Pharmacometabolomics in TB meningitis-Understanding the pharmacokinetic, metabolic, and immune factors associated with anti-TB drug concentrations in cerebrospinal fluid. Poor penetration of many anti-tuberculosis (TB) antibiotics into the central nervous system (CNS) is thought to be a major driver of morbidity and mortality in TB meningitis (TBM). While the amount of a particular drug
Plasma pharmacometabolomics of inhaled corticosteroid-related adrenal suppression in asthma. Inhaled corticosteroids (ICS) are frequently prescribed medications for asthma symptoms, but higher doses can increase risks of adrenal insufficiency through suppression of endogenous cortisol production. Understanding which patients may be at increased risk for developing adrenal suppression related
Pharmacometabolomics applied to low-dose interleukin-2 treatment in amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low-dose (ld) interleukin-2 (IL-2). We propose a pharmacometabolomics approach to decipher metabolic modifications occurring in patients treated with ld-IL-2 and its relationship with Treg response. Blood metabolomic profiles were determined on days D1, D64, and D85 from patients receiving 2 MIU of IL-2 (n = 12) and patients receiving a placebo (n = 12). We discriminated the three time points
Pharmacometabolomic profiles in type 2 diabetic subjects treated with liraglutide or glimepiride. Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) leads to multiple metabolic changes, reduction in glucose levels and body weight are well established. In people with type 2 diabetes, GLP-1 RAs reduce the risk of cardiovascular (CV) disease and may also potentially represent
Preanalytical Processing and Biobanking Procedures of Biological Samples for Metabolomics Research: A White Paper, Community Perspective (for "Precision Medicine and Pharmacometabolomics Task Group"-The Metabolomics Society Initiative). The metabolome of any given biological system contains a diverse range of low molecular weight molecules (metabolites), whose abundances can be affected
A Pharmacometabolomic Approach to Predict Response to Metformin in Early-Phase Type 2 Diabetes Mellitus Patients Metformin is a first-line medication for type 2 diabetes mellitus (T2DM). Based on its universal use, the consideration of inter-individual variability and development of predictive biomarkers are clinically significant. We aimed to identify endogenous markers of metformin responses using a pharmacometabolomic approach. Twenty-nine patients with early-phase T2DM were enrolled and orally administered metformin daily for 6 months. A total of 22 subjects were included in the final analysis. Patients were defined as responders or non-responders based on changes in their glycated haemoglobin A1c (HbA1c) from baseline, over 3 months. Urine metabolites at baseline, as well as at the 3
Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate Carboxylesterase 1 (CES1) metabolizes methylphenidate and other drugs. CES1 gene variation only partially explains pharmacokinetic (PK) variability. Biomarkers predicting the PKs of drugs metabolized by CES1 are needed. We identified lipids in plasma from 44 healthy subjects that correlated with CES1 activity
Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity In this report, we present a case study of how pharmacogenomics and pharmacometabolomics can be useful to characterize safety and pharmacokinetic profiles in early phase new drug development clinical trials. During conducting a first-in-human trial
H NMR based pharmacometabolomics analysis of metabolic phenotype on predicting metabolism characteristics of losartan in healthy volunteers. Inter-individual variability in drug metabolism and disposition is common in both preclinical and clinical researches. Losartan and its active metabolite EXP3174 present a high degree of inter-individual differences in blood concentrations that affect drug efficacy and side effect. Pharmacometabolomics has been increasingly applied on predicting the drug responses by analyzing the differences in metabolic profile. A pre-dose metabolic phenotype was investigated to interpret inter-individual variations in the metabolism characteristics of losartan. H Nuclear Magnetic Resonance (NMR) spectroscopy-based metabolic profiles were performed on 36 healthy Chinese
Pharmacometabolomics for predicting variable busulfan exposure in paediatric haematopoietic stem cell transplantation patients Owing to its narrow therapeutic range and high pharmacokinetic variability, optimal dosing for busulfan is important to minimise overexposure-related systemic toxicity and underexposure-related graft failure. Using global metabolomics, we investigated biomarkers
Pharmacometabolomics identifies dodecanamide and leukotriene B4 dimethylamide as a predictor of chemosensitivity for patients with acute myeloid leukemia treated with cytarabine and anthracycline Clinical responses to standard cytarabine plus anthracycline regimen in acute myeloid leukemia (AML) are heterogeneous and there is an unmet need for biological predictors of response to this regimen . Here, we applied a pharmacometabolomics approach to identify potential biomarkers associated with response to this regimen in AML patients. Based on clinical response the enrolled 82 patients were subdivided into two groups: complete remission(CR) responders (n=42) and non-responders (n=40). Metabolic profiles of pre-treatment serum from patients were analyzed by ultra-high performance liquid
