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Personalized Medicine: Pharmacokinetics
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Personalized Medicine: Pharmacokinetics

A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Pharmacogenetics".

Deadline for manuscript submissions: closed (20 July 2021) | Viewed by 28440

Special Issue Editor

Prof. Dr. Youssef Daali

E-Mail Website
Guest Editor
Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, 1205 Geneva, Switzerland
Interests: pharmacology; LC-MS; biostatistics; analytical chemistry; medicinal and pharmaceutical chemistry; pharmacokinetics; pharmacodynamics; LC-MS/MS; tandem mass spectrometry; pharmaceutical analysis

Special Issue Information

Dear colleagues,

Personalized medicine is a challenging target in a real-life clinical setting. Even if it is widely reported in scientific and medical literature, its use in patient care is not yet a common practice, due to many factors, such as healthcare professionals’ teaching and information, large clinical validation, and the complexity and interplay between sources of variability. Pharmacogenetics is widely used in oncology to select the best drugs for specific pharmacodynamic targets. One of the principal sources of variability is linked to the pharmacokinetics of drugs. Drug metabolic enzymes and transporters are the key factors in this variability. Genetic and environmental factors, such as drug–drug interactions and clearance organs failure (kidney and liver), affect the pharmacokinetics of drugs, affecting their safety and efficacy. In some cases, drugs’ metabolites could be responsible for toxicity, like for reactive metabolites. Many drugs are generally produced as stereoisomers, but only one of the isomers is active, and sometimes the other one is toxic, such as methadone where (R)-methadone is responsible of the opioid effect, while (S)-methadone is responsible for the cardiac toxicity of this molecule. Genetic polymorphisms and drug–drug interactions affecting the pharmacodynamic targets are also important in the variability of drug response, and need to be more studied and validated in large clinical studies.

The present issue could address:

  • Recent updates in genetic polymorphisms of metabolic enzymes, transporters and their implication in different medical fields (oncology, psychiatry, cardiovascular, etc.)
  • Genetic polymorphisms affecting pharmacodynamics of drugs in oncology
  • Pharmacogenetics and pharmacogenomics of tyrosine kinase inhibitors
  • Pharmacogenetics and pharmacogenomics of anticoagulant and antiplatelet drugs
  • Better characterization of drugs metabolism and transport during the development and use of physiologically based pharmacokinetics (PBPK) for optimal use in clinical settings

Prof. Dr. Youssef Daali
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • pharmacogenetics
  • drugs metabolism
  • transporters
  • pharmacokinetics
  • pharmacodynamics
  • PBPK
  • drug development
  • oncology
  • psychiatry
  • cardiovascular drugs

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Published Papers (8 papers)

