Pharmacogenomics
Clopidogrel Therapy and <em>CYP2C19</em> Genotype
2012 Mar 8 [updated 2022 Dec 1]. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.
ABSTRACT
Clopidogrel (brand name Plavix) is an antiplatelet medicine that reduces the risk of myocardial infarction (MI) and stroke in individuals with acute coronary syndrome (ACS), and in individuals with atherosclerotic vascular disease (indicated by a recent MI or stroke, or established peripheral arterial disease) (1). Clopidogrel is also indicated in combination with aspirin for individuals undergoing percutaneous coronary interventions (PCI), including stent placement.
The effectiveness of clopidogrel depends on its conversion to an active metabolite, which is accomplished by the cytochrome P450 2C19 (CYP2C19) enzyme. Individuals who have 2 loss-of-function copies of the CYP2C19 gene are classified as CYP2C19 poor metabolizers (PM). Individuals with a CYP2C19 PM phenotype have significantly reduced enzyme activity and cannot activate clopidogrel via CYP2C19, which means the drug will have a reduced antiplatelet effect. Approximately 2% of Caucasians, 4% of African Americans, 14% of Chinese, and 57% of Oceanians are CYP2C19 PMs (2). The effectiveness of clopidogrel is also reduced in individuals who are CYP2C19 intermediate metabolizers (IM). These individuals have one loss-of-function copy of CYP2C19, with either one normal function copy or one increased function copy. The frequency of the IM phenotype is more than 45% in individuals of East Asian descent, more than 40% in individuals of Central or South Asian descent, 36% in the Oceanian population, approximately 30% in individuals of African descent, 20–26% in individuals of American, European, or Near Eastern descent, and just under 20% in individuals of Latino descent (2).
The 2022 FDA-approved drug label for clopidogrel includes a boxed warning on the diminished antiplatelet effect of clopidogrel in CYP2C19 PMs (Table 1). The warning states that tests are available to identify individuals who are CYP2C19 PMs, and to consider the use of another platelet P2Y12 (purinergic receptor P2Y, G-protein coupled 12) inhibitor in individuals identified as CYP2C19 PMs.
The 2022 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for clopidogrel recommends that for individuals with ACS or non-ACS indications who are undergoing PCI, being treated for peripheral arterial disease (PAD), or stable coronary artery disease following MI, an alternative antiplatelet therapy (for example, prasugrel or ticagrelor) should be considered for CYP2C19 PMs if there is no contraindication (Table 2) (3). Similarly, CPIC strongly recommends that CYP2C19 IMs should avoid clopidogrel for ACS or PCI but makes no recommendations for other cardiovascular indications (Table 2). For neurovascular indications, CPIC recommends avoidance of clopidogrel for CYP2C19 PMs and consideration of alternative medications for both IMs and PMs if not contraindicated (Table 3) (3).
The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) have also made antiplatelet therapy recommendations based on CYP2C19 genotype. For individuals with ACS who undergo PCI, they recommend an alternative antiplatelet agent in PMs, and for IMs they recommend choosing an alternative antiplatelet agent or doubling the dose of clopidogrel to 150 mg daily dose, 600 mg loading dose (Table 4) (4).
Oxycodone Therapy and <em>CYP2D6</em> Genotype
2022 Oct 4. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kane MS, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012–.
ABSTRACT
Oxycodone (brand names OxyContin, Roxicodone, Xtampza ER, and Oxaydo), is an opioid analgesic used for moderate to severe pain caused by various conditions for which alternative analgesic treatments are inadequate.(1) Oxycodone exerts its analgesic affects by binding to the mu-opioid receptors (MOR) in the central and peripheral nervous system. While it is an effective pain reliever, this agent also has a high potential for addiction, abuse, and misuse.
Oxycodone is metabolized by members of the cytochrome P450 (CYP) enzyme superfamily. The CYP3A4, CYP3A5, and CYP2D6 enzymes convert oxycodone to either less-active (CYP3A4 and CYP3A5) or more-active (CYP2D6) metabolites. Most of the analgesic effect is mediated by oxycodone itself, rather than its metabolites. Variation at the CYP3A4 and CYP3A5 loci leading to altered enzyme activity is rare. A handful of altered-function alleles are known, but there is no documented evidence to support altered oxycodone response in the presence of these variant alleles. The FDA approved drug label for oxycodone cautions that co-medication with CYP3A inhibitors or inducers may lead to altered pharmacokinetics and analgesia, but does not discuss genotype-based recommendations for prescribing (1).
Genetic variation at the CYP2D6 locus has conflicting evidence regarding altered response of individuals to oxycodone therapy. Thus, the Clinical Pharmacogenetics Implementation Consortium (CPIC) has determined that there is insufficient evidence to recommend alterations to standard clinical use based on CYP2D6 genotype (2). Similarly, the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) recognizes the drug-gene interaction between CYP2D6 and oxycodone but states that the interaction does not affect analgesia achieved by the medication (3, 4). The PharmGKB online resource reports that drug labels in Switzerland (regulated by Swissmedic) state that CYP2D6 variation can alter oxycodone response (5, 6).
Interactions among drugs from polypharmacy may be further enhanced by genetic variation, but there are no professional recommendations to alter prescribing based on drug-drug-gene interactions. Regardless of genotype, oxycodone is contraindicated in individuals with significant respiratory depression, acute or severe bronchial asthma, known or suspect gastrointestinal obstruction, or known hypersensitivity to the medication (1).
Codeine
2021 Aug 16. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006–.
ABSTRACT
Maternal use of codeine during breastfeeding can cause infant drowsiness, central nervous system depression and possibly even death, with pharmacogenetics possibly playing a role.[1,2] Newborn infants seem to be particularly sensitive to the effects of even small dosages of narcotic analgesics. Once the mother's milk comes in, it is best to provide pain control with a nonnarcotic analgesic and limit maternal intake of oral codeine to 2 to 4 days at a low dosage with close infant monitoring, especially in the outpatient setting.[2-4] If the baby shows signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness, a physician should be contacted immediately.[5] Excessive sedation in the mother often correlates with excess sedation in the breastfed infant. Following these precautions can lower the risk of neonatal sedation.[6] Numerous professional organizations and regulatory agencies recommend that other agents are preferred over codeine or to avoid codeine completely during breastfeeding;[7-11] however, other opioid alternatives have been studied less and may not be safer.[12,13]
Dihydrocodeine
2021 Jun 21. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006–.
ABSTRACT
Maternal use of oral narcotics during breastfeeding can cause infant drowsiness, central nervous system (CNS) depression and even death. Like codeine, pharmacogenetics probably plays a role in the extent of CNS depression. Newborn infants seem to be particularly sensitive to the effects of even small dosages of narcotic analgesics. Dihydrocodeine possibly caused severe respiratory depression in one newborn infant whose mother was taking the drug for cough. Once the mother's milk comes in, it is best to provide pain control with a nonnarcotic analgesic and limit maternal intake of hydromorphone to a few days at a low dosage with close infant monitoring. If the baby shows signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness, a physician should be contacted immediately. Because there is little published experience with dihydrocodeine during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.