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1,384 results on '"Pirmohamed M"'

1. Drug–Drug–Gene Interactions in Cardiovascular Medicine

Author

Asiimwe IG and Pirmohamed M

Subjects
drug–drug interactions, drug–gene interactions, drug–drug–gene interactions, drug–gene–gene interactions, pharmacogenomics, Therapeutics. Pharmacology, RM1-950
Abstract

Innocent G Asiimwe, Munir Pirmohamed The Wolfson Centre for Personalized Medicine, MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UKCorrespondence: Innocent G Asiimwe; Munir Pirmohamed, Tel +44 151 7955387 ; +44 151 794 5549, Fax +44 151 794 5059, Email i.asiimwe@liverpool.ac.uk; munirp@liverpool.ac.ukAbstract: Cardiovascular disease remains a leading cause of both morbidity and mortality worldwide. It is widely accepted that both concomitant medications (drug–drug interactions, DDIs) and genomic factors (drug–gene interactions, DGIs) can influence cardiovascular drug-related efficacy and safety outcomes. Although thousands of DDI and DGI (aka pharmacogenomic) studies have been published to date, the literature on drug–drug–gene interactions (DDGIs, cumulative effects of DDIs and DGIs) remains scarce. Moreover, multimorbidity is common in cardiovascular disease patients and is often associated with polypharmacy, which increases the likelihood of clinically relevant drug-related interactions. These, in turn, can lead to reduced drug efficacy, medication-related harm (adverse drug reactions, longer hospitalizations, mortality) and increased healthcare costs. To examine the extent to which DDGIs and other interactions influence efficacy and safety outcomes in the field of cardiovascular medicine, we review current evidence in the field. We describe the different categories of DDIs and DGIs before illustrating how these two interact to produce DDGIs and other complex interactions. We provide examples of studies that have reported the prevalence of clinically relevant interactions and the most implicated cardiovascular medicines before outlining the challenges associated with dealing with these interactions in clinical practice. Finally, we provide recommendations on how to manage the challenges including but not limited to expanding the scope of drug information compendia, interaction databases and clinical implementation guidelines (to include clinically relevant DDGIs and other complex interactions) and work towards their harmonization; better use of electronic decision support tools; using big data and novel computational techniques; using clinically relevant endpoints, preemptive genotyping; ensuring ethnic diversity; and upskilling of clinicians in pharmacogenomics and personalized medicine.Keywords: drug–drug interactions, drug–gene interactions, drug–drug–gene interactions, drug–gene–gene interactions, pharmacogenomics

Published
2022

2. Chromosomal Region 11p14.1 is Associated with Pharmacokinetics and Pharmacodynamics of Bisoprolol

Author

Fontana V, Turner RM, Francis B, Yin P, Pütz B, Hiltunen TP, Ruotsalainen S, Kontula KK, Müller-Myhsok B, and Pirmohamed M

Subjects
bisoprolol, pharmacokinetics, genome-wide association., Therapeutics. Pharmacology, RM1-950
Abstract

Vanessa Fontana,1,2 Richard Myles Turner,1,2 Ben Francis,3 Peng Yin,3 Benno Pütz,4 Timo P Hiltunen,5 Sanni Ruotsalainen,6 Kimmo K Kontula,5 Bertam Müller-Myhsok,1,4 Munir Pirmohamed1,2,7 1The Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; 2MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK; 3Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; 4Max Planck Institute of Psychiatry, Munich, Germany; 5Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 6Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, Helsinki, Finland; 7Royal Liverpool and Broadgreen University Hospitals NHS Trust, and Liverpool Health Partners, Liverpool, UKCorrespondence: Vanessa Fontana, MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Block A: Waterhouse Buildings, 1-5 Brownlow Street, Liverpool, L69 3GL, UK, Fax +44 151 794 5059, Email V.Fontana@liverpool.ac.ukPurpose: Bisoprolol is a widely used beta-blocker in patients with cardiovascular diseases. As with other beta-blockers, there is variability in response to bisoprolol, but the underlying reasons for this have not been clearly elucidated. Our aim was to investigate genetic factors that affect bisoprolol pharmacokinetics (PK) and pharmacodynamics (PD), and potentially the clinical outcomes.Patients and Methods: Patients with non-ST elevation acute coronary syndrome were recruited prospectively on admission to hospital and followed up for up to 2 years. Patients from this cohort who were on treatment with bisoprolol, at any dose, had bisoprolol adherence data and a plasma sample, one month after discharge from index hospitalisation were included in the study. Individual bisoprolol clearance values were estimated using population pharmacokinetic modeling. Genome-wide association analysis after genotyping was undertaken using an Illumina HumanOmniExpressExome-8 v1.0 BeadChip array, while CYP2D6 copy number variations were determined by PCR techniques and phenotypes for CYP2D6 and CYP3A were inferred from the genotype. GWAS significant SNPs were analysed for heart rate response to bisoprolol in an independent cohort of hypertensive subjects.Results: Six hundred twenty-two patients on bisoprolol underwent both PK and genome wide analysis. The mean (IQR) of the estimated clearance in this population was 13.6 (10.0– 18.0) L/h. Bisoprolol clearance was associated with rs11029955 (p=7.17× 10− 9) mapped to the region of coiled-coil domain containing 34 region (CCDC34) on chromosome 11, and with rs116702638 (p=2.54× 10− 8). Each copy of the minor allele of rs11029955 was associated with 2.2 L/h increase in clearance. In an independent cohort of hypertensive subjects, rs11029955 was associated with 24-hour heart rate response to 4-week treatment with bisoprolol (p= 9.3× 10− 5), but not with rs116702638.Conclusion: A novel locus on the chromosomal region 11p14.1 was associated with bisoprolol clearance in a real-world cohort of patients and was validated in independent cohort with a pharmacodynamic association.Keywords: bisoprolol, pharmacokinetics, genome-wide association