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Research

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16 pages, 283 KiB  
Article
TPMT*3C as a Predictor of 6-Mercaptopurine-Induced Myelotoxicity in Thai Children with Acute Lymphoblastic Leukemia
by Thawinee Jantararoungtong, Supaporn Wiwattanakul, Rawiporn Tiyasirichokchai, Santirhat Prommas, Rattanaporn Sukprasong, Napatrupron Koomdee, Pimonpan Jinda, Jiratha Rachanakul, Nutthan Nuntharadthanaphong, Samart Pakakasama, Usanarat Anurathapan, Suradej Hongeng and Chonlaphat Sukasem
J. Pers. Med. 2021, 11(8), 783; https://doi.org/10.3390/jpm11080783 - 11 Aug 2021
Cited by 7 | Viewed by 2519
Abstract
The response to 6-mercaptopurine (6-MP) can be altered by genetic polymorphisms in genes encoding drug-metabolizing enzymes and drug transporters. The purpose of this study was to investigate the association between genetic polymorphisms of drug-metabolizing enzymes (TPMT 719A > G (*3C), [...] Read more.
The response to 6-mercaptopurine (6-MP) can be altered by genetic polymorphisms in genes encoding drug-metabolizing enzymes and drug transporters. The purpose of this study was to investigate the association between genetic polymorphisms of drug-metabolizing enzymes (TPMT 719A > G (*3C), ITPA 94C > A and ITPA 123G > A) and drug transporters (MRP4 912C > A and MRP4 2269G > A) with 6-MP-related myelotoxicity and hepatotoxicity in Thai children with acute lymphoblastic leukemia (ALL). The prescribed dosage of 6-MP and its adverse effects were assessed from medical records during the first 8 weeks and 9–24 weeks of maintenance therapy. Children with the TPMT*1/*3C genotype had a higher risk of leukopenia with an odds ratio (OR) of 4.10 (95% confidence interval (CI) of 1.06–15.94; p = 0.033) compared to wild type (TPMT*1/*1) patients. Heterozygous TPMT*3C was significantly associated with severe neutropenia with an increased risk (OR, 4.17; 95% CI, 1.25–13.90); p = 0.014) during the first 8 weeks. No association was found among ITPA94C > A, ITPA123G > A, MRP4 912C > A, and MRP4 2269G > A with myelotoxicity and hepatotoxicity. The evidence that TPMT heterozygotes confer risks of 6-MP-induced myelotoxicity also supports the convincing need to genotype this pharmacogenetic marker before the initiation of 6-MP therapy. Full article
(This article belongs to the Special Issue Personalized Medicine: Pharmacokinetics)
8 pages, 386 KiB  
Article
Significant Association of Polymorphisms in the TCF7L2 Gene with a Higher Risk of Type 2 Diabetes in a Moroccan Population
by Sarah Elhourch, Housna Arrouchi, Nour Mekkaoui, Younes Allou, Fatima Ghrifi, Loubna Allam, Naima Elhafidi, Lahcen Belyamani, Azeddine Ibrahimi, Naoual Elomri and Rachid Eljaoudi
J. Pers. Med. 2021, 11(6), 461; https://doi.org/10.3390/jpm11060461 - 24 May 2021
Cited by 7 | Viewed by 2571
Abstract
Background and aims: Several studies have shown that genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) are highly associated with the development of type 2 diabetes mellitus (T2DM) and its associated complications in several populations. The aim of our study was to [...] Read more.
Background and aims: Several studies have shown that genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) are highly associated with the development of type 2 diabetes mellitus (T2DM) and its associated complications in several populations. The aim of our study was to investigate the association of the rs7903146 (C/T) and rs12255372 (G/T) polymorphism in the TCF7L2 gene with the risk of developing T2DM in the Moroccan population. Material and methods: A total of 150 T2DM patients and 100 healthy controls were recruited for various anthropometric, biochemical and genetic parameters. Genotyping was performed by using Real Time-PCR. The frequency of genotypes, alleles, anthropometric measures, glycemia, glycated hemoglobin (HbA1c) were evaluated in patients and control, while lipid profile was available only for T2DM group. Results: Glycemia, HbA1c and body mass index (BMI) were significantly higher in T2DM group than control. Analysis of the distribution of the TCF7L2 rs7903146 genotype and allele revealed that the TT genotype was more frequent in T2DM group (24.0%) than in healthy controls (5%) (OR = 4.08, 95% confidence interval (CI = 1.95–11.80, p < 0.0001). The