Personalized Medicine: From Pharmacogenetics to Pharmacometabonomics

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Pharmacology and Drug Metabolism".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 8678

Special Issue Editors


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Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy
Interests: pharmacogenetics and pharmacogenomics; personalised medicine; cardiovascular research; anti-cancer pharmacology; pharmacovigilance

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Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy
Interests: pharmacology; natural products; oxidative stress; inflammatory disease; atherosclerosis; metabolic disease; neurodegenerative diseases; autophagy; proliferation and differentiation process
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Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, 56121 Pisa, Italy
Interests: pharmacogenetics; chemotherapy; targeted therapy; immunotherapy; toxicities; metabolism
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Experimental and Clinical Pharmacology Unit, IRCCS CRO Aviano National Cancer Institute, via Franco Gallini, 2 33081 Aviano, PN, Italy
Interests: pharmacogenetics; TDM; chemotherapy; target therapy; toxicities; metabolism; personalized medicine; oral anti-cancer drugs
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Special Issue Information

Dear Colleagues,

Individual responses to drugs vary widely among patients, and it is difficult to predict a priori how a person will respond to a particular medication and how effective or safe it will be. This interpatient variability is multifactorial and is known to largely result from polymorphisms in genes encoding for metabolizing enzymes, transporters, and/or target proteins involved in pharmacokinetic and pharmacodynamic pathways. These polymorphisms can influence the clinical efficacy, tolerability, and safety of various drugs. In recent years, pharmacometabonomics has been recognized as a new field of science focused on personalized therapy that uses metabolic phenotypes to predict drug effects, through the analysis of predose, biofluid metabolite profiles.

Knowledge of a patient’s genetic background and metabolic profiling can be useful for clinicians to develop tailored treatments to improve clinical outcomes and reduce the risk of serious adverse events. This Special Issue is dedicated to the publication of recent advancements in the field of pharmacogenetics, pharmacometabonomics, and personalized medicine. We are pleased to invite and welcome all authors to contribute with reviews and original research articles.

Dr. Valentina Manzo
Dr. Federica Mannino
Dr. Stefania Crucitta
Dr. Rossana Roncato
Guest Editors

Manuscript Submission Information

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Keywords

  •  pharmacogenetics
  •  pharmacogenomics
  •  polymorphisms
  •  drug-metabolizing enzymes
  •  transporters
  •  personalized medicine
  •  toxicity
  •  pharmacometabonomics
  •  predictive metabonomics
  •  therapeutic drug monitoring
  •  LC-MS/MS

Published Papers (4 papers)