Published
2022

3. The HLA-A*31:01 allele: influence on carbamazepine treatment

Author

Yip VLM and Pirmohamed M

Subjects
Carbamazepine, hypersensitivity, pharmacogenetics, HLA, Therapeutics. Pharmacology, RM1-950
Abstract

Vincent Lai Ming Yip,1,2 Munir Pirmohamed1,2 1MRC Centre for Drug Safety Science, Institute of Translational Medicine, Department of Molecular and Clinical Pharmacology, University of Liverpool, 2Department of Clinical Pharmacology,The Royal Liverpool and Broadgreen University Hospital NHS Trust, Liverpool, UK Abstract: Carbamazepine (CBZ) is an effective anticonvulsant that can sometimes cause hypersensitivity reactions that vary in frequency and severity. Strong associations have been reported between specific human leukocyte antigen (HLA) alleles and susceptibility to CBZ hypersensitivity reactions. Screening for HLA-B*15:02 is mandated in patients from South East Asia because of a strong association with Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). HLA-A*31:01 predisposes to multiple phenotypes of CBZ hypersensitivity including maculopapular exanthema, hypersensitivity syndrome, and SJS/TEN in a range of populations including Europeans, Japanese, South Koreans and Han Chinese, although the effect size varies between the different phenotypes and populations. Between 47 Caucasians and 67 Japanese patients would need to be tested for HLA-A*31:01 in order to avoid a single case of CBZ hypersensitivity. A cost-effectiveness study has demonstrated that HLA-A*31:01 screening would be cost-effective. Patient preference assessment has also revealed that patients prefer pharmacogenetic screening and prescription of alternative anticonvulsants compared to current standard of practice without pharmacogenetic testing. For patients who test positive for HLA-A*31:01, alternative treatments are available. When alternatives have failed or are unavailable, HLA-A*31:01 testing can alert clinicians to 1) patients who are at increased risk of CBZ hypersensitivity who can then be targeted for more intensive monitoring and 2) increase diagnostic certainty in cases where hypersensitivity has already occurred, so patients can be advised to avoid structurally related drugs in the future. On the basis of the current evidence, we would favor screening all patients for HLA-A*31:01 and HLA-B*15:02 prior to starting CBZ therapy. Keywords: carbamazepine, oxcarbazepine, hypersensitivity, adverse drug reaction, pharmacogenetics, HLA

Published
2017

9. ST13 polymorphisms and their effect on exacerbations in steroid‐treated asthmatic children and young adults

Author

Vijverberg, SJH, Koster, ES, Tavendale, R, Leusink, M, Koenderman, L, Raaijmakers, JAM, Postma, DS, Koppelman, GH, Turner, SW, Mukhopadhyay, S, Tse, SM, Tantisira, KG, Hawcutt, DB, Francis, B, Pirmohamed, M, Pino-Yanes, M, Eng, C, Burchard, EG, Palmer, CNA, and Maitland-van der Zee, AH

Subjects
Biomedical and Clinical Sciences, Immunology, Clinical Research, Lung, Pediatric, Asthma, Genetics, Aetiology, 2.1 Biological and endogenous factors, Respiratory, Adolescent, Adrenal Cortex Hormones, Anti-Asthmatic Agents, Carrier Proteins, Child, Child, Preschool, Cohort Studies, Disease Progression, Female, Humans, Male, Odds Ratio, Polymorphism, Single Nucleotide, Treatment Outcome, Tumor Suppressor Proteins, Young Adult, childhood asthma, corticosteroids, exacerbations, pharmacogenomics, ST13, Nutrition and Dietetics, Public Health and Health Services, Allergy
Abstract

BackgroundThe clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS.MethodsWe performed a meta-analysis of three cohort studies: Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory effects (n = 357, age: 4-12 years, the Netherlands), BREATHE (n = 820, age: 3-22 years, UK) and Paediatric Asthma Gene Environment Study (n = 391, age: 2-16 years, UK). Seventeen genes were selected based on a role in the glucocorticoid signalling pathway or a reported association with asthma. Two outcome parameters were used to reflect exacerbations: hospital visits and oral corticosteroid (OCS) use in the previous year. The most significant associations were tested in three independent validation cohorts; the Childhood Asthma Management Programme (clinical trial, n = 172, age: 5-12 years, USA), the Genes- environment and Mixture in Latino Americans II- study (n = 745, age: 8-21, USA) and the Pharmacogenetics of adrenal suppression cohort (n = 391, age: 5-18, UK) to test the robustness of the findings. Finally, all results were meta-analysed.ResultsTwo SNPs in ST13 (rs138335 and rs138337), but not in the other genes, were associated at a nominal level with an increased risk of exacerbations in asthmatics using ICS in the three cohorts studied. In a meta-analysis of all six studies, ST13 rs138335 remained associated with an increased risk of asthma-related hospital visits and OCS use in the previous year; OR = 1.22 (P = 0.013) and OR = 1.22 (P = 0.0017), respectively.Conclusion and clinical relevanceA novel susceptibility gene, ST13, coding for a cochaperone of the glucocorticoid receptor, is associated with exacerbations in asthmatic children and young adults despite their ICS use. Genetic variation in the glucocorticoid signalling pathway may contribute to the interindividual variability in clinical response to ICS treatment in children and young adults.

