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Your patient is a middle-aged male from the inner city who is receiving oxycodone for severe, chronic pain. He says that the pain pills don’t seem to be working. You suspect that he might be diverting the drug. What do you do?

I have known a physician or two who would fire the patient. While understandable, a better response would be to do some drug level monitoring such as hair testing (to document long-term compliance) or measuring blood levels after an observed dose. So, let’s assume that we’re not going to jump to conclusions and instead, we’ll take the more measured, circumspect approach. 

First, consider the possibility of hypermetabolism of the drug, resulting in rapid clearance with decreased effectiveness.  After investigating metabolic effects, next you can consider the effect of genetics. Medical algorithms can help clinicians determine drug response based on these factors and many others. Sample medical calculators are suggested below that can aid a clinician in determining what the cause of low drug absorption could be.

  • Effect of Polymorphism in Cytochrome P450 (CYP) CYP2D6 on the Metabolism of OxycodoneEffect of Polymorphism in Cytochrome P450 (CYP) CYP2D6 on the Metabolism of Oxycodone

Pharmacogenetics and Pharmacogenetics Testing

Pharmacogenetics is a topic within the domain of personalized medicine. A person’s genetic makeup might influence response to medications in several ways. How the person absorbs or metabolizes a drug might affect its pharmacokinetics while changes to binding receptors may influence the drug’s performance.

Recognition

When should you suspect a pharmacogenetic issue? Some possible presentations include:

  1. An appropriate dose of a drug fails to achieve the desired effect
  2. A higher than normal dose is needed to achieve the desired effect
  3. Doses of the drug need to be given more often than usual
  4. The patient is experiencing drug-related toxicity at a normal dose
  5. The effect of a drug is greater or more prolonged than usual
  6. The person belongs to a population known to have issues with a drug

These issues can arise because of a genetic variation that results in:

  1. Excessive metabolism or excretion of the drug
  2. Decreased metabolism or excretion
  3. The generation of toxic metabolites
  4. Decreased absorption
  5. Altered binding of the drug to receptor(s)

One of the most common situations where this is encountered is with warfarin therapy. Some people need a relatively high dose to achieve a target INR, while other patients require only a very low dose.

  • Models for Determining Daily Dose of Warfarin That Include Genotypic Analysis of CYP2C9 and VKORC1Models for Determining Daily Dose of Warfarin That Include Genotypic Analysis of CYP2C9 and VKORC1
  • Indications for Testing a Patient on Warfarin for Polymorphism in Cytochrome P450 (CYP) CYP2C9Indications for Testing a Patient on Warfarin for Polymorphism in Cytochrome P450 (CYP) CYP2C9

Some patients present because they fail therapy despite adequate dosing and being compliant. In these cases a genetic change increases drug metabolism.

  • Identifying a Patient Failing Therapy for Helicobacter pylori Who Should be Phenotyped for CYP2C19Identifying a Patient Failing Therapy for Helicobacter pylori Who Should be Phenotyped for CYP2C19  
  • Identifying a Woman at Risk for Reduced Effectiveness of Tamoxifen Therapy Secondary to Altered Biotransformation Identifying a Woman at Risk for Reduced Effectiveness of Tamoxifen Therapy Secondary to Altered Biotransformation
  • Pharmacogenetic Model for Predicting the Efficacy of Methotrexate Monotherapy at 6 Months in a Patient with Rheumatoid ArthritisPharmacogenetic Model for Predicting the Efficacy of Methotrexate Monotherapy at 6 Months in a Patient with Rheumatoid Arthritis
  • Impact of CYP2C19 Phenotype on Clopidogrel ResponseImpact of CYP2C19 Phenotype on Clopidogrel Response

Another group of patients present with unexpected toxicity. Many of us remember the hepatotoxicity associated with isoniazid therapy. Many other drugs are more toxic in some groups than others.

  • Determining the Isoniazid Acetylation Phenotype Based on Measurement of Urinary Isoniazid and AcetylisoniazidDetermining the Isoniazid Acetylation Phenotype Based on Measurement of Urinary Isoniazid and Acetylisoniazid
  • Identifying Patients at Risk for Irinotecan (Camptosar) Myelotoxicity Based on UGT1A1 Genotype (Including Gilbert’s Syndrome)Identifying Patients at Risk for Irinotecan (Camptosar) Myelotoxicity Based on UGT1A1 Genotype (Including Gilbert’s Syndrome)
  • Methotrexate Toxicity and MTHFR (Methelenetetrahydrofolate Reductase) C677T PolymorphismMethotrexate Toxicity and MTHFR (Methelenetetrahydrofolate Reductase) C677T Polymorphism
  • Efavirenz Dose Reduction in an HIV-1 Infected Patient Based on CYP2B6 GenotypeEfavirenz Dose Reduction in an HIV-1 Infected Patient Based on CYP2B6 Genotype
  • Nomogram for Predicting Severe Toxicity Associated with Fluorouracil (5-FU) TherapyNomogram for Predicting Severe Toxicity Associated with Fluorouracil (5-FU) Therapy
  • Screening to Identify an Asian Patient at Risk for Carbamazepine-Associated Stevens-Johnson SyndromeScreening to Identify an Asian Patient at Risk for Carbamazepine-Associated Stevens-Johnson Syndrome

Differential Diagnosis

One of the challenges in dealing with a possible pharmacogenetic situation is excluding all of the conditions that can look like it. It becomes more of a challenge when more than one problem is present. The differential diagnosis includes:

  1. Drug or food interactions affecting the cytochrome P450 system
  2. Differences between generic and brand name formulations
  3. Nonadherence or overadherence
  4. Comorbid kidney or liver disease
  5. A prescription error
  6. Drug malabsorption
  7. Drug hypersensitivity
  • Warfarin Resistance Associated with Poor Intestinal AbsorptionWarfarin Resistance Associated with Poor Intestinal Absorption
  • Adjustment in Daily Warfarin Dose for a Patient Receiving Long-Term Amiodarone TherapyAdjustment in Daily Warfarin Dose for a Patient Receiving Long-Term Amiodarone Therapy

Workup

Usually testing related to pharmacogenetics is done after other explanations have been ruled out. This is because testing may not be readily available or it may be expensive. The good news is that once testing is done then it usually does not need to be repeated. Another benefit is that a positive result can help to identify family members who may also be at risk, simplifying their care.

Take-Home Messages

A person’s genetics can influence how the person responds to a medication. Medical algorithms can help a clinician navigate issues that are unfamiliar or expensive to solve.


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