TIMING OF METABOLISM STUDIES IN DRUG METABOLISM/DRUG INTERACTION STUDIES IN THE DRUG DEVELOPMENT PROCESS: STUDIES IN VITRO
TIMING OF METABOLISM STUDIES
LABELING
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.
LABELING
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
=====================================================================================================
Do you know now this website has become a most popular and most referred website in pharmaceutical industry and pharmaceutical companies and pharmaceutical manufacturers from all over the world ,for almost all topics related to Pharmaceutical Manufacturing , Pharmaceutical Regulatory Affairs and Good Manufacturing Practice for Pharmaceutical Manufacturing (c GMP guidelines ) and latest news and new drugs developments.
=====================================================================================================
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Here are some articles which will be useful for you in further understanding of aspects of sterile dosage form manufacturing and regulatory affairs and good manufacturing practice in
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Here are some interesting articles on Quality assurance systems for pharmaceutical company
1.Quality assurance in pharma industry
2.Quality by designe concept for pharmaceutical industry
3.Quality by designe concept in pharmaceutical industryan explanation
TIMING OF METABOLISM STUDIES
LABELING
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.
LABELING
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
=====================================================================================================
Do you know now this website has become a most popular and most referred website in pharmaceutical industry and pharmaceutical companies and pharmaceutical manufacturers from all over the world ,for almost all topics related to Pharmaceutical Manufacturing , Pharmaceutical Regulatory Affairs and Good Manufacturing Practice for Pharmaceutical Manufacturing (c GMP guidelines ) and latest news and new drugs developments.
=====================================================================================================
You may also like following articles
Whar is Referance Listed Drug ? ( RLD )
What is Pharmaceutical Equivalents
What is Pharmaceutical Alternatives
What is Therapeutic Equivalents
Do Physical properties contribute to drug activity.
What is drug receptor , How a drug resistance occurs
Mechanism of drug resistance
What is drug interaction
Drug interaction, and its examples
What is first pass metabolism of a drug
What is What is 510(k) Clearances ?
What is 510(k) Clearances,
Premarket Notification for medical devices - PMN or 510(k)
What is a drug interaction
Examples of drug interactions
Antibiotic Definition and classification
Antibiotic resitance and Antibiotic resistance mechanism
Antioxidants food suppliments
Vitamin D Details on FDA cautions on accurate dosage of Vitamin D
What is an antibody? what is monoclonal and polyclonal antibodies?
Terminologies In vaccine Production
Multi stage testing of Virus vaccine production
Testing of vaccines at different stages of production
TESTING FOR ADVENTITIOUS AGENTS CELL PROPERTIES IN VIRAL VACCINE PRODUCTION
Enzyme linked immunosorbent assay ELISA
Raido Immuno assay
http://whoguideline.blogspot.com/2010/04/terminalogy-and-their-explanations.html
Pharmaceutical Aseptic Manufacturing Process Terms , Terminology and Definitions.
http://whoguideline.blogspot.com/2010/02/pharmaceutical-aseptic-manufacturing.html
Here are some articles which will be useful for you in further understanding of aspects of sterile dosage form manufacturing and regulatory affairs and good manufacturing practice in
pharmaceutical industry
Pharmaceutical Validation
Types of validations in pharmaceutical manufacturing
Requirements of documents for validation of sterilisation process
How to investigate OOS out of specification results
Determination of Phenol coefficient of a disinfectant
Sterility testing
Cleen Room Classification
Time limitations in sterile pharmaceuticals processing
Aspects of validation of manufacturing process in sterile pharmaceuticals
Clinical Trials
Controlling Pyrogens in injectable dosage forms
Media fill run process simulation aspects Validation of Aseptic Process and Sterilisation
New Drug Application (NDA) how to make a New Drug Application (NDA) to US FDA
Abbreviated New Drug Application (ANDA) What is ANDA , detaied information about ANDA preparation and submission to US FDA
How to make Investigational New Drug (IND) Application to US FDA
Drug applications submission to us fda Over the counter Drugs OTC drugs
BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS
Electronic record in pharmaceutical manufacturing industry
Good manufacturing practice in pharmaceutical industry
Pharmaceutical industry pharmaceutical companies and FDA latest updates
Here is an interesting article on world wide pharmaceutical industry and making a carrier in one of pharmaceutical companies article on Pharmaceutical Industry pharmaceutical industry
Find a Job in Pharmaceutical Company
To Find Pharmaceutical jobs and make a Pharmaceutical careers see here pharmaceutical companies
Here are some interesting articles on Quality assurance systems for pharmaceutical company
1.Quality assurance in pharma industry
2.Quality by designe concept for pharmaceutical industry
3.Quality by designe concept in pharmaceutical industryan explanation
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