Published
2015

10. Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA‐B Genotype and Abacavir Dosing: 2014 Update

Author

Martin, MA, Hoffman, JM, Freimuth, RR, Klein, TE, Dong, BJ, Pirmohamed, M, Hicks, JK, Wilkinson, MR, Haas, DW, and Kroetz, DL

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Genetics, Good Health and Well Being, Anti-HIV Agents, Dideoxynucleosides, Electronic Health Records, Genotype, HLA-B Antigens, Humans, Pharmacogenetics, Clinical Pharmacogenetics Implementation Consortium, Pharmacology & Pharmacy, Pharmacology and pharmaceutical sciences
Abstract

The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA-B Genotype and Abacavir Dosing were originally published in April 2012. We reviewed recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplementary Material online and included additional resources for applying CPIC guidelines to the electronic health record. Up-to-date information can be found at PharmGKB (http://www.pharmgkb.org).

Published
2014

15. A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study

Author

Swen, J. J., van der Wouden, C. H., Manson, L. E., Abdullah-Koolmees, H., Blagec, K., Blagus, T., Bohringer, S., Cambon-Thomsen, A., Cecchin, E., Cheung, K. -C., Deneer, V. H., Dupui, M., Ingelman-Sundberg, M., Jonsson, S., Joefield-Roka, C., Just, K. S., Karlsson, M. O., Konta, L., Koopmann, R., Kriek, M., Lehr, T., Mitropoulou, C., Rial-Sebbag, E., Rollinson, V., Roncato, R., Samwald, M., Schaeffeler, E., Skokou, M., Schwab, M., Steinberger, D., Stingl, J. C., Tremmel, R., Turner, R. M., van Rhenen, M. H., Davila Fajardo, C. L., Dolzan, V., Patrinos, G. P., Pirmohamed, M., Sunder-Plassmann, G., Toffoli, G., Guchelaar, H. -J., Buunk, A., Goossens, H., Baas, G., Algera, M., Schuil-Vlassak, E., Ambagts, T., De Hoog-Schouten, L., Musaafir, S., Bosch, R., Tjong, C., Steeman, S., Van der Plas, M., Baldew, G., Den Hollander, I., De Waal, Z., Heijn, A., Nelemans, L., Kouwen-Lubbers, K., Van Leeuwen, M., Hoogenboom, S., Van Doremalen, J., Ton, C., Beetstra, B., Meijs, V., Dikken, J., Dubero, D., Slager, M., Houben, T., Kanis, T., Overmars, W., Nijenhuis, M., Steffens, M., Bergs, I., Karamperis, K., Siamoglou, S., Ivantsik, O., Samiou, G. -C., Kordou, Z., Tsermpini, E., Ferentinos, P., Karaivazoglou, A., Rigas, G., Gerasimou, H., Voukelatou, G., Georgila, E., Tsermpini, E. E., Mendrinou, E., Chalikiopoulou, K., Kolliopoulou, A., Mitropoulos, K., Stratopoulos, A., Liopetas, I., Tsikrika, A., Barba, E., Emmanouil, G., Stamopoulou, T., Stathoulias, A., Giannopoulos, P., Kanellakis, F., Bartsakoulia, M., Katsila, T., Douzenis, A., Gourzis, F., Assimakopoulos, K., Bignucolo, A., Dal Cin, L., Comello, F., Mezzalira, S., Puglisi, F., Spina, M., Foltran, L., Guardascione, M., Buonadonna, A., Bartoletti, M., Corsetti, S., Ongaro, E., Da Ros, L., Bolzonello, S., Spazzapan, S., Freschi, A., Di Nardo, P., Palazzari, E., Navarria, F., Innocente, R., Berretta, M., D'Andrea, M., Angelini, F., Diraimo, T., Favaretto, A., Davila-Fajardo, C. L., Diaz-Villamarin, X., Martinez-Gonzalez, L. J., Antunez-Rodriguez, A., Moreno-Escobar, E., Fernandez-Gonzalez, A. E., Garcia-Navas, P., Bautista-Paves, A. B. P., Burillo-Gomez, F., Villegas-Rodriguez, I., Sanchez-Ramos, J. G., Antolinos-Perez, M. J., Rivera, R., Martinez-Huertas, S., Thomas-, J., Carazo, J. J., Yanez-Sanchez, M. I., Blancas-Lopez-Navajas, R., Garcia-Orta, B., Gonzalez-Astorga, C. J., Rodriguez-Gonzalez, F. J., Ruiz-Carazo, M., Lopez-Perez, I., Cano-Herrera, R., Herrera, T., Gil-Jimenez, Delgado-Urena, M. T., Trivino-Juarez, J. M., Campos-Velazquez, S., Alcantara-Espadafor, S., Moreno Aguilar, M. R., Ontiveros-Ortega, M. C., Carnerero-Cordoba, L., Guerrero-Jimenez, M., Legeren-Alvarez, M., Yelamos-Vargas, M., Castillo-Perez, I., Aomar-Millan, I., Anguita-Romero, M., Sanchez-Garcia, M. J., Sequero-Lopez, S., Faro-Miguez, N., Lopez-Fernandez, S., Leyva-Ferrer, R. N., Herrera-Gomez, N., Pertejo-Manzano, L., Perez-Gutierrez, E. M., Martin-de la Higuera, A. J., Plaza-Carrera, J., Baena-Garzon, F., Toledo-Frias, P., Cruz-Valero, I., Chacon-McWeeny, V., Gallardo-Sanchez, I., Arrebola, A., Guillen-Zafra, L., Ceballos-Torres, A., Guardia-Mancilla, P., Guirao-Arrabal, E., Canterero-Hinojosa, J., Velasco-Fuentes, S., Sanchez-Cano, D., Aguilar-Jaldo, M. D. P., Caballero-Borrego, J., Praznik, M., Slapsak, U., Voncina, B., Rajter, B., Skrinjar, A., Marjetic Ulcakar, A., Zidansek, A., Stegne Ignjatvic, T., Mazej Poredos, B., Vivod Pecnik, Z., Poplas Susic, T., Jutersek, M., Klen, J., Skoporc, J., Kotar, T., Petek Ster, M., Zvezdana Dernovsk, M., Mlinsek, G., Miklavcic, P., Plemenitas Iljes, A., Grasic