genome-wide association; metamizole; metabolic toxicity; drug-induced agranulocytosis; immune-mediated toxicity
Bachmann Fabio, Blaser Lea, Haschke Manuel, Krähenbühl Stephan, Duthaler Urs (2020), Development and validation of an LC–MS/MS method for the bioanalysis of the major metamizole metabolites in human plasma, in Bioanalysis
, 12(3), 175-189.
Rudin Deborah, Spoendlin Julia, Cismaru Anca L., Liakoni Evangelia, Bonadies Nicolas, Amstutz Ursula, Meier Christoph R., Krähenbühl Stephan, Haschke Manuel (2019), Metamizole-associated neutropenia: Comparison of patients with neutropenia and metamizole-tolerant patients, in European Journal of Internal Medicine
, 68, 36-43.
Rudin Deborah, Roos Noëmi Johanna, Duthaler Urs, Krähenbühl Stephan (2019), Toxicity of metamizole on differentiating HL60 cells and human neutrophil granulocytes, in Toxicology
, 426, 152254-152254.
Rudin Deborah, Lanzilotto Angelo, Bachmann Fabio, Housecroft Catherine E, Constable Edwin C, Drewe Jürgen, Haschke Manuel, Krähenbühl Stephan (2019), Non-immunological toxicological mechanisms of metamizole-associated neutropenia in HL60 cells., in Biochemical pharmacology
, 163, 345-356.
Bachmann Fabio, Duthaler Urs, Rudin Deborah, Krähenbühl Stephan, Haschke Manuel (2018), N -demethylation of N -methyl-4-aminoantipyrine, the main metabolite of metamizole, in European Journal of Pharmaceutical Sciences
, 120, 172-180.
Metamizole is an analgesic and antipyretic drug widely used in many parts of the world, including European countries such as Germany, France and Switzerland. Although metamizole has a favorable overall safety profile, susceptible patients can experience agranulocytosis, a severe and potentially fatal loss of neutrophil granulocytes. This serious adverse drug reaction has led to the withdrawal of metamizole from the market in some countries. However, drug withdrawal is not an optimal solution, as metamizole, due to its favorable gastrointestinal and renal tolerability is a valuable treatment option for patients intolerant to conventional non-steroidal antiinflammatory drugs. This has led to a continuous rise in metamizole prescriptions in recent years, paralleled by a growing number of safety reports on metamizole-induced hematologic toxicity, including multiple cases with fatal outcome. Despite the use of broad-spectrum antibiotics and granulocyte growth factors, the fatality rate of metamizole-induced agranulocytosis is approximately 10%. The increasing use of metamizole and the severity of its hematologic toxicity highlight the need to improve the safety of metamizole treatment.To date, the mechanisms underlying metamizole-induced agranulocytosis are poorly understood. Whilesome evidence points to immune-mediated mechanisms, other observations, such as the rapid onset of the adverse reaction in some patients and the observation that bi-and pancytopenia can occur, favor a direct toxic mechanism on hematopoiesis. Since hematotoxicity of metamizole is an idiosyncratic adverse reaction (i.e. rare manifestation at therapeutic dose), affected patients must have susceptibility factors. Regardless of the mechanism of toxicity, individual susceptibility risk may be determined by genetic factors.To improve the safety of the growing number of patients treated with metamizole, a better understanding of such susceptibility factors is needed. We therefore propose a project for the comprehensive investigation of the mechanisms and genetics of metamizole-induced agranulocytosis, with the goal of identifying susceptibility factors that would allow efficient pre-treatment risk stratification. Similar approaches have already successfully been implemented for other drugs (e.g. abacavir, carbamazepine, azathioprine), resulting in a major improvement of their benefit-risk profile and preventing their removal from the market.In our project, we plan to investigate in the first part, whether A) direct metabolic toxicity or B) immune-mediatedmechanisms can lead to metamizole-induced agranulocytosis. In the second part, we will conduct a case-control association study to identify genetic risk factors. To this aim, we will compare a unique case cohort of patients who suffered metamizole-induced agranulocytosis with metamizole-tolerant and matched population controls. Using recent genotyping and sequencing technology, we plan to use a complementary approach of a targeted, comprehensive investigation of HLA genomic regions often implicated in immunemediated drug reactions, and a genome-wide analysis of genetic variation to investigate novel pathways potentially involved in metamizole-induced agranulocytosis.By comprehensively investigating underlying mechanisms and the potential genetic basis of metamizoleinduced agranulocytosis, this project is expected to generate important new knowledge regarding factors associated with susceptibility to this serious adverse drug reaction. The results of the project will facilitate informed clinical decision-making and have direct implications for patient safety and the healthcare system, both by preventing exposure of at-risk patients and by saving expenses for the treatment of affected patients.