T allele was more frequent in diabetic patients (45.2%) than healthy control (34.5%) and it was associated with high risk of diabetes (OR = 2.13, 95% CI = 1.12–7.31, p = 0.005). The same results were found regarding rs12255372, TT genotype frequencies were 18,7% and 6.0% in T2DM and control group, respectively (OR = 3.11, 95% CI = 1.33–7.24, p = 0.004). The T allele was over-presented in diabetics compared to controls (45.3% and 38.0%, respectively) and increases the risk of T2DM (OR = 2.01, 95% CI = 1.04–3.10, p = 0.01). However, there was no significant difference between the three genotypes of rs7903146 and rs12255372 regarding age, BMI, glycemia, HbA1c and lipid profile. Conclusion: The present study confirmed a significant association of the TCF7L2 gene (rs7903146 (C/T) and rs12255372 (G/T) polymorphisms with a higher risk to T2DM in the Moroccan population. No significant difference in respect to anthropometric and metabolic parameters between different genotypes. Full article
(This article belongs to the Special Issue Personalized Medicine: Pharmacokinetics)
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21 pages, 1462 KiB  
Article
Interaction between Omeprazole and Gliclazide in Relation to CYP2C19 Phenotype
by Tanja Dujic, Sandra Cvijic, Amar Elezovic, Tamer Bego, Selma Imamovic Kadric, Maja Malenica, Alisa Elezovic, Ewan R. Pearson and Aida Kulo
J. Pers. Med. 2021, 11(5), 367; https://doi.org/10.3390/jpm11050367 - 3 May 2021
Cited by 7 | Viewed by 3661
Abstract
The antidiabetic drug gliclazide is partly metabolized by CYP2C19, the main enzyme involved in omeprazole metabolism. The aim of the study was to explore the interaction between omeprazole and gliclazide in relation to CYP2C19 phenotype using physiologically based pharmacokinetic (PBPK) modeling approach. Developed [...] Read more.
The antidiabetic drug gliclazide is partly metabolized by CYP2C19, the main enzyme involved in omeprazole metabolism. The aim of the study was to explore the interaction between omeprazole and gliclazide in relation to CYP2C19 phenotype using physiologically based pharmacokinetic (PBPK) modeling approach. Developed PBPK models were verified using in vivo pharmacokinetic profiles obtained from a clinical trial on omeprazole-gliclazide interaction in healthy volunteers, CYP2C19 normal/rapid/ultrarapid metabolizers (NM/RM/UM). In addition, the association of omeprazole cotreatment with gliclazide-induced hypoglycemia was explored in 267 patients with type 2 diabetes (T2D) from the GoDARTS cohort, Scotland. The PBPK simulations predicted 1.4–1.6-fold higher gliclazide area under the curve (AUC) after 5-day treatment with 20 mg omeprazole in all CYP2C19 phenotype groups except in poor metabolizers. The predicted gliclazide AUC increased 2.1 and 2.5-fold in intermediate metabolizers, and 2.6- and 3.8-fold in NM/RM/UM group, after simulated 20-day dosing with 40 mg omeprazole once and twice daily, respectively. The predicted results were corroborated by findings in patients with T2D which demonstrated 3.3-fold higher odds of severe gliclazide-induced hypoglycemia in NM/RM/UM patients concomitantly treated with omeprazole. Our results indicate that omeprazole may increase exposure to gliclazide and thus increase the risk of gliclazide-associated hypoglycemia in the majority of patients. Full article
(This article belongs to the Special Issue Personalized Medicine: Pharmacokinetics)
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13 pages, 868 KiB  
Article
An Ex Vivo and In Silico Study Providing Insights into the Interplay of Circulating miRNAs Level, Platelet Reactivity and Thrombin Generation: Looking beyond Traditional Pharmacogenetics
by Alix Garcia, Sylvie Dunoyer-Geindre, Séverine Nolli, Jean-Luc Reny and Pierre Fontana
J. Pers. Med. 2021, 11(5), 323; https://doi.org/10.3390/jpm11050323 - 21 Apr 2021
Cited by 5 | Viewed by 2226
Abstract
Platelet reactivity (PR), a key pharmacodynamic (PD) component of the action of antiplatelet drugs in cardiovascular disease (CVD) patients, is highly variable. PR is associated with occurrence or recurrence of thrombotic and bleeding events, but this association is modulated by several factors. Conventional [...] Read more.