Kuhar, C., Oblak, I., Strazisar, B., Strbac, D., Matos, E., Mencinger, M., Vrbnjak, M., Saje, M., Radovanovic, M., Jeras, K., Bukovec, L., Terzic, T., Minichmayr, I., Nanah, A., Nielsen, E., Zou, Y., Lauschke, V., Johansson, I., Zhou, Y., Nordling, A., Aigner, C., Dames-Ludwig, M., Monteforte, R., Sunder-Plassmann, R., Steinhauser, C., Sengoelge, G., Winnicki, W., Schmidt, A., Vasileios, F., Fontana, V., Hanson, A., Little, M., Hornby, R., Dello Russo, Cinzia, French, S., Hampson, J., Gumustekin, M., Anyfantis, G., Hampson, L., Lewis, D., Westhead, R., Prince, C., Rajasingam, A., Dello Russo C. (ORCID:0000-0002-2538-3832), Swen, J. J., van der Wouden, C. H., Manson, L. E., Abdullah-Koolmees, H., Blagec, K., Blagus, T., Bohringer, S., Cambon-Thomsen, A., Cecchin, E., Cheung, K. -C., Deneer, V. H., Dupui, M., Ingelman-Sundberg, M., Jonsson, S., Joefield-Roka, C., Just, K. S., Karlsson, M. O., Konta, L., Koopmann, R., Kriek, M., Lehr, T., Mitropoulou, C., Rial-Sebbag, E., Rollinson, V., Roncato, R., Samwald, M., Schaeffeler, E., Skokou, M., Schwab, M., Steinberger, D., Stingl, J. C., Tremmel, R., Turner, R. M., van Rhenen, M. H., Davila Fajardo, C. L., Dolzan, V., Patrinos, G. P., Pirmohamed, M., Sunder-Plassmann, G., Toffoli, G., Guchelaar, H. -J., Buunk, A., Goossens, H., Baas, G., Algera, M., Schuil-Vlassak, E., Ambagts, T., De Hoog-Schouten, L., Musaafir, S., Bosch, R., Tjong, C., Steeman, S., Van der Plas, M., Baldew, G., Den Hollander, I., De Waal, Z., Heijn, A., Nelemans, L., Kouwen-Lubbers, K., Van Leeuwen, M., Hoogenboom, S., Van Doremalen, J., Ton, C., Beetstra, B., Meijs, V., Dikken, J., Dubero, D., Slager, M., Houben, T., Kanis, T., Overmars, W., Nijenhuis, M., Steffens, M., Bergs, I., Karamperis, K., Siamoglou, S., Ivantsik, O., Samiou, G. -C., Kordou, Z., Tsermpini, E., Ferentinos, P., Karaivazoglou, A., Rigas, G., Gerasimou, H., Voukelatou, G., Georgila, E., Tsermpini, E. E., Mendrinou, E., Chalikiopoulou, K., Kolliopoulou, A., Mitropoulos, K., Stratopoulos, A., Liopetas, I., Tsikrika, A., Barba, E., Emmanouil, G., Stamopoulou, T., Stathoulias, A., Giannopoulos, P., Kanellakis, F., Bartsakoulia, M., Katsila, T., Douzenis, A., Gourzis, F., Assimakopoulos, K., Bignucolo, A., Dal Cin, L., Comello, F., Mezzalira, S., Puglisi, F., Spina, M., Foltran, L., Guardascione, M., Buonadonna, A., Bartoletti, M., Corsetti, S., Ongaro, E., Da Ros, L., Bolzonello, S., Spazzapan, S., Freschi, A., Di Nardo, P., Palazzari, E., Navarria, F., Innocente, R., Berretta, M., D'Andrea, M., Angelini, F., Diraimo, T., Favaretto, A., Davila-Fajardo, C. L., Diaz-Villamarin, X., Martinez-Gonzalez, L. J., Antunez-Rodriguez, A., Moreno-Escobar, E., Fernandez-Gonzalez, A. E., Garcia-Navas, P., Bautista-Paves, A. B. P., Burillo-Gomez, F., Villegas-Rodriguez, I., Sanchez-Ramos, J. G., Antolinos-Perez, M. J., Rivera, R., Martinez-Huertas, S., Thomas-, J., Carazo, J. J., Yanez-Sanchez, M. I., Blancas-Lopez-Navajas, R., Garcia-Orta, B., Gonzalez-Astorga, C. J., Rodriguez-Gonzalez, F. J., Ruiz-Carazo, M., Lopez-Perez, I., Cano-Herrera, R., Herrera, T., Gil-Jimenez, Delgado-Urena, M. T., Trivino-Juarez, J. M., Campos-Velazquez, S., Alcantara-Espadafor, S., Moreno Aguilar, M. R., Ontiveros-Ortega, M. C., Carnerero-Cordoba, L., Guerrero-Jimenez, M., Legeren-Alvarez, M., Yelamos-Vargas, M., Castillo-Perez, I., Aomar-Millan, I., Anguita-Romero, M., Sanchez-Garcia, M. J., Sequero-Lopez, S., Faro-Miguez, N., Lopez-Fernandez, S., Leyva-Ferrer, R. N., Herrera-Gomez, N., Pertejo-Manzano, L., Perez-Gutierrez, E. M., Martin-de la Higuera, A. J., Plaza-Carrera, J., Baena-Garzon, F., Toledo-Frias, P., Cruz-Valero, I., Chacon-McWeeny, V., Gallardo-Sanchez, I., Arrebola, A., Guillen-Zafra, L., Ceballos-Torres, A., Guardia-Mancilla, P., Guirao-Arrabal, E., Canterero-Hinojosa, J., Velasco-Fuentes, S., Sanchez-Cano, D., Aguilar-Jaldo, M. D. P., Caballero-Borrego, J., Praznik, M., Slapsak, U., Voncina, B., Rajter, B., Skrinjar, A., Marjetic Ulcakar, A., Zidansek, A., Stegne Ignjatvic, T., Mazej Poredos, B., Vivod Pecnik, Z., Poplas Susic, T., Jutersek, M., Klen, J., Skoporc, J., Kotar, T., Petek Ster, M., Zvezdana Dernovsk, M., Mlinsek, G., Miklavcic, P., Plemenitas Iljes, A., Grasic Kuhar, C., Oblak, I., Strazisar, B., Strbac, D., Matos, E., Mencinger, M., Vrbnjak, M., Saje, M., Radovanovic, M., Jeras, K., Bukovec, L., Terzic, T., Minichmayr, I., Nanah, A., Nielsen, E., Zou, Y., Lauschke, V., Johansson, I., Zhou, Y., Nordling, A., Aigner, C., Dames-Ludwig, M., Monteforte, R., Sunder-Plassmann, R., Steinhauser, C., Sengoelge, G., Winnicki, W., Schmidt, A., Vasileios, F., Fontana, V., Hanson, A., Little, M., Hornby, R., Dello Russo, Cinzia, French, S., Hampson, J., Gumustekin, M., Anyfantis, G., Hampson, L., Lewis, D., Westhead, R., Prince, C., Rajasingam, A., and Dello Russo C. (ORCID:0000-0002-2538-3832)

