Severe systemic adverse reactions to ophthalmic timolol in a CYP2D6 homozygous *4 allele carrier: a case report.

A woman with ocular hypertension suffered from severe bradycardia, hypotension and syncope attacks in temporal relation with ophthalmic timolol application. Topically applied timolol is nasally absorbed and has been shown to reach potentially relevant systemic concentrations. Timolol is mainly metabolized by CYP2D6, which exhibits interindividual metabolic capacity due to genetic variations. A reactive pharmacogenetic panel test identified the patient as a CYP2D6 homozygous *4 allele carrier, which has been associated with a poor metabolizer phenotype and lacking enzyme activity. Thus, the adverse drug reactions possibly resulted from increased systemic timolol exposure. This case report highlights that pharmacogenetic panel testing can contribute to safe and effective pharmacotherapy, even for topically applied drugs.

Genotyping of Patients with Adverse Drug Reaction or Therapy Failure: Database Analysis of a Pharmacogenetics Case Series Study.

Purpose: Pharmacogenetics (PGx) is an emerging aspect of personalized medicine with the potential to increase efficacy and safety of pharmacotherapy. However, PGx testing is still not routinely integrated into clinical practice. We conducted an observational case series study where PGx information from a commercially available panel test covering 30 genes was integrated into medication reviews. The aim of the study was to identify the drugs that are most frequently object of drug-gene-interactions (DGI) in the study population. Patients and Methods: In out-patient and in-patient settings, we recruited 142 patients experiencing adverse drug reaction (ADR) and/or therapy failure (TF). Collected anonymized data from the individual patient was harmonized and transferred to a structured database. Results: The majority of the patients had a main diagnosis of a mental or behavioral disorder (ICD-10: F, 61%), of musculoskeletal system and connective tissue diseases (ICD-10: M, 21%), and of the circulatory system (ICD-10: I, 11%). The number of prescribed medicines reached a median of 7 per person, resulting in a majority of patients with polypharmacy (≥5 prescribed medicines, 65%). In total, 559 suspected DGI were identified in 142 patients. After genetic testing, an association with at least one genetic variation was confirmed for 324 suspected DGI (58%) caused by 64 different drugs and 21 different genes in 141 patients. After 6 months, PGx-based medication adjustments were recorded for 62% of the study population, whereby differences were identified in subgroups. Conclusion: The data analysis from this study provides valuable insights for the main focus of further research in the context of PGx. The results indicate that most of the selected patients in our sample represent suitable target groups for PGx panel testing in clinical practice, notably those taking drugs for mental or behavioral disorder, circulatory diseases, immunological diseases, pain-related diseases, and patients experiencing polypharmacy.

Pharmacogenetic testing and counselling in the community pharmacy: mixed-methods study of a new pharmacist-led service.

BACKGROUND: Pharmacogenetic (PGx) testing and counselling (short: PGx service) in the community pharmacy is not routinely practiced. We propose a comprehensive pharmacist-led service where PGx information is integrated into medication reviews. AIM: To evaluate the pharmacist-led service comprising PGx testing and counselling (PGx service) from the perspective of patients. METHOD: For this mixed-methods study, we conducted two follow-up interviews F1 and F2 with patients recruited for the PGx service in a community pharmacy after 1st of January 2020. The semi-structured interviews were held by phone call and covered understanding of PGx, the implementation of recommendations, handling of PGx documents (list of concerned substances and PGx recommendation), gain in medication knowledge, and willingness to pay for the PGx service. RESULTS: We interviewed 25 patients in F1 and 42 patients in F2. Patients were generally able to understand and use results of the PGx service. At least one PGx recommendation was implemented for 69% of the patients. Handling of PGx documents ranged from patients having forgotten about the PGx results to patients consulting the list for every medication-related decision; the latter often expecting negative effects. Finally, 62% of the patients were willing to pay for the PGx service. CONCLUSION: For future PGx testing and counselling, HCPs should consider the patients' health literacy in a standardized way and use adequate communication skills to enhance the patient's understanding in PGx and to attenuate potential negative expectations.

A Guide to a Pharmacist-Led Pharmacogenetic Testing and Counselling Service in an Interprofessional Healthcare Setting.

Genetic predisposition is one factor influencing interindividual drug response. Pharmacogenetic information can be used to guide the selection and dosing of certain drugs. However, the implementation of pharmacogenetics (PGx) in clinical practice remains challenging. Defining a formal structure, as well as concrete procedures and clearly defined responsibilities, may facilitate and increase the use of PGx in clinical practice. Over 140 patient cases from an observational study in Switzerland formed the basis for the design and refinement of a pharmacist-led pharmacogenetics testing and counselling service (PGx service) in an interprofessional setting. Herein, we defined a six-step approach, including: (1) patient referral; (2) pre-test-counselling; (3) PGx testing; (4) medication review; (5) counselling; (6) follow-up. The six-step approach supports the importance of an interprofessional collaboration and the role of pharmacists in PGx testing and counselling across healthcare settings.

Is Pharmacogenetic Panel Testing Applicable to Low-Dose Methotrexate in Rheumatoid Arthritis? - A Case Report.

