NEW DRUG DEVELOPMENT (ANTI RETROVIRAL HIV) AND CONSIDERATIONS OF DRUG RESISTANCE TESTING IN HIV .
Why there is no drug that is completely effective against HIV virus infection , why these HIV virus get resistance very quikely to a perticular drug , not only that it also develops cross resistance to other drug belongin to same group.
We are provinding here a complete guide for developing new drug after studing its for resistance .
Why there is no effective drug for treating HIV infection , whey HIV virus develop resistance with these drugs?
Because of high rate of replication of HIV virus (10rest to 9 , –to-- 10 rest to 10 virions per person per day) and error-prone polymerase, HIV can easily develop mutations that alter susceptibility to antiretroviral drugs. As a result, the emergence of resistance to one or more antiretroviral drugs is one of the more common reasons for therapeutic failure in the treatment of HIV. In addition, the emergence of resistance to one antiretroviral drug sometimes confers a reduction in or a loss of susceptibility to other or all drugs of the same class.
The application of laboratory technologies, such as gene amplification, automated nucleic acid sequencing, and nucleic acid hybridization, and the availability of recombinant viruses for testing phenotypic susceptibility have permitted advances in HIV resistance testing. Many clinicians and investigators are currently using these technologies in the clinical management of HIV. However, performance characteristics (e.g., sensitivity, specificity, and reproducibility) for many of the assays in investigational use have not been fully established. In addition, the clinical significance of many mutations or mutational patterns has not been defined completely for many antiretroviral drugs. Likewise, the quantitative relationship between reductions of cell culture susceptibility and loss of clinical activity has not been established for most drugs. Consequently, many of the current package inserts are deficient in the amount and type of resistance data describing the utility of a drug in the setting of resistance or reduced susceptibility.
Despite limitations of resistance assays and their interpretation, several randomized controlled studies have demonstrated that virologic outcome, at least over the short term, may be improved when genotypic or phenotypic data are used to guide choice of drug regimens in patients with loss of virologic response to prior regimens (Baxter et al. 2000; Cohen et al. 2002; Durant et al. 1999; Melnick et al. 2000; Meynard et al. 2000; Tural et al. 2002). It is recommended that characterization of resistance and cross-resistance be a part of antiretroviral drug development so that clinically relevant information is available at the time of approval. An efficient way to accomplish the goal of having clinically relevant information available at the time of approval is to include resistance testing in all phases of drug development. As discussed below, assessment of resistance should not be delayed until phase 3 or post-approval. We recommend that, before or during phase 1 and phase 2 studies, investigators begin assessing the potential of a drug to select resistant viruses and the drug’s activity against HIV isolates resistant to other antiretroviral agents. During early development, a wide range of doses should be evaluated and pharmacokinetic data should be collected, providing information to investigate the relationship between drug exposure and resistance
Optimally, a comprehensive evaluation of a new drug’s resistance and cross-resistance profile will promote more rational use of antiretroviral drug combinations in the future.
Once drug resistance factors are overcome , we will be able to provide a life saving treatment for HIV positive peoples , so far it is not completely achived , but i am going to present you a nice article , that will cover , the detailed road map or guidelines for developing a drug after scrining its resisntance, following are the topic which are descussed in detailes.
IV. NONCLINICAL STUDIES
A. Mechanism of Action
B. Antiviral Activity in Cell Culture
C. Cytotoxicity and Therapeutic Indexes
D. Protein Binding
E. Selection of Drug-Resistant HIV-1 Variants in Cell Culture
1. Genotype
2. Phenotype
F. Cross-Resistance
G. Characterization of Genotypic and Phenotypic Assays
1. Genotypic Assays
2. Phenotypic Assays
V. CLINICAL STUDIES: USE OF RESISTANCE TESTING IN CLINICAL PHASES OF DRUG DEVELOPMENT
A. General Considerations
B. Data Collection
C. Methods and Types of Analyses
1. Baseline Genotype and Virologic Response
2. Development of HIV Mutations
3. Baseline Phenotype and Virologic Response
4. Genotypic and Phenotypic Correlations: Changes in Susceptibility from Baseline
5. Cross-Resistance
6. Additional Analyses
D. Other Considerations
1. Role for Supporting Initial Activity and Dose-Finding Studies
2. Data Collection from Dose-Finding Trials
3. Use of Resistance Data to Establish an Indication
4. Use of Resistance Data for Study Enrollment Criteria, Background Regimen Selection, and Stratification Factors
5. Nonclade B Subtypes
E. Monitoring during Phase 4
REGULATORY REQUIREMENTS FOR SUBMITTING HIV RESISTANCE DATA
SUMMARY
Resistance analyses provide information regarding which mutations may have an effect on the therapeutic success of a given antiretroviral drug product. Such information potentially can be included in drug labeling to facilitate appropriate prescribing of products and to maximize the chance for therapeutic success.
Accessory or compensatory mutation:
A mutation that by itself does not confer a decrease in susceptibility to antiretroviral agents. Accessory or compensatory mutations can augment key mutations and, perhaps, fitness mutations.
Fitness mutation: An amino acid change that compensates for the reduced virus growth resulting from a drug resistance-conferring mutation.
Key mutation: A treatment-selected amino acid change that can cause a decrease in susceptibility to one or more antiretroviral agents of the same class.
Polymorphism: Natural variation in the HIV-1 genome.