The Personalization of Clopidogrel Antiplatelet Therapy: The Role of Integrative Pharmacogenetics and Pharmacometabolomics Dual antiplatelet therapy of aspirin and clopidogrel is pivotal for patients undergoing percutaneous coronary intervention. However, the variable platelets reactivity response to clopidogrel may lead to outcome failure and recurrence of cardiovascular events. Although many prediction. Pharmacometabolomics which is an approach to identify novel biomarkers of drug response or toxicity in biofluids has been investigated to predict drug response. The advantage of pharmacometabolomics is that it does not only predict the response but also provide extensive information on the metabolic pathways implicated with the response. Integrating pharmacogenetics with pharmacometabolomics
Pharmacometabolomic Profiling of Antihypertensive Drug Response: A Systematic Review PROSPEROInternational prospective register of systematic reviews Print | PDFPharmacometabolomic Profiling of Antihypertensive Drug Response: A Systematic Reviewelahe zare borzeshi, Jonathan Knikman, Merys Valdez, Thomas Hankemeier, Diederick E GrobbeeTo enable PROSPERO to focus on COVID-19 submissions , Thomas Hankemeier, Diederick E Grobbee. Pharmacometabolomic Profiling of Antihypertensive Drug Response: A Systematic Review. PROSPERO 2024 CRD42024501059 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024501059Review question1) What are the key metabolites that are associated with changes in blood pressure in response to antihypertensive drugs. 2) What is the strength
Pharmacometabolomics Informs Viromics toward Precision Medicine Nowadays, we are experiencing the big data era with the emerging challenge of single data interpretation. Although the advent of high-throughput technologies as well as chemo- and bio-informatics tools presents pan-omics data as the way forward to precision medicine, personalized health care and tailored-made therapeutics can be only . Herein, we focus on the host-microbiome interplay and its direct and indirect impact on efficacy and toxicity of xenobiotics and we inevitably wonder about the role of viruses, as the least acknowledged ones. We present the emerging discipline of pharmacometabolomics-informed viromics, in which pre-dose metabotypes can assist modeling and prediction of interindividual response to/toxicity
Pharmacometabolomics informs Pharmacogenomics The initial decades of the 21 century have witnessed striking technical advances that have made it possible to detect, identify and quantitatively measure large numbers of plasma or tissue metabolites. In parallel, similar advances have taken place in our ability to sequence DNA and RNA. Those advances have moved us beyond studies of single " will outline some of the challenges and opportunities associated with studies in which metabolomic data have been merged with genomics in an attempt to gain novel insight into mechanisms associated with variation in drug response phenotypes, with an emphasis on the application of a pharmacometabolomics-informed pharmacogenomic research strategy and with selected examples of the application of that strategy
Pharmacometabolomics study identifies circulating spermidine and tryptophan as potential biomarkers associated with the complete pathological response to trastuzumab-paclitaxel neoadjuvant therapy in HER-2 positive breast cancer Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate to guide patient selection for personalized cancer treatments. In the present study, we applied a pharmacometabolomics approach to identify biomarkers potentially associated with pathological complete response to trastuzumab-paclitaxel neoadjuvant therapy in HER-2 positive breast cancer patients. Based on histological response the 34 patients enrolled in the study were subdivided into two groups: good responders (n = 15) and poor responders (n = 19). The pre-treatment serum
Pharmacometabolomic Assessment of Metformin in Non-diabetic, African Americans Millions of individuals are diagnosed with type 2 diabetes mellitus (T2D), which increases the risk for a plethora of adverse outcomes including cardiovascular events and kidney disease. Metformin is the most widely prescribed medication for the treatment of T2D; however, its mechanism is not fully understood and individuals vary in their response to this therapy. Here, we use a non-targeted, pharmacometabolomics approach to measure 384 metabolites in 33 non-diabetic, African American subjects dosed with metformin. Three plasma samples were obtained from each subject, one before and two after metformin administration. Validation studies were performed in wildtype mice given metformin. Fifty-four metabolites
Integration of pharmacometabolomics with pharmacokinetics and pharmacodynamics: towards personalized drug therapy Personalized medicine, in modern drug therapy, aims at a tailored drug treatment accounting for inter-individual variations in drug pharmacology to treat individuals effectively and safely. The inter-individual variability in drug response upon drug administration is caused to achieve personalized medicine. Here, we highlight the potential of pharmacometabolomics in prospectively informing on the inter-individual differences in drug pharmacology, including both pharmacokinetic (PK) and pharmacodynamic (PD) processes, and thereby guiding drug selection and drug dosing. This review focusses on the pharmacometabolomics studies that have additional value on top
Prediction of Intravenous Busulfan Clearance by Endogenous Plasma Biomarkers Using Global Pharmacometabolomics High-dose busulfan (busulfan) is an integral part of the majority of hematopoietic cell transplantation conditioning regimens. Intravenous (IV) busulfan doses are personalized using pharmacokinetics (PK)-based dosing where the patient's IV busulfan clearance is calculated after the first dose and is used to personalize subsequent doses to a target plasma exposure. PK-guided dosing has improved patient outcomes and is clinically accepted but highly resource intensive. We sought to discover endogenous plasma biomarkers predictive of IV busulfan clearance using a global pharmacometabolomics-based approach. Using LC-QTOF, we analyzed 59 (discovery) and 88 (validation) plasma samples