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CHAPTER OBJECTIVES

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  • 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.

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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. 13-1). 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 pharmacogenetics, which seeks to characterize inter-individual drug-response variability at the genetic level (Mancinelli et al, 2000). A related term, pharmacogenomics, is often used interchangeably but includes the study of the genetic basis of disease and the pharmacological impact of drugs on the disease process (Mancinelli et al, 2000).

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FIGURE 13-1

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

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Advances in pharmacogenetics have been enabled by high-throughput technology that allows for the screening of tens of thousands of genes rapidly and simultaneously. For example, the DNA chip is a microchip that uses hybridization technology to concurrently detect the presence of tens of thousands of sequences 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). Other rapid and low-cost sequencing technologies such as ULCS (ultra-low-cost sequencing) or cyclic array technologies will also permit rapid and high-volume sequencing and/or sequencing of individual genomes. These technologies usually rely on some combination of miniaturization, multiplex or parallel assays, analyte amplification and/or concentration, and detection signal amplification.

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Application of pharmacogenetics to pharmacokinetics and pharmacodynamics helps in development of models that may predict an individual’s risk to an adverse drug event ...

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