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Does Pharmacogenetics have a Role in Veterinary Medicine?
L. Troutman
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What is pharmacogenomics or pharmacogenetics? Pharmacogenomics is a broader term encompassing pharmacogenetics. Pharmacogenomics can be defined as the science of understanding the correlation between pharmacologically responsive genes of an individual or the gene interactions and metabolic pathways involved in the drug response, described in general terms for an entire population. Studying the genetic basis of patient response to therapeutics allows drug developers to more effectively design therapeutic treatments.
Pharmacogenetics can be defined as a subset of pharmacogenomics, encompassing the study of genetic variation underlying differential responses to drugs, particularly genes involved in drug metabolism. It is the effect of an individual’s specific genotype on the effectiveness, safety, and metabolism of the drug, or on the drug mechanism of action. Differences in an individual’s genotype may be a result of alternate alleles, a single nucleotide polymorphism (SNP) which is a change, deletion, or insertion of one DNA nucleotide in a gene, or a mutation of a gene which may result in alteration or inactivation of gene expression.
Pharmacogenetics or genomics can be used to study the effect of an individual’s genotype on the absorption, distribution, metabolism and elimination of a particular drug. This knowledge can be used in drug development process in designing new drugs and studying the mechanism of action of a drug. The information is helpful in evaluating the effectiveness, safety and toxicity of a drug in relation to individuals taking the drug. In particular, it can be used to discover new biomarkers used to evaluate safety or effectiveness. It can also be used as selection criteria for participants in a clinical trial. Finally, it can be used as a tool for preventing drug use in high-risk populations by including pharmacogenomic information in the drug labeling.
All individuals in a population do not have the same response to a particular drug at the same dose. Some individuals do not respond to the drug, called nonresponders, others respond in the expected manner, and others are extremely sensitive to the drug and may experience some toxicity. The field of pharmacogenomics can help us understand why some individuals are poor metabolizers of drugs and therefore may develop toxicity to a drug while others are ultrarapid metabolizers and do not respond to a drug. Biomarkers are used to screen individuals to determine if they will respond appropriately to a particular drug.
A biomarker is defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Examples of classic biomarkers are clinical chemistry values, blood pressure measurements, and temperature. Pharmacogenetic biomarkers are gene mutations, alternate alleles, or characteristic clusters of genes obtained from microarray data.
A known valid biomarker is defined as a biomarker measured in an analytical test system with well-established performance characteristics and for which there is widespread agreement in the medical or scientific community about the physiologic, toxicologic, pharmacologic, or clinical significance of the results. Usually there is a validated test available for a known valid biomarker. A probable valid biomarker is a biomarker that is measured in an analytical test system with well-established performance characteristics and for which there is a scientific framework or body of evidence that appears to elucidate the physiologic, toxicologic, pharmacologic, or clinical significance of the test results. A valid test may not be available for a probable biomarker.
Drug Metabolizing Enzymes
The field of pharmacogenetics encompasses the evaluation of drug metabolizing enzymes, drug transporters, receptors and any targets that can modulate a drug response. Cytochrome P450 system is an example of drug metabolizing enzymes. In humans, CYP2D6 is well characterized and classified as a known valid biomarker. Variations in CYP2D6 can cause people to become ultrarapid metabolizers (up to 30% of East Africans), excess metabolizers, or poor metabolizers (5 - 10% of Caucasians) of a drug compound that is a CYP2D6 substrate. A large number of drugs are metabolized by CYP2D6, including antiarrhythmics (quinidine, flecainide), antidepressants (amitriptyline, clomipramine, fluoxetine, paroxetine, imipramine), beta-blockers (carvedilol, propanolol, timolol, metroprolol), neuroleptics, and opioid derivatives such as codeine, dextromethorphan, and tamoxifen. Knowing an individual’s genotype for CYP2D6 can affect the amount of drug that individual is given. For example ultrarapid metabolizers would need at least five times the dosage of a normal responder in order to achieve effectiveness and a poor metabolizer would require 1/10th of the dose in order to avoid toxicity.
