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CHAPTER OBJECTIVES

  • Define pharmacogenetics and pharmacogenomics.

  • Define genetic polymorphism and explain the difference between genotype and phenotype.

  • Explain with relevant examples how genetic variability influences drug response, pharmacokinetics, and dosing regimen design.

  • Describe the relevance of CYP enzymes and their genetic variability to pharmacokinetics and dosing.

  • List the major drug transporters and describe how their genetic variability can impact pharmacokinetics.

  • Discuss the main issues in applying genomic data to patient care; for example, clinical interpretation of data from various laboratories and accuracy of record keeping of large amounts of genomic data.

Variable response to a drug in the general population is thought to follow a normal or Gaussian distribution about a mean or average dose, ED50 (Fig. 21-1). Patients who fall within region A of the curve may be described as hyper-responders while those in region B may be characterized as poor or hypo-responders. While pharmacokinetic and pharmacodynamic differences are thought to be primarily responsible for this Gaussian variation in drug response, the extremes in drug response may be due to unique interindividual genetic variability. Modern genetic methods have identified alterations in drug-metabolizing enzymes, drug transporters, and drug receptors that, at least in part, explain many of these extremes in drug response. This has given birth to the field of pharmacogenomics, which the FDA defines as “the study of variations of DNA and RNA characteristics as related to drug response.” Pharmacogenomics seeks to characterize inter-individual drug-response variability at the genetic level (Ventola, 2011). A related term, pharmacogenetics, is often used interchangeably but is defined by the FDA as “the study of variations in DNA sequence as related to drug response” (Ventola, 2011).

FIGURE 21-1

Simulated Gaussian distribution of population response to a hypothetical drug. ED50 indicates the mean dose producing a therapeutic outcome, while regions A and B highlight patients who are hyper- or hypo-responders to the drug effect, respectively.

Advances in pharmacogenetics have been enabled by high-throughput technology that allows for the screening of tens of thousands to a million genetic variants rapidly and simultaneously. These technologies usually rely on target enrichment, hybridization, or amplification-based strategies. For example, the DNA chip is a microchip that uses hybridization technology to concurrently detect the presence of tens of thousands of sequence variants in a small sample. The probes (of known sequence) are spotted onto discreet locations on the chip, so that complementary DNA hybridization from the patient’s sample to a probe residing in a defined location indicates the presence of a specific sequence (Mancinelli et al, 2000; Dodgan et al, 2013). In contrast to searching for only known common genetic variants, next generation sequencing technology can provide sequencing of entire genes or exomes (Schwarz et al, 2019). This technology enables the identification of novel and rare variants in an individual or population.

Application of pharmacogenetics ...

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