Purpose: Pharmacogenetic (PGx) panel testing could help to determine the heritable component of a rheumatoid arthritis (RA) patient's susceptibility for therapy failure and/or adverse drug reactions (ADRs) from methotrexate (MTX). Considering the literature mentioning the potential applicability of PGx panel testing within MTX regimens, we discuss the case of a patient who was treated with MTX, suffered from ADRs, and obtained a reactive PGx panel testing. Genotyping: We used a commercial PGx panel test involving the ABC-transporters P-glycoprotein (P-gp; gene: ABCB1), and breast cancer resistance protein (BCRP; gene: ABCG2), the solute carriers reduced folate carrier 1 (RFC1; gene: SLC19A1), and organic anion transporting polypeptide 1B1 (OATP1B1; gene: SLCO1B1), and the enzymes inosine triphosphatase (ITPA), and glutathione transferase P1 (GSTP1). In addition, we genotyped the patient for the enzymes 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICAR)/inosine monophosphate (IMP) cyclohydrolase (gene name: ATIC), gamma-glutamyl hydrolase (gene name: GGH) and methylenetetrahydrofolate reductase (gene name: MTHFR). Results: The PGx profile of the patient revealed genetic variants in SLC19A1, ABCB1, and MTHFR, which may explain the ADRs experienced during the treatment with MTX and a potentially lower efficacy of MTX. Based on our interpretation of the PGx profile, we recommended the patient to avoid MTX in the future. Conclusion: The MTX pathway is complex, which makes the interpretation of genetic variants affecting metabolism challenging. A reactive PGx panel test was applicable to explain ADRs experienced during MTX treatment for a patient with RA. However, the clinical utility of PGx-guided MTX treatment in a primary care setting is still limited. In order to base a recommendation for MTX on PGx data, we need genome-wide association studies, large prospective multicenter studies and PGx studies, which analyze different multi-gene haplotypes and gene-drug-drug interactions for MTX.

Pharmacogenetics in Pharmaceutical Care-Piloting an Application-Oriented Blended Learning Concept.

To enable application-oriented training of Swiss pharmacists on pharmacogenetic (PGx) testing, an advanced, digital training program was conceptualized based on the Miller's Pyramid framework, using a blended learning approach. The PGx advanced training program included an asynchronous self-study online module, synchronous virtual classroom sessions with lectures and workshops, and a follow-up case study for in-depth applied learning including the analysis of the participants' PGx profile. The evaluation of the training program consisted of (a) an assessment of the participants' development of knowledge, competencies and attitudes towards PGx testing in the pharmacy setting; (b) a satisfaction survey including; (c) questions about their future plans for implementing a PGx service. Twenty-one pharmacists participated in this pilot program. The evaluation showed: (a) a significant improvement of their PGx knowledge (mean score in the knowledge test 75.3% before to 90.3% after training completion) and a significant increase of their self-perceived competencies in applying PGx counselling; (b) a high level of satisfaction with the training program content and the format (at least 79% expressed high/very high agreement with the statements in the questionnaire); (c) a mixed view on whether participants will implement PGx testing as a pharmacy service (indecisive 8; agreed/completely agreed to implement 7/1; disagreed 3 (n = 19)). We consider ongoing education as an important driver for the implementation of PGx in pharmacy practice.

HLA-associated adverse drug reactions - scoping review.

Alleles of the human leukocyte antigen (HLA) system have been associated with the occurrence of idiosyncratic adverse drug reactions (ADRs). Accordingly, it is assumed that pre-emptive testing for the presence of certain HLA alleles (HLA-typing) could prevent these ADRs in carriers. In order to perceive the current evidence for HLA-associated ADRs, we conducted a scoping review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The literature search on PubMed and on Embase was carried out on the July 8 and 9, 2020, respectively. To be included in the scoping review, the studies had to investigate an association of any HLA-associated ADR with any small molecule approved and available on the Swiss market. We considered English and German primary literature published since 2002. A total of 149 studies were included, whereof most were retrospective, whereas one was a prospective randomized controlled trial. The majority of the studies (n = 33) described the association of HLA-B*15:02 with carbamazepine. It was not possible to directly compare the studies, as they were too heterogeneous in terms of the ADR definition, the HLA alleles, the number of participants, and the study types. Therefore, we summarized the results in a descriptive manner. Even if an interpretation of the outcomes remains open, the descriptive overview revealed the prevailing complexity and uncertainty in the field. For the future, consistent definitions on the different phenotypes need to be established and applied and the reporting of association studies should follow a harmonized structure.

Enriching Medication Review with a Pharmacogenetic Profile - A Case of Tamoxifen Adverse Drug Reactions.

Pharmacogenotyping is applied to determine the hereditable component of a patient's susceptibility to experience therapy failure and/or adverse drug reactions (ADRs). We present the case of a female patient diagnosed with breast cancer and treated with tamoxifen as recurrence therapy who experienced various ADRs. Pharmacogenotyping revealed variants in the cytochrome P450 (CYP) enzymes CYP2D6, CYP2C9, and CYP2C19. The observed genotype was associated with a risk for lower tamoxifen efficacy. Aside from the tamoxifen therapy, the comedication was reviewed for the influence of the patient's pharmacogenetic profile. As a result of this pharmacist-led medication review with pharmacogenetic analyses, concrete genotype-driven recommendations for the treating gynecologist were compiled. This case revealed the added value of a large pharmacogenetic panel and the complexity of integrating a pharmacogenetic profile into a recommendation.