When Is It Appropriate to Use Pharmacogenetics and Pharmacogenomics for Inclusion Exclusion Criteria or Stratification or When Is It Appropriate for Pharmacogenetic and Pharmacogenomic Relationships to be Explored Post

Participants concluded that the use of pharmacogenetics and pharmacogenomics in early Phase I would be an important step in generating information that could be confirmed or validated in Phase II. Most participants thought that pharmacogenetic and pharmacoge-nomic objectives in Phase I should be considered exploratory (not confirmatory) in nature, and that pharmacogenetics and pharmacogenomics should not be used as inclusion/exclusion criteria for a single- or multiple-dose first-time-in-humans (FTIH) study. However, under a few circumstances for variants with well-established functional significance (e.g., alleles of CYP2D6, CYP2C19), a Phase I study may be confirmatory and still use small numbers of patients. Also, in drug interaction studies for drugs metabolized by polymorphic CYP enzymes (e.g., CYP2D6, CYP2C9, and CYP2C19), pharmacogenetics and pharmacogenomics should be considered as inclusion/exclusion criteria or for stratification.

Because of the availability of plasma concentration-time data following administration of many doses, Phase I provides a unique opportunity to explore the relationships between genetic variants in genes related to metabolic enzymes and transporters and the PK properties of the compound. Because Phase I dose-ranging studies include a broader range of doses of drugs administered to subjects (and possibly resulting in a higher rate of adverse events), and since some of these doses are rarely repeated in later trials, Phase I provides a unique opportunity to explore the relationships among genetic variants in the drug target and adverse events. In addition, when an appropriate tissue is available, Phase I provides an early opportunity to evaluate gene expression profiles to identify associations with safety and efficacy at a wide range of doses.

When pharmacogenetics and pharmacogenomics are included in Phase I, gene variants that should be studied should include those encoding for the activity of drug-metabolizing enzymes and transporters, the drug target, and any pharmacological pathways related to important safety outcomes in healthy volunteers. In addition, if patients are studied, validated disease genes (that could affect drug response) should be evaluated. Investigators should attempt to identify trends and how well the clinical data correspond to preclinical data.

With regard to Phase Ib/2a (dose-ranging and PoC studies), there is a need to have some confirmation or validation before using pharmacogenetics and pharmacogenomics as inclusion/exclusion criteria or for stratification in a Phase Ib/2a study. There could be a benefit to include all genotypes in PoC studies if all patients have a potential to benefit. However, the dose may require adjustment for subjects with genotypes resulting in reduced enzyme activity (e.g., CYP2D6).

Several participants felt that pharmacogenetics and pharmacogenomics should not be treated differently from any other covariate. In some cases, more confirmation would be required prior to using these data as inclusion/exclusion criteria (or for stratification), and pharmacogenetics and pharmacogenomics would be viewed as a covariate in the post hoc analyses.

In this regard, the following factors should be considered in the context of stratification or use as inclusion/exclusion criteria.

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