10th German Pharm-Tox Summit / 91. Jahrestagung der Deutschen Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie (DGPT)

Prof. Dr.

Chair

Dr. rer. nat.

PharmFreq: a comprehensive database of worldwide allelic frequencies in clinically important pharmacogenes

Pharmacogenomics and personalized medicine

AP06

Objective: Pharmacogenetic (PGx) variability in drug metabolism and transport plays a significant role in inter-individual differences in drug efficacy and safety. Genetic variants, particularly in CYP, UGT, and SULT families, explain much of the variability in the expression and activity of these enzymes and transporters. PGx guidelines offer evidence-based recommendations for drug selection and dosing in personalized medicine. However, worldwide clinical implementation requires access to population-specific PGx variant frequencies. This study aimed to summarize global frequency data on key pharmacogenes, creating a comprehensive population pharmacogenomics database to support personalized medicine.Methods: We systematically collected allele frequency data from pharmacogenes with available clinical guidelines including CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A5, DPYD, TPMT, and UGT1A1. Frequency data was sourced from PharmGKB and supplemented with literature accessible through PubMed. Information on allele frequencies, cohort sizes, and ethnic backgrounds was documented. A R-Shiny web application was used to visualize and share the data via a web-based interactive website available at www.pharmfreq.com.Results: Data was aggregated from over 1200 studies, covering 144 countries and more than 10 million individuals. The dataset includes frequency information for 21 genes and more than 600 alleles and haplotypes, with the majority of studies conducted in populations of East Asian (28.5%) and European (26.9%) ancestry. Underrepresented populations include those from Africa, South America, and Oceania. Genetic complexity and allele frequency differences across populations (e.g., for DPYD, CYP2D6, and HLA-B) were highlighted. Correlations were observed between the number of studies per country and both population size (R=0.47, p=0.0004) and GDP (R=0.56, p=3*10^-9). Notably, 43% of all analyzed alleles had absent or decreased function, while only 3% had increased function according to CPIC.Conclusion: The PharmFreq database presents a comprehensive, open-access resource for global pharmacogenetic variant frequencies. It highlights significant ethnogeographic diversity and underrepresentation in PGx research, providing an important tool to guide implementation projects and future investigations. Users can explore country-specific data and contribute to expanding this valuable resource.This work was supported by the Robert Bosch Stiftung (Stuttgart, Germany)

Applied Pharmacology

Short talk

What do we know about the eligibility of GLP-1 receptor agonists and SGLT-2 inhibitors for elderly patients?

Pharmacoepidemiology and drug safety

AP07

GLP-1 receptor agonists and SGLT-2 inhibitors are widely used due to their numerous positive clinical effects, for example in type 2 diabetes mellitus, weight reduction/obesity, chronic heart failure and chronic kidney disease. Due to the increased prevalence of these diseases with increasing age, elderly patients use these drugs rather frequently. The aim of this literature search was to obtain a detailed overview of the representation of elderly patients in approval studies of GLP-1 receptor agonists and SGLT-2 inhibitors.In our analysis, we focused on the active substances liraglutide, dulaglutide, semaglutide, tirzepatide, dapagliflozin and empagliflozin, due to the number of prescriptions in Germany. We analyzed publications of all studies that were mentioned in the respective SmPC (Summary of product characteristics) or in the efficacy and safety assessment reports of the EMA (European Medicine Agency), data in the assessment reports themselves, and additional information from the public database ClinicalTrials.gov.The inclusion criteria of the reviewed studies frequently started at the age of 18, mostly without specifying a maximum inclusion age. In our research, we were not able to find any information on the proportion of elderly patients in 48 of the 104 studies reviewed (46%). Patients aged 75 or older were strongly underrepresented in almost all studies.Subgroup analyses results of the efficacy or primary endpoints for different age groups are rather rare. However, cardiovascular outcome trials and studies including patients with chronic heart failure or chronic kidney disease had a higher inclusion age (e.g. from 50 years on), and reported comparisons of the primary endpoints in different age groups more often. Efficacy results from other studies, if any, can only be found in EMA assessment reports. Based on the available data, we did not find signs of different efficacy of liraglutide, dulaglutide, semaglutide, tirzepatide, dapagliflozin and empagliflozin in the different age groups.Safety data are mainly provided in the EMA assessment reports. Most of the studies showed an increasing frequency of adverse events or discontinuation of study drug due to adverse events with increasing age. Overall, these findings were not deemed to be of clinical relevance by the authors of publication or regulatory agencies.

sGC stimulator BAY41-8543 improves the survival of hypertensive rats with chemotherapy-induced heart failure

Disease models, drug development

BR07

Doxorubicin (DOXO) and other anthracyclines remain among the most effective anticancer drugs, however in the long-term perspective, due to their dose-dependent cardiotoxicity, they can lead to the development of chemotherapy-induced heart failure with reduced ejection fraction (HFrEF).In the current study we have tested the effectiveness of soluble guanylate cyclase (sGC) stimulator BAY41-8543 for the treatment of DOXO-induced HFrEF. This model, in which DOXO was administered to ren-2 transgenic rats (TGR) via five intravenous injections in a cumulative dose of 10 mg/kg of body weight, was recently developed in our laboratory. Hypertension and increased activity of the renin-angiotensin system, which are both present in TGR, are recognized risk factors for the development of HF. We have evaluated the long-term survival (20 weeks) of rats after the treatment with sGC stimulator in comparison to angiotensin-converting enzyme inhibitor (ACEi), which is still considered as a golden therapeutic standard for HFrEF.The treatment with sGC stimulator significantly improved the survival of DOXO-treated TGR, however slightly better effectiveness exhibited the ACEi. Cardiac output (CO) decreased in all DOXO groups, but four weeks of treatment with sGC stimulator significantly attenuated this decline, while CO decreased further in the placebo and ACEi-treated groups. The fractional area change of right ventricle was also preserved after treatment with sGC stimulator, whereas in untreated group and ACEi-treated animals there was further decrease after four weeks. In conclusion, the treatment with sGC stimulator improved survival rate and attenuated cardiac dysfunction in this model of chemotherapy-induced HFrEF. Hence, the application of sGC stimulator could be a promising therapeutic strategy for the treatment of this form HFrEF and further studies are warranted.Supported by MH CZ - DRO ("Institute for Clinical and Experimental Medicine - IKEM, IN 00023001")

Short talk 14
Pharmacoepidemiology and oncological drug development

Appointment

Chair

Programme

Short talk 14Pharmacoepidemiology and oncological drug development

Appointment

Chair

Programme

Short talk 14
Pharmacoepidemiology and oncological drug development