Bristol-Myers Squibb Co and Sanofi, the manufacturers of Plavix (clopidogrel) have been ordered to pay over $834 million to the state of Hawaii after failing to warn about the drug’s potential health risks to patients with combinations of CYP2C19 variants which result in a CYP2C19 poor metabolizer status. Clopidogrel is metabolized to its active metabolite by CYP2C19, as shown in the PharmGKB clopidogrel pathway. Patients carrying CYP2C19 no function alleles (e.g. CYP2C19*2) have reduced or no conversion of clopidogrel to the active metabolite, which puts them at an increased risk of cardiovascular events. The CPIC guideline for clopidogrel recommends that CYP2C19 intermediate and poor metabolizers receive alternative antiplatelet therapy. The companies were found to have violated Hawaii’s consumer protection laws by not disclosing that Plavix would be ineffective for as many as 30% of patients in Hawaii, many of whom are of Asian and Pacific Islander descent. Some CYP2C19 no function variants, such as CYP2C19*2, are found at higher frequencies in Asian and Pacific Islander populations compared to their frequency in European populations (see the CYP2C19 allele frequency table). Judge Dean Ochiai ruled that Bristol-Myers Squibb Co and Sanofi “knowingly placed Plavix patients at grave risk of serious injury or death in order to substantially increase their profits” over a 12-year period from 1998 to 2010. Information about the effect of CYP2C19 no function alleles on the efficacy of Plavix was added to the drug label in 2009, and a Black Box warning to consider alternate therapy for CYP2C19 poor metabolizers was added in 2010. PharmGKB has annotated the Plavix label and highlights pharmacogenomic information found within the label. Hawaii Attorney General Clare Connors emphasized the growing impact of pharmacogenomics on the pharmaceutical industry: “The order entered by the court today puts the pharmaceutical industry on notice that it will be held accountable for conduct that deceives the public and places profit above safety”. In a joint statement, the companies said that “the overwhelming body of scientific evidence demonstrates that Plavix is a safe and effective therapy, including for people of Asian descent.” and that they plan to appeal. Posted by Rachel Huddart, Curator , CPIC https://www.nasdaq.com/articles/bristol-myers-sanofi-ordered-to-pay-%24834-mln-over-plavix-in-hawaii-2021-02-16
Preparation of a clinical studyThe Parker Institute and Genetelligence is in collaboration about a new clinical study with the purpose to investigate safety of pharmacogenetic-guided methotrexate treatment versus standard of care. A pilot study is currently running to perform consept mapping in relevance to PMP before the clinical study can be initiated.Read more about concept mapping by e.g., Trochim and Kane. Concept mapping: an introduction to structured conceptualization in health care. International Journal for Quality in Health Care 2005; Volume 17, Number 3: pp. 187-191.
A Danish register study shows that 49 drugs have "actionable guidelines" related to CYP2C6 and CYP2C19 corresponding 14.5% of the total sales in DDD. Pantoprazole, lansoprazole, omeprazole, clopidogrel and metoprolol constituted fifty-eight percent of the consumption in DDD of drugs having "actionable guidelines". The consumption of antidepressant drugs, opioides, and antipsychotic drugs were 441.850 users, 427.765 users and 128.935 users, respectively. Age distribution of consumption of drugs and drug combinations e.g., for sertraline redeemed either alone or in combination with metoprolol and tramadol, are presented in the study. The exploratory register study clearly showed that a large fraction of the Danish population, especially the elderly, are exposed to drugs or drug combinations for which there excist "actionable guidelines" related to CYP2C6 AND CYP2C19. Westergaard et al. J. Pers.Med 2020, 10(3); doi:10.3390/jpm10010003
Pharmacogenomics can play an important role in identifying responders and non-responders to medications, avoiding adverse events, and optimizing drug dose. Drug labeling may contain information on genomic biomarkers and can describe: Drug exposure and clinical response variability Risk for adverse events Genotype-specific dosing Mechanisms of drug action Polymorphic drug target and disposition genes Trial design features https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling
Around 9 million of the 17 million individuals aged ≥65 years in Germany potentially have an elevated risk for adverse drug reactions and 4.6 million potentially have a highly elevated risk. Analyses were based on the first 5,000 participants of the Rhineland Study (mean age 55 years; 57% women). Of our participants, 66.0% reported the use of a drug regularly, which increased to 87.4% in participants aged ≥65 years (n=1,301). The use of polypharmacy, potentially inappropriate medication, and pharmacogenomic drugs was 15.9%, 6.4%, and 20.5%, respectively. In participants <65 years, 16.0% (95%CI 14.8;17.3) had at least one risk factor. In participants aged ≥65 years, 54.1% (95%CI 51.4;56.8) had at least one, and 27.4% (95%CI 25.0;29.9) had at least two risk factors. Extrapolating these numbers to the German population implies, that around 9 of the 17 million individuals aged 65 years or older are potentially at an elevated risk for adverse drug reactions, of which 4.6 million are at a potentially highly elevated risk for adverse drug reactions. Conclusion: Our study shows that drug use is common and the individual risk for an adverse drug reaction in our population is high. This suggests room for improvement in general medication use. Please cite this article as doi: 10.1111/bcp.14671 (article accepted for review) Polypharmacy, potentially inappropriate medication, and pharmacogenomics drug exposure in the Rhineland Study. Short running title: Suboptimal drug use and adverse effect risk Folgerdiena M de Vries1, Julia C Stingl2, and Monique M B Breteler1,3 The authors confirm that the PI for this paper is Monique M. B. Breteler. 1. Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany 2. Institute of Clinical Pharmacology University Hospital of RWTH Aachen, Germany. 3. Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Bonn, Germany
There are multiple causes of adverse drug reactions, some of which are preventable. Pharmacogenomics accounts for app. 80% variability in drug efficacy and safety. Over 400 genes are clinically relevant in drug metabolism, and app. 200 pharmagenes are associated with adverse drug reactions. The condition of extensive metabolizer in the european (caucasian) population is lower than 20%, and about 60% of patients are exposed to potential adverse drug reactions. Expert opinion: The regulatory Agencies should make recommendations to the pharmaceutical industry in favor of the introduction of pharmacogenomics in drug development and the inclusion of pharmacogenomic information on drug labels, with specific warnings for the population at risk. Expert Review of Clinical Pharmacology 2019, vol 12, No. 5, 407-442, Taylor & Francis Group.