Abstract

Background: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene–drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. Methods: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug–gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug–gene interaction in the study group versus the

Published
2023

16. Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia

Author

Hurkmans, E. G. E., Klumpers, M. J., Dello Russo, Cinzia, De Witte, W., Guchelaar, H. -J., Gelderblom, H., Cleton-Jansen, A. -M., Vermeulen, S. H., Kaal, S., van der Graaf, W. T. A., Flucke, U., Gidding, C. E. M., Schreuder, H. W. B., de Bont, E. S. J. M., Caron, H. N., Gattuso, G., Schiavello, E., Terenziani, M., Massimino, M., Mccowage, G., Nagabushan, S., Limaye, A., Rose, V., Catchpoole, D., Jorgensen, A. L., Barton, C., Delaney, L., Hawcutt, D. B., Pirmohamed, M., Pizer, B., Coenen, M. J. H., te Loo, D. M. W. M., Dello Russo C. (ORCID:0000-0002-2538-3832), Hurkmans, E. G. E., Klumpers, M. J., Dello Russo, Cinzia, De Witte, W., Guchelaar, H. -J., Gelderblom, H., Cleton-Jansen, A. -M., Vermeulen, S. H., Kaal, S., van der Graaf, W. T. A., Flucke, U., Gidding, C. E. M., Schreuder, H. W. B., de Bont, E. S. J. M., Caron, H. N., Gattuso, G., Schiavello, E., Terenziani, M., Massimino, M., Mccowage, G., Nagabushan, S., Limaye, A., Rose, V., Catchpoole, D., Jorgensen, A. L., Barton, C., Delaney, L., Hawcutt, D. B., Pirmohamed, M., Pizer, B., Coenen, M. J. H., te Loo, D. M. W. M., and Dello Russo C. (ORCID:0000-0002-2538-3832)

Abstract

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value <10-5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p-value 5.0 × 10-7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.

Published
2023

17. Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia

Author

Hurkmans, E.G.E., Klumpers, M.J., Dello Russo, C., Witte, W. de, Guchelaar, H.J., Gelderblom, H., Cleton-Jansen, A.M., Vermeulen, S.H., Kaal, S., Graaf, W.T.A. van der, Flucke, U., Gidding, C.E.M., Schreuder, H.W.B., Bont, E.S.J.M. de, Caron, H.N., Gattuso, G., Schiavello, E., Terenziani, M., Massimino, M., McCowage, G., Nagabushan, S., Limaye, A., Rose, V., Catchpoole, D., Jorgensen, A.L., Barton, C., Delaney, L., Hawcutt, D.B., Pirmohamed, M., Pizer, B., Coenen, M.J.H., and Loo, D.M.W.M. te

Subjects
Pharmacology, Settore BIO/14 - FARMACOLOGIA, TSPAN5, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], cisplatin, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10], ototoxicity, All institutes and research themes of the Radboud University Medical Center, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], carboplatin, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], childhood cancer, GWAS, Pharmacology (medical), Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value −5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5–2.7), p-value 5.0 × 10−7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.