Source:
Drug Resistance Assay and Antiretroviral drug development guidance--->
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071173.pdf
Last Updated : 28-Oct-2010
Why there is no drug that is completely effective against HIV virus infection , why these HIV virus get resistance very quikely to a perticular drug , not only that it also develops cross resistance to other drug belongin to same group.
We are provinding here a complete guide for developing new drug after studing its for resistance .
Why there is no effective drug for treating HIV infection , whey HIV virus develop resistance with these drugs?
Because of high rate of replication of HIV virus (10rest to 9 , –to-- 10 rest to 10 virions per person per day) and error-prone polymerase, HIV can easily develop mutations that alter susceptibility to antiretroviral drugs. As a result, the emergence of resistance to one or more antiretroviral drugs is one of the more common reasons for therapeutic failure in the treatment of HIV. In addition, the emergence of resistance to one antiretroviral drug sometimes confers a reduction in or a loss of susceptibility to other or all drugs of the same class.
The application of laboratory technologies, such as gene amplification, automated nucleic acid sequencing, and nucleic acid hybridization, and the availability of recombinant viruses for testing phenotypic susceptibility have permitted advances in HIV resistance testing. Many clinicians and investigators are currently using these technologies in the clinical management of HIV. However, performance characteristics (e.g., sensitivity, specificity, and reproducibility) for many of the assays in investigational use have not been fully established. In addition, the clinical significance of many mutations or mutational patterns has not been defined completely for many antiretroviral drugs. Likewise, the quantitative relationship between reductions of cell culture susceptibility and loss of clinical activity has not been established for most drugs. Consequently, many of the current package inserts are deficient in the amount and type of resistance data describing the utility of a drug in the setting of resistance or reduced susceptibility.
Despite limitations of resistance assays and their interpretation, several randomized controlled studies have demonstrated that virologic outcome, at least over the short term, may be improved when genotypic or phenotypic data are used to guide choice of drug regimens in patients with loss of virologic response to prior regimens (Baxter et al. 2000; Cohen et al. 2002; Durant et al. 1999; Melnick et al. 2000; Meynard et al. 2000; Tural et al. 2002). It is recommended that characterization of resistance and cross-resistance be a part of antiretroviral drug development so that clinically relevant information is available at the time of approval. An efficient way to accomplish the goal of having clinically relevant information available at the time of approval is to include resistance testing in all phases of drug development. As discussed below, assessment of resistance should not be delayed until phase 3 or post-approval. We recommend that, before or during phase 1 and phase 2 studies, investigators begin assessing the potential of a drug to select resistant viruses and the drug’s activity against HIV isolates resistant to other antiretroviral agents. During early development, a wide range of doses should be evaluated and pharmacokinetic data should be collected, providing information to investigate the relationship between drug exposure and resistance
Optimally, a comprehensive evaluation of a new drug’s resistance and cross-resistance profile will promote more rational use of antiretroviral drug combinations in the future.
Once drug resistance factors are overcome , we will be able to provide a life saving treatment for HIV positive peoples , so far it is not completely achived , but i am going to present you a nice article , that will cover , the detailed road map or guidelines for developing a drug after scrining its resisntance, following are the topic which are descussed in detailes.
IV. NONCLINICAL STUDIES
A. Mechanism of Action
B. Antiviral Activity in Cell Culture
C. Cytotoxicity and Therapeutic Indexes
D. Protein Binding
E. Selection of Drug-Resistant HIV-1 Variants in Cell Culture
1. Genotype
2. Phenotype
F. Cross-Resistance
G. Characterization of Genotypic and Phenotypic Assays
1. Genotypic Assays
2. Phenotypic Assays
V. CLINICAL STUDIES: USE OF RESISTANCE TESTING IN CLINICAL PHASES OF DRUG DEVELOPMENT
A. General Considerations
B. Data Collection
C. Methods and Types of Analyses
1. Baseline Genotype and Virologic Response
2. Development of HIV Mutations
3. Baseline Phenotype and Virologic Response
4. Genotypic and Phenotypic Correlations: Changes in Susceptibility from Baseline
5. Cross-Resistance
6. Additional Analyses
D. Other Considerations
1. Role for Supporting Initial Activity and Dose-Finding Studies
2. Data Collection from Dose-Finding Trials
3. Use of Resistance Data to Establish an Indication
4. Use of Resistance Data for Study Enrollment Criteria, Background Regimen Selection, and Stratification Factors
5. Nonclade B Subtypes
E. Monitoring during Phase 4
REGULATORY REQUIREMENTS FOR SUBMITTING HIV RESISTANCE DATA
SUMMARY
Resistance analyses provide information regarding which mutations may have an effect on the therapeutic success of a given antiretroviral drug product. Such information potentially can be included in drug labeling to facilitate appropriate prescribing of products and to maximize the chance for therapeutic success.
Accessory or compensatory mutation:
A mutation that by itself does not confer a decrease in susceptibility to antiretroviral agents. Accessory or compensatory mutations can augment key mutations and, perhaps, fitness mutations.
Fitness mutation: An amino acid change that compensates for the reduced virus growth resulting from a drug resistance-conferring mutation.
Key mutation: A treatment-selected amino acid change that can cause a decrease in susceptibility to one or more antiretroviral agents of the same class.
Polymorphism: Natural variation in the HIV-1 genome.
Source:
Drug Resistance Assay and Antiretroviral drug development guidance--->
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071173.pdf
Last Updated : 28-Oct-2010
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