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By Rutwij Dave

Rutwij DaveFor the past several decades, scientists, heath care providers, and the public at large have increasingly recognized the potential and promise that has come with the advent of personalized medicine. The high rate of toxicity and adverse events to drugs in some individuals or cohorts, and the lack of desired therapeutic efficacy in others, prompted scientists to pursue variations in patient genotypes as the potential cause of the clinically observed phenotypes. Extensive research has been done to evaluate the impact of genetic variations on many disease areas such as oncology, chronic inflammation, hemophilia, and many metabolic disorders, with varying success. 

Although the phrase personalized (or precision) medicine first appeared in several publications in 1999, the term pharmacogenetics was coined by Friederich Vogel in 1959. However, it was not until the late 1980s when the first pharmacogenetic variation (in CYP2D6) was reported.

Shortly thereafter, the word pharmacogenomics was introduced to scientific literature. The success of the Human Genome Project established the firm basis for pharmacogenetic and pharmacogenomic research. Two key discoveries that greatly facilitated pharmacogenetic and pharmacogenomic research within the field of personalized medicine are single nucleotide polymorphism (SNP) genotyping and microarray/biochips. SNPs in drug metabolizing analyses and drug transporters are very frequent across populations and account for ~90% of all known genetic polymorphisms. Microarrays allow rapid and efficient determination of SNPs and enable scientists to develop potential personalized medicine strategies to achieve the targeted drug efficacy based on the individual genotypes.

One good example of preventing adverse drug effects through pharmacogenetics is abacavir, a nucleotide reverse transcriptase inhibitor used to treat patients with HIV. Abacavir is known to cause a hypersensitivity reaction in some patients within six weeks of the onset of therapy. In 2002, two independent studies (by Mallal S, Nolan D, Witt C, et al; and by Hetherington S, Hughes AR, Mosteller M, et al) demonstrated a possible genetic link between the hypersensitivity reaction and the major histocompatibility complex class I allele HLA-B*57:01. It was demonstrated that patients that have the HLA-B*57:01 gene have a 60% chance of developing a hypersensitivity reaction when treated with abacavir. This landmark finding persuaded the U.S. Food and Drug Administration and the European Medicines Agency to alter the abacavir label to advise testing for the HLA-B*57:01 alleles prior to initiating abacavir therapy.

Personalized medicine can also be used to determine appropriate doses of drugs in patients with genetic variability. Inter-individual variability in the effects of warfarin in patients is attributed to five factors: (i) age, (ii) weight, (iii) CYP2C9, a gene encoding the enzyme responsible for warfarin metabolism, (iv) VKORC1, a gene encoding the enzyme that recycles vitamin K (warfarin’s primary target), and (v) CYP4F2, a gene encoding the enzyme responsible for vitamin K metabolism. Currently, the warfarin label contains this information along with considerations for the initiation of warfarin therapy.

Finally, personalized medicine can help predict patients’ genetic predisposition of developing certain diseases. Well-known examples are mutations of the BRCA1 and BRCA2 genes that have been implicated in familial breast cancers and the loss of APC gene function in familial adenomatous polyposis.

Examples of genetic polymorphisms that influence drug effects in humans include: azathioprine and mercaptopurine (TPMT), irinotecan (UGT1A1), antidepressants and β-blockers (CYP2D6), omeprazole (CYP2C19), and HIV protease inhibitors (ABCB1), among others.

Advances in pharmacogenetic and pharmacogenomic research and recent results indicate that personalized medicine will have an increased impact on drug research and development, clinical trials, and in clinical practice. However, three major challenges remain:

  1. Identifying patients within a population who are at an increased risk for developing specific diseases.
  2. There are more than 350 genetic tests available to screen patients for a range of diseases, but most of these tests are for rare diseases. Therefore, more research needs be directed toward tests for more prevalent disorders.
  3. Parsimony and cost-effectiveness in terms of early diagnosis of diseases in patients.

We, therefore, must ask when thinking about personalized medicine: Are we there yet?

The scientific community must strive to discover, develop, and deliver health care and treatment options that are innovative but also affordable.

The AAPS Drug Metabolism focus group (DMFG) plans to highlight the efforts of this exciting field of research through DMFG’s newsletter, Transform Vol. 4. We are also developing a webinar on personalized medicine. Stay tuned for more!

Rutwij Dave, Ph.D., is a postdoctoral associate at the University at Buffalo. His current research focus is to develop PK/PD modeling and simulation-based solutions to guide early discovery and transnational research for Principia Biopharma.