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Research

11 pages, 1132 KiB  
Article
Dolutegravir Discontinuation for Neuropsychiatric Symptoms in People Living with HIV and Their Outcomes after Treatment Change: A Pharmacogenetic Study
by Jessica Cusato, Alberto Borghetti, Elisabetta Teti, Maurizio Milesi, Maria Cristina Tettoni, Stefano Bonora, Mattia Trunfio, Antonio D’Avolio, Mirko Compagno, Simona Di Giambenedetto, Giovanni Di Perri and Andrea Calcagno
Metabolites 2022, 12(12), 1202; https://doi.org/10.3390/metabo12121202 - 1 Dec 2022
Cited by 4 | Viewed by 1522
Abstract
Neuropsychiatric symptoms have been reported in patients receiving dolutegravir, a known inhibitor of the renal and neuronal-expressed organic anion transporter 2 (encoded by SLC22A2 gene). The effect of the genetic variant SLC22A2 808C>A on dolutegravir discontinuation was assessed and analyzed by real-time PCR. [...] Read more.
Neuropsychiatric symptoms have been reported in patients receiving dolutegravir, a known inhibitor of the renal and neuronal-expressed organic anion transporter 2 (encoded by SLC22A2 gene). The effect of the genetic variant SLC22A2 808C>A on dolutegravir discontinuation was assessed and analyzed by real-time PCR. We enrolled 627 participants: CA/AA carriers showed a higher prevalence of pre-existing psychiatric comorbidities and use of antidepressants. After 27.9 months, 108 participants discontinued dolutegravir, 64 for neuropsychiatric symptoms. Patients with pre-existing psychiatric comorbidities were at higher risk of dolutegravir discontinuation, while patients carrying the SLC22A2 CA/AA genotype were not. Combining the two variables, an opposite effect of SLC22A2 variants according to pre-existing psychiatric disorders was observed. Using multivariate Cox models, the combined variable pre-existing psychiatric comorbidities/SLC22A2 variants and the use of non-tenofovir alafenamide containing antiretroviral regimens were predictors of dolutegravir discontinuation for neuropsychiatric symptoms. Within 30 days, the majority of participants had a complete resolution of symptoms (61.8%), while 32.7% and 5.5% had partial or no change after dolutegravir discontinuation, respectively. Discontinuation of dolutegravir for neuropsychiatric symptoms was not uncommon and more frequent in participants with pre-existing psychiatric disorders. We described an interaction between SLC22A2 genetic variant and psychiatric comorbidities. In 38.2% of patients, a complete neuropsychiatric symptoms resolution was not observed after dolutegravir discontinuation suggesting the involvement of additional factors. Full article
(This article belongs to the Special Issue Personalized Medicine: From Pharmacogenetics to Pharmacometabonomics)
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10 pages, 998 KiB  
Article
Categorization of Cytochrome P4502D6 Activity Score by Urinary Amphetamine/Methamphetamine Ratios
by Jatuporn Chaichana, Manee Khamenkhetkarn, Thanapat Sastraruji, Tawachai Monum, Timothy E. O’Brien, Yutti Amornlertwatana and Churdsak Jaikang
Metabolites 2022, 12(12), 1174; https://doi.org/10.3390/metabo12121174 - 25 Nov 2022
Cited by 1 | Viewed by 2675
Abstract
Methamphetamine (MA) level in urine has been used for judgment in MA consumption. Metabolism and intoxication of MA are correlated with the activity of cytochrome P450 2D6 (CYP2D6). The activity score (AS) is a potential tool for predicting exposure and personalized dose of [...] Read more.
Methamphetamine (MA) level in urine has been used for judgment in MA consumption. Metabolism and intoxication of MA are correlated with the activity of cytochrome P450 2D6 (CYP2D6). The activity score (AS) is a potential tool for predicting exposure and personalized dose of drugs metabolized by CYP2D6. Prediction of the CYP2D6 activity score might be described as MA intoxication. The objective of this study was to categorize the CYP2D6 activity score using the urinary amphetamine (AM)/MA ratio. Urine samples (n = 23,258) were collected. The levels of MA and AM were determined by a gas chromatography–nitrogen–phosphorus detector. The log AS was calculated by an AM/MA ratio and classified into four groups following the percentile position: lower than the 2.5th, the 2.5th–the 50th, the 50th–97.5th, and greater than the 97.5th percentile, respectively. The AS value for males presented was less than 0.024, 0.024–0.141, 0.141–0.836, and greater than 0.836. Meanwhile, the AS values were revealed to be lower than 0.023, 0.023–0.148, 0.148–0.850, and higher than 0.850 for females. The AS value of CYP2D6 can be applied to describe the toxicity of MA in forensic crime scenes and relapse behavior. Full article
(This article belongs to the Special Issue Personalized Medicine: From Pharmacogenetics to Pharmacometabonomics)