Published
2023

21. Multi-ancestral meta-analysis yields novel genetic loci for asthma exacerbations

Author

Herrera Luis, E, primary, Ortega, V E, additional, Ampleford, E J, additional, Sio, Y Y, additional, Granell, R, additional, De Roos, E, additional, Terzikhan, N, additional, Elorduy Vergara, E, additional, Hernandez-Pacheco, N, additional, Perez-Garcia, J, additional, Martin-Gonzalez, E, additional, Lorenzo-Diaz, F, additional, Hashimoto, S, additional, Brinkman, P, additional, Jorgensen, A L, additional, Yan, Q, additional, Forno, E, additional, Vijverberg, S J, additional, Lethem, R, additional, Espuela-Ortiz, A, additional, Gorenjak, M, additional, Eng, C, additional, González-Pérez, R, additional, Hernández-Pérez, J M, additional, Poza-Guedes, P, additional, Sardón, O, additional, Corcuera, P, additional, Hawkins, G A, additional, Marsico, A, additional, Bahmer, T, additional, Rabe, K F, additional, Hansen, G, additional, Kopp, M V, additional, Rios, R, additional, Cruz, M J, additional, González-Barcala, F, additional, Olaguibel, J M, additional, Plaza, V, additional, Quirce, S, additional, Canino, G, additional, Cloutier, M, additional, Del Pozo, V, additional, Rodriguez-Santana, J R, additional, Korta-Murua, J, additional, Villar, J, additional, Potočnik, U, additional, Figueiredo, C, additional, Kabesch, M, additional, Mukhopadhyay, S, additional, Pirmohamed, M, additional, Hawcutt, D B, additional, Melén, E, additional, Palmer, C N, additional, Turner, S, additional, Maitland-Van Der Zee, A H, additional, Von Mutius, E, additional, Celedón, J C, additional, Brusselle, G, additional, Chew, F T, additional, Bleecker, E, additional, Meyers, D, additional, G Burchard, E, additional, and Pino-Yanes, M, additional

Published
2022
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22. Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia.

Author

Hurkmans, EGE, Klumpers, MJ, Dello Russo, C, De Witte, W, Guchelaar, H-J, Gelderblom, H, Cleton-Jansen, A-M, Vermeulen, SH, Kaal, S, van der Graaf, WTA, Flucke, U, Gidding, CEM, Schreuder, HWB, de Bont, ESJM, Caron, HN, Gattuso, G, Schiavello, E, Terenziani, M, Massimino, M, McCowage, G, Nagabushan, S, Limaye, A, Rose, V, Catchpoole, D, Jorgensen, AL, Barton, C, Delaney, L, Hawcutt, DB, Pirmohamed, M, Pizer, B, Coenen, MJH, Te Loo, DMWM, Hurkmans, EGE, Klumpers, MJ, Dello Russo, C, De Witte, W, Guchelaar, H-J, Gelderblom, H, Cleton-Jansen, A-M, Vermeulen, SH, Kaal, S, van der Graaf, WTA, Flucke, U, Gidding, CEM, Schreuder, HWB, de Bont, ESJM, Caron, HN, Gattuso, G, Schiavello, E, Terenziani, M, Massimino, M, McCowage, G, Nagabushan, S, Limaye, A, Rose, V, Catchpoole, D, Jorgensen, AL, Barton, C, Delaney, L, Hawcutt, DB, Pirmohamed, M, Pizer, B, Coenen, MJH, and Te Loo, DMWM

Abstract

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value <10-5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p-value 5.0 × 10-7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.

Published
2022

25. Implementing Pharmacogenomics in Europe: Design and Implementation Strategy of the Ubiquitous Pharmacogenomics Consortium

Author

van der Wouden, CH, CambonThomsen, A, Cecchin, E, Cheung, KC, DávilaFajardo, CL, Deneer, VH, Dolžan, V, IngelmanSundberg, M, Jönsson, S, Karlsson, MO, Kriek, M, Mitropoulou, C, Patrinos, GP, Pirmohamed, M, Samwald, M, Schaeffeler, E, Schwab, M, Steinberger, D, Stingl, J, SunderPlassmann, G, Toffoli, G, Turner, RM, van Rhenen, MH, Swen, JJ, and Guchelaar, HJ

Published
2017
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28. List of Contributors

Author

Alfirevic, A., primary, Antonarakis, S.E., additional, Bhardwaj, A., additional, Borry, P., additional, Børsting, C., additional, Busi, M.V., additional, Dissanayake, V.H.W., additional, Festenstein, R., additional, Gaff, C.L., additional, Gomez-Casati, D.F., additional, Grisolía, M., additional, Gupta, P., additional, Haworth, A., additional, Kerr, B., additional, Knoppers, B.M., additional, Korf, B., additional, Kumar, D., additional, Lench, N., additional, Lucassen, A., additional, Macciocca, I., additional, Maher, E., additional, Manolio, T.A., additional, McHale, D., additional, Morling, N., additional, Mutreja, A., additional, Penny, M., additional, Pirmohamed, M., additional, Rajput, N.K., additional, Rogers, Y.-H., additional, Savage, H., additional, Saxena, R., additional, Shabani, M., additional, Sharma, V.K., additional, Singh, V., additional, Sirisena, N., additional, Sumathipala, D., additional, van Langen, I., additional, Wettasinghe, K., additional, Whitworth, J., additional, Wise, A.L., additional, and Zhang, C., additional

Published
2016
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29. Pharmacogenomics decision support in the U-PGx project: Results and advice from clinical implementation across seven European countries

Author

Blagec, K., Swen, J.J., Koopmann, R., Cheung, K.C., Crommentuijn-van Rhenen, M., Holsappel, I., Konta, L., Ott, S., Steinberger, D., Xu, H., Cecchin, E., Dolzan, V., Davila-Fajardo, C.L., Patrinos, G.P., Sunder-Plassmann, G., Turner, R.M., Pirmohamed, M., Guchelaar, H.J., Samwald, M., and Ubiquitous Pharmacogenomics Consor

