are lacking.
This understanding relies on knowledge about the activity of the drug and its metabolites. Similarly, it would be helpful to know what metabolic pathways are not involved in the elimination of a drug. When generalizations are made from studies in vitro, the conditions of extrapolation should be explicitly stated. Thus, conclusions based on data gained from in vitro studies that are extrapolated to the clinical situation should be identified and distinguished from conclusions based on clinical observations in vivo. Under these circumstances, the best advice available at any given time may be provided, and class effects may be updated as new information is obtained.
RELATED APPLICATIONS AND CONSIDERATIONS
The same techniques for evaluating potential drug-drug interactions can also provide information related to the influence of social (smoking, alcohol), environmental (diet, e.g.,grapefruit juice), and genetic factors upon therapeutics. For example, several studies have demonstrated that tobacco smoking is a strong inducer of the CYP450 1A2 enzymes. As a result, larger doses of theophylline are recommended for patients who smoke and receive this drug. In the future, evidence of induction as well as inhibition may also be developed via in vitro studies. Metabolic characterization of racemic drugs should be conducted in accordance with previously expressed guidances and guidelines on the development of stereoisomers. In particular, if the development of a single enantiomer is to be pursued, the preclinical metabolism studies in vitro should be conducted with the relevant enantiomer, rather than the racemic mixture.
Also see :
DRUG METABOLISM/DRUG INTERACTION STUDIES IN THE DRUG DEVELOPMENT PROCESS: STUDIES IN VITRO
TECHNIQUES AND APPROACHES FOR STUDIES IN VITRO OF DRUG METABOLISM AND DRUG INTERACTIONS
CORRELATION BETWEEN STUDIES IN VITRO AND IN VIVO IN DRUG METABOLISM/DRUG INTERACTION STUDIES IN THE DRUG DEVELOPMENT PROCESS: STUDIES IN VITRO
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