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13 pages, 6097 KiB  
Article
A Validated HPLC–Diode Array Detection Method for Therapeutic Drug Monitoring of Thiopurines in Pediatric Patients: From Bench to Bedside
by Martina Franzin, Debora Curci, Marianna Lucafò, Matteo Bramuzzo, Marco Rabusin, Antonella Fabretto, Riccardo Addobbati, Gabriele Stocco and Giuliana Decorti
Metabolites 2022, 12(12), 1173; https://doi.org/10.3390/metabo12121173 - 24 Nov 2022
Cited by 1 | Viewed by 1119
Abstract
Thiopurine drugs are part of the therapeutic armamentarium for pediatric patients suffering from inflammatory bowel disease (IBD) and acute lymphoblastic leukemia (ALL). The therapeutic drug monitoring of these drugs, consisting of measurements of the thiopurine metabolites thioguanine nucleotides (TGN) and methylmercaptopurine nucleotides (MMPN) [...] Read more.
Thiopurine drugs are part of the therapeutic armamentarium for pediatric patients suffering from inflammatory bowel disease (IBD) and acute lymphoblastic leukemia (ALL). The therapeutic drug monitoring of these drugs, consisting of measurements of the thiopurine metabolites thioguanine nucleotides (TGN) and methylmercaptopurine nucleotides (MMPN) are used to optimize the effectiveness of treatment and prevent adverse effects. In this context, we developed and validated a high-performance liquid chromatography—diode array detection (HPLC–DAD) method for the simultaneous quantification of thiopurine metabolites according to the most recent International Council for Harmonisation (ICH) guidelines. The calibration curves were built in the clinically relevant range of concentrations for TGN of 300–12,000 nM and for MMPN of 3000–60,000 nM. The limit of detection and the lower limit of quantification were 100 and 300 nM for TGN and 900 and 3000 nM for MMPN, respectively. The percentage of inter-day accuracy and precision (CV%) varied between 85 and 104% and 1.6 and 13.8%. Stability was demonstrated for both of the metabolites for at least 50 days at −20 °C. The proposed HPLC–DAD method showed an appropriate selectivity, specificity, linearity, accuracy, precision and good applicability to samples from patients with IBD and ALL undergoing thiopurine treatment. Full article
(This article belongs to the Special Issue Personalized Medicine: From Pharmacogenetics to Pharmacometabonomics)
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11 pages, 1145 KiB  
Article
Performance Verification of CYP2C19 Enzyme Abundance Polymorphism Settings within the Simcyp Simulator v21
by Caroline Sychterz, Iain Gardner, Manting Chiang, Ramakrishna Rachumallu, Sibylle Neuhoff, Vidya Perera, Samira Merali, Brian J. Schmidt and Lu Gaohua
Metabolites 2022, 12(10), 1001; https://doi.org/10.3390/metabo12101001 - 20 Oct 2022
Cited by 3 | Viewed by 2356
Abstract
Physiologically based pharmacokinetic (PBPK) modeling has a number of applications, including assessing drug–drug interactions (DDIs) in polymorphic populations, and should be iteratively refined as science progresses. The Simcyp Simulator is annually updated and version 21 included updates to hepatic and intestinal CYP2C19 enzyme [...] Read more.
Physiologically based pharmacokinetic (PBPK) modeling has a number of applications, including assessing drug–drug interactions (DDIs) in polymorphic populations, and should be iteratively refined as science progresses. The Simcyp Simulator is annually updated and version 21 included updates to hepatic and intestinal CYP2C19 enzyme abundance, including addition of intermediate and rapid metabolizer phenotypes and changes to the ultra-rapid metabolizer enzyme abundance, with implications for population clearance and DDI predictions. This work details verification of the updates with sensitive CYP2C19 substrates, omeprazole and lansoprazole, using available clinical data from literature. Multiple assessments were performed, including recovery of areas under the concentration-time curve (AUC) and Cmax from compiled datasets for each drug, recovery of victim DDI ratios with CYP2C19 and/or CYP3A4 inhibition and recovery of relative exposure between phenotypes. Simulated data were within respective acceptance criteria for >80% of omeprazole AUC values, >70% of lansoprazole AUC and Cmax, >60% of AUC and Cmax DDI ratios and >80% of exposure ratios between different phenotypes. Recovery of omeprazole Cmax was lower (>50–70% within 2-fold) and possibly attributed to the variety of formulations used in the clinical dataset. Overall, the results demonstrated that the updated data used to parameterize CYP2C19 phenotypes reasonably described the pharmacokinetics of omeprazole and lansoprazole in genotyped or phenotyped individuals. Full article
(This article belongs to the Special Issue Personalized Medicine: From Pharmacogenetics to Pharmacometabonomics)
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