Subjects
Multidisciplinary, Pharmacogenetics, Precision Medicine, Decision Support Systems, Clinical, Software, Retrospective Studies
Abstract

Background The clinical implementation of pharmacogenomics (PGx) could be one of the first milestones towards realizing personalized medicine in routine care. However, its widespread adoption requires the availability of suitable clinical decision support (CDS) systems, which is often impeded by the fragmentation or absence of adequate health IT infrastructures. We report results of CDS implementation in the large-scale European research project Ubiquitous Pharmacogenomics (U-PGx), in which PGx CDS was rolled out and evaluated across more than 15 clinical sites in the Netherlands, Spain, Slovenia, Italy, Greece, United Kingdom and Austria, covering a wide variety of healthcare settings. Methods We evaluated the CDS implementation process through qualitative and quantitative process indicators. Quantitative indicators included statistics on generated PGx reports, median time from sampled upload until report delivery and statistics on report retrievals via the mobile-based CDS tool. Adoption of different CDS tools, uptake and usability were further investigated through a user survey among healthcare providers. Results of a risk assessment conducted prior to the implementation process were retrospectively analyzed and compared to actual encountered difficulties and their impact. Results As of March 2021, personalized PGx reports were produced from 6884 genotyped samples with a median delivery time of twenty minutes. Out of 131 invited healthcare providers, 65 completed the questionnaire (response rate: 49.6%). Overall satisfaction rates with the different CDS tools varied between 63.6% and 85.2% per tool. Delays in implementation were caused by challenges including institutional factors and complexities in the development of required tools and reference data resources, such as genotype-phenotype mappings. Conclusions We demonstrated the feasibility of implementing a standardized PGx decision support solution in a multinational, multi-language and multi-center setting. Remaining challenges for future wide-scale roll-out include the harmonization of existing PGx information in guidelines and drug labels, the need for strategies to lower the barrier of PGx CDS adoption for healthcare institutions and providers, and easier compliance with regulatory and legal frameworks.

Published
2022

31. 825 DEVELOPMENT OF THE ANTICHOLINERGIC MEDICATION INDEX (ACMI)

Author

Best, K, primary, Alderson, S, additional, Alldred, D, additional, Bonnet, L, additional, Buchan, I, additional, Butters, O, additional, Farrin, A, additional, Foy, R, additional, Johnson, O, additional, McInerney, C, additional, Mehdizadeh, D, additional, Lawton, T, additional, Lawton, R, additional, Rodgers, S, additional, Teale, E, additional, Walker, L, additional, West, R, additional, Young, B, additional, Pirmohamed, M, additional, and Clegg, A, additional

Published
2022
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45. AGILE: a seamless phase I/IIa platform for the rapid evaluation of candidates for COVID-19 treatment:an update to the structured summary of a study protocol for a randomised platform trial letter

Author

Griffiths, G.O., FitzGerald, R., Jaki, T., Corkhill, A., Reynolds, H., Ewings, S., Condie, S., Tilt, E., Johnson, L., Radford, M., Simpson, C., Saunders, G., Yeats, S., Mozgunov, P., Tansley-Hancock, O., Martin, K., Downs, N., Eberhart, I., Martin, J.W.B., Goncalves, C., Song, A., Fletcher, T., Byrne, K., Lalloo, D.G., Owen, A., Jacobs, M., Walker, L., Lyon, R., Woods, C., Gibney, J., Chiong, J., Chandiwana, N., Jacob, S., Lamorde, M., Orrell, C., Pirmohamed, M., Khoo, S., investigators, on behalf of the AGILE, Griffiths, G.O., FitzGerald, R., Jaki, T., Corkhill, A., Reynolds, H., Ewings, S., Condie, S., Tilt, E., Johnson, L., Radford, M., Simpson, C., Saunders, G., Yeats, S., Mozgunov, P., Tansley-Hancock, O., Martin, K., Downs, N., Eberhart, I., Martin, J.W.B., Goncalves, C., Song, A., Fletcher, T., Byrne, K., Lalloo, D.G., Owen, A., Jacobs, M., Walker, L., Lyon, R., Woods, C., Gibney, J., Chiong, J., Chandiwana, N., Jacob, S., Lamorde, M., Orrell, C., Pirmohamed, M., Khoo, S., and investigators, on behalf of the AGILE

Abstract

Background: There is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pressing need to investigate novel candidates within early phase trial platforms, from which promising candidates can feed into established later phase platforms. AGILE grew from a UK-wide collaboration to undertake early stage clinical evaluation of candidates for SARS-CoV-2 infection to accelerate national and global healthcare interventions. Methods/design: AGILE is a seamless phase I/IIa platform study to establish the optimum dose, determine the activity and safety of each candidate and recommend whether it should be evaluated further. Each candidate is evaluated in its own trial, either as an open label single arm healthy volunteer study or in patients, randomising between candidate and control usually in a 2:1 allocation in favour of the candidate. Each dose is assessed sequentially for safety usually in cohorts of 6 patients. Once a phase II dose has been identified, efficacy is assessed by seamlessly expanding into a larger cohort. AGILE is completely flexible in that the core design in the master protocol can be adapted for each candidate based on prior knowledge of the candidate (i.e. population, primary endpoint and sample size can be amended). This information is detailed in each candidate specific trial protocol of the master protocol. Discussion: Few approved treatments for COVID-19 are available such as dexamethasone, remdesivir and tocilizumab in hospitalised patients. The AGILE platform aims to rapidly identify new efficacious and safe treatments to help end the current global COVID-19 pandemic. We currently have three candidate specific trials within this platform study that are open to recruitment. Trial

