Potential Research Questions
Which is the mode of action of this drug?
How can efficacy and toxicity be monitored?
Which biomarker profile predicts response to this drug?
Status Quo and Medical Need
For most drugs it is still not possible to predict which patient is going to respond based on pharmacogenetics alone. Attrition rates remain high, with limited knowledge about how the drugs work being among the reasons this is attributed to.
The response to drugs depends on much more than the genetic background of a patient. It is intuitively clear considering that a child will respond differently to a drug than an adult, and an adult will respond differently than an elderly patient; in spite of the genotype remaining unchanged.
Metabolomics is increasingly being used by pharmaceutical researchers as well as health authorities to gather additional information about how drugs work, how they cause toxicity, and which age or lifestyle factors might determine response.
Relevant Metabolite Classes
- Lipid neogenesis is expected to increase upon mTOR activation.
- Lipid metabolism is involved in the LDL lowering effect of metformin.
- Acylcarnitines have been shown to be related to nephrotoxicity.
- Mitochondrial beta oxidation may be relevant to assess activity of drugs that enhance mitochondrial function, such as pan-PPAR agonists.
Amino acids and biogenic amines:
- The citrulline to arginine ratio as indicator for NO synthase activity is related to angiogenesis.
- Amino acids, especially leucine and arginine, activate mTOR.
- Tryptophan and kynurenine are the educt and product of the IDO pathway, a major immune regulatory pathway.
- Bile acids are expected to be altered in liver toxicity.
- Upon administration of liver directed drugs, especially FXR or FGF19 inhibitors, biosynthesis may be altered.
Eicosanoids & Prostaglandins:
- Prostaglandin synthesis is inhibited by COX-2 inhibitors (e.g. acetylsalicylic acid)
- Slopianka et al.: Quantitative targeted bile acid profiling as new markers for DILI in a model of methapyrilene-induced liver injury in rats; Toxicology 2017
- Ryan et al.: Microbiome and metabolome modifying effects of several cardiovascular disease interventions in apo-E(-/-) mice; Microbiome 2017
- Ang et al.: Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation; Molecular Cancer Therapies 2016
- Bhattacharyya et al.: Targeted Metabolomic Profiling Indicates Structure-based Perturbations in Serum Phospholipids in Children with Acetaminophen Overdose; Toxicology Reports 2016
- Brunelli et al.: Comparative metabolomics profiling of isogenic KRAS wild type and mutant NSCLC cells in vitro and in vivo; Scientific Reports 2016
- Kazierad et al.: Effects of multiple ascending doses of the glucagon receptor antagonist, PF-06291874, in patients with type 2 diabetes mellitus; Diabetes, Obesity and Metabolism 2016
- Miolo et al.: Phamacometabolomics 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; Oncotarget 2016
- Pena et al.: Serum metabolites predict response to angiotensin II receptor blockers in patients with diabetes mellitus; Journal of Translational Medicine 2016
- Rotroff et al.: Metabolomic signatures of drug response phenotypes for ketamine and esketamine in subjects with refractory major depressive disorder: new mechanistic insights for rapid acting antidepressants; Transl Psychiatry 2016
- Xu et al.: Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes; Diabetes Care 2015
- Zwadlo et al.: Antiandrogenic Therapy With Finasteride Attenuates Cardiac Hypertrophy and Left Ventricular Dysfunction; Circulation 2015
- Hotze et al.: Increased efficacy of omalizumab in atopic dermatitis patients with wild-type filaggrin status and higher serum levels of phosphatidylcholines; Allergy 2014
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