Thiopurine S-methyltransferase (TPMT) is a phase II metabolizing enzyme that detoxifies thiopurine metabolites (azothioprine, mercaptopurine). A study that screened 144 dogs resulted in finding nine canine polymorphisms, including three insertion/deletion events and six SNPs6. The six SNPs are associated with phenotypic differences in canine red blood cell TPMT activity. Therefore, TPMT is a probable biomarker in dogs for evaluating the metabolism of thiopurine drugs.
Drug Transporters
The field of pharmacogenetics also encompasses drug transporters. In veterinary medicine, a mutation in the canine MDR1 gene is known to cause an increased sensitivity to a wide variety of drugs. The MDR-1 (multidrug resistance) gene, also known as the ABCB1 gene, encodes a 170 kDa transmembrane protein pump called P-glycoprotein (P-gp). P-gp is a member of the ATP-binding cassette superfamily (ABC family) of transport proteins. P-gp’s are mainly localized in the plasma membrane where they can actively extrude a wide range of drugs from the cell, thus providing protection from the toxic action of these drugs. P-gp’s provide protection across the blood/brain barrier, gastrointestinal tract, and through renal excretion. In dogs, a 4 base pair deletion in the gene generates a premature stop codon resulting in the production of a truncated, nonfunctional protein. The absence of the protein allows drugs to enter into the brain or other areas in a higher concentration than normal, usually resulting in a drug toxicity. The mutation of the MDR1 gene (mdr1-1Δ) is responsible for the ivermectin sensitivity seen in some Collies and other related breeds. Mdr1-1Δ has been found in at least nine breeds including the Collie, Australian shepherd, miniature Australian shepherd, English shepherd, Longhaired Whippet, McNab, Old English Sheepdog, Shetland Sheepdog and Silken Windhound.
Drugs relevant to veterinary medicine that have been shown to be P-gp substrates include anticancer drugs (doxorubicin, vincristine, vinblastine, mitoxantrone, paclitaxel), antimicrobials and antiparasitics (tetracycline, ivermectin), cardiac drugs (digoxin, diltiazem, verapamil) and other drugs such as cyclosporine, dexamethasone, and loperamide. Many of these drugs have the potential to cause neurotoxicity.
A DNA test for the presence of the mdr1-1 mutation is offered by Washington State University, which allows veterinarians to screen dogs for the mutation and individualize drug therapy to dogs at risk for developing toxicity. The test could also be used as a screening tool to ultimately eliminate the mutation from breeding gene pools.
Regulatory Medicine
In human regulatory medicine and drug development, there is an impetus to incorporate pharmacogenetics into the drug development process. Currently there are two draft guidances available from FDA entitled Pharmacogenomic Data Submissions and Pharmacogenetic Tests and Genetic Tests for Heritable Markers. Co-development of a drug and a biomarker test is becoming more common to help individualize medicine and tailor the drug dosage to each individual’s need. Veterinary medicine may be following this lead in the near future.
An example of co-development of a drug and in vitro diagnostic test is Herceptin® (Trastuzumab) which is indicated for the treatment of breast cancer in humans. It was co-developed and marketed simultaneously with a diagnostic test for the HER2 oncoprotein. Herceptin is a humanized anti-HER2 monoclonal antibody. Approximately 20 to 25% of breast cancer patients express this protein. Herceptin is only effective in this select population of patients. Therefore, CBER required that Genentech, Inc have a commercially available in vitro diagnostic test for HER2 in order to market Herceptin. Genentech partnered with another company to develop the test. Herceptin and the in vitro diagnostic test were concurrently approved by both CBER and CDRH.
Information regarding known valid biomarkers or certain breed sensitivities can be incorporated into the drug labeling. The information will allow practitioners to individualize drug therapy for maximum effectiveness and minimal toxicity.
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