Published
2021

46. Corrigendum to ‘SJS/TEN 2019: From science to translation’ [J. Dermatol. Sci. 98/1 (2020) 2–12]

Author

Chang, W-C, Abe, R., Anderson, P., Anderson, W., Ardern-Jones, M.R., Beachkofsky, T.M., Bellón, T., Biala, A.K., Bouchard, C., Cavalleri, G.L., Chapman, N., Chodosh, J., Choi, H.K., Cibotti, R.R., Divito, S.J., Dewar, K., Dehaeck, U., Etminan, M., Forbes, D., Fuchs, E., Goldman, J.L., Holmes, J.H., Hope, E.A., Hung, S-L, Hsieh, C-L, Iovieno, A., Jagdeo, J., Kim, M.K., Koelle, D.M., Lacouture, M.E., Le Pallec, S., Lehloenya, R.J., Lim, R., Lowe, A., McCawley, J., Micheletti, R.G., Mockenhaupt, M., Niemeyer, K., Norcross, M.A., Oboh, D., Olteanu, C., Pasieka, H.B., Peters, J., Pirmohamed, M., Rieder, M., Saeed, H.N., Shear, N.H., Shieh, C., Straus, S., Sukasem, C., Sung, C., Trubiano, J.A., Tsou, S-Y, Ueta, M., Volpi, S., Wan, C., Wang, H., Wang, Z-Q, Weintraub, J., Whale, C., Wheatley, L.M., Whyte-Croasdaile, S., Williams, K.B., Wright, G., Yeung, S.N., Zhou, L., Chung, W-H, Phillips, E.J., Carleton, B.C., Chang, W-C, Abe, R., Anderson, P., Anderson, W., Ardern-Jones, M.R., Beachkofsky, T.M., Bellón, T., Biala, A.K., Bouchard, C., Cavalleri, G.L., Chapman, N., Chodosh, J., Choi, H.K., Cibotti, R.R., Divito, S.J., Dewar, K., Dehaeck, U., Etminan, M., Forbes, D., Fuchs, E., Goldman, J.L., Holmes, J.H., Hope, E.A., Hung, S-L, Hsieh, C-L, Iovieno, A., Jagdeo, J., Kim, M.K., Koelle, D.M., Lacouture, M.E., Le Pallec, S., Lehloenya, R.J., Lim, R., Lowe, A., McCawley, J., Micheletti, R.G., Mockenhaupt, M., Niemeyer, K., Norcross, M.A., Oboh, D., Olteanu, C., Pasieka, H.B., Peters, J., Pirmohamed, M., Rieder, M., Saeed, H.N., Shear, N.H., Shieh, C., Straus, S., Sukasem, C., Sung, C., Trubiano, J.A., Tsou, S-Y, Ueta, M., Volpi, S., Wan, C., Wang, H., Wang, Z-Q, Weintraub, J., Whale, C., Wheatley, L.M., Whyte-Croasdaile, S., Williams, K.B., Wright, G., Yeung, S.N., Zhou, L., Chung, W-H, Phillips, E.J., and Carleton, B.C.

Abstract

The authors regret not all contributing authors correctly acknowledged funding. Jonathan Peter’s IMARI-Africa project (AFRISCAR) is part of the EDCTP2 programme supported by the European Union (grant number TMA2017SF-1981 ). The authors would like to apologise for any inconvenience caused.

Published
2021

47. Dimethyl fumarate induced lymphopenia in multiple sclerosis: A review of the literature

Author

Dello Russo, Cinzia, Scott, K. A., Pirmohamed, M., Dello Russo C. (ORCID:0000-0002-2538-3832), Dello Russo, Cinzia, Scott, K. A., Pirmohamed, M., and Dello Russo C. (ORCID:0000-0002-2538-3832)

Abstract

Dimethyl fumarate (DMF) is a first line medication for multiple sclerosis. It has a favourable safety profile, however, there is concern regarding the occurrence of moderate-severe and sustained lymphopenia and the associated risk of progressive multifocal leukoencephalopathy. We carried out an extensive literature review to understand the molecular mechanisms underlying this adverse reaction. Dynamic changes in certain components of the immune system are likely to be important for the therapeutic effects of DMF, including depletion of memory T cells and decrease in activated T cells together with expansion of naïve T cells. Similar modifications were reported for the B cell components. CD8+ T cells are particularly susceptible to DMF-induced cell death, with marked reductions observed in lymphopenic subjects. The reasons underlying such increased sensitivity are not known, nor it is known how expansion of other lymphocyte subsets occurs. Understanding the molecular mechanisms underlying DMF action is challenging: in vivo DMF is rapidly metabolized to monomethyl fumarate (MMF), a less potent immunomodulator in vitro. Pharmacokinetics indicate that MMF is the main active species in vivo. However, the relative importance of DMF and MMF in toxicity remains unclear, with evidence presented in favour of either of the compounds as toxic species. Pharmacogenetic studies to identify genetic predictors of DMF-induced lymphopenia are limited, with inconclusive results. A role of the gut microbiome in the pharmacological effects of DMF is emerging. It is clear that further investigations are necessary to understand the mechanisms of DMF-induced lymphopenia and devise preventive strategies. Periodic monitoring of absolute lymphocyte counts, currently performed in clinical practise, allows for the early detection of lymphopenia as a risk-minimization strategy.

Published
2021

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