Platelet reactivity (PR), a key pharmacodynamic (PD) component of the action of antiplatelet drugs in cardiovascular disease (CVD) patients, is highly variable. PR is associated with occurrence or recurrence of thrombotic and bleeding events, but this association is modulated by several factors. Conventional pharmacogenetics explains a minor part of this PR variability, and among determinants of PR, circulating microRNAs (miRNAs) have been the focus of attention during these last years as biomarkers to predict PR and clinical outcomes in CVD. This being said, the impact of miRNAs on platelet function and the mechanisms behind it are largely unknown. The level of a set of candidate miRNAs including miR-126-3p, miR-150-5p, miR-204-5p and miR-223-3p was quantified in plasma samples of stable CVD patients and correlated with PR as assessed by light-transmission aggregometry and in vivo thrombin generation markers. Finally, miRNA target networks were built based on genes involved in platelet function. We show that all candidate miRNAs were associated with platelet aggregation, while only miR-126-3p and miR-223-3p were positively correlated with in vivo thrombin generation markers. In silico analysis identified putative miRNA targets involved in platelet function regulation. Circulating miRNAs were associated with different aspects of platelet reactivity, including platelet aggregation and platelet-supported thrombin generation. This paves the way to a personalized antithrombotic treatment according to miRNA profile in CVD patients. Full article
(This article belongs to the Special Issue Personalized Medicine: Pharmacokinetics)
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16 pages, 691 KiB  
Article
Evaluation of Phenotypic and Genotypic Variations of Drug Metabolising Enzymes and Transporters in Chronic Pain Patients Facing Adverse Drug Reactions or Non-Response to Analgesics: A Retrospective Study
by Victoria Rollason, Célia Lloret-Linares, Kuntheavy Ing Lorenzini, Youssef Daali, Marianne Gex-Fabry, Valérie Piguet, Marie Besson, Caroline Samer and Jules Desmeules
J. Pers. Med. 2020, 10(4), 198; https://doi.org/10.3390/jpm10040198 - 27 Oct 2020
Cited by 10 | Viewed by 2831
Abstract
This retrospective study evaluates the link between an adverse drug reaction (ADR) or a non-response to treatment and cytochromes P450 (CYP), P-glycoprotein (P-gp) or catechol-O-methyltransferase (COMT) activity in patients taking analgesic drugs for chronic pain. Patients referred to a pain center for an [...] Read more.
This retrospective study evaluates the link between an adverse drug reaction (ADR) or a non-response to treatment and cytochromes P450 (CYP), P-glycoprotein (P-gp) or catechol-O-methyltransferase (COMT) activity in patients taking analgesic drugs for chronic pain. Patients referred to a pain center for an ADR or a non-response to an analgesic drug between January 2005 and November 2014 were included. The genotype and/or phenotype was obtained for assessment of the CYPs, P-gp or COMT activities. The relation between the event and the result of the genotype and/or phenotype was evaluated using a semi-quantitative scale. Our analysis included 243 individual genotypic and/or phenotypic explorations. Genotypes/phenotypes were mainly assessed because of an ADR (n = 145, 59.7%), and the majority of clinical situations were observed with prodrug opioids (n = 148, 60.9%). The probability of a link between an ADR or a non-response and the genotypic/phenotypic status of the patient was evaluated as intermediate to high in 40% and 28.2% of all cases, respectively. The drugs in which the probability of an association was the strongest were the prodrug opioids, with an intermediate to high link in 45.6% of the cases for occurrence of ADRs and 36.0% of the cases for non-response. This study shows that the genotypic and phenotypic approach is useful to understand ADRs or therapeutic resistance to a usual therapeutic dosage, and can be part of the evaluation of chronic pain patients. Full article
(This article belongs to the Special Issue Personalized Medicine: Pharmacokinetics)
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Review

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14 pages, 2282 KiB  
Review
Frequency of Important CYP450 Enzyme Gene Polymorphisms in the Iranian Population in Comparison with Other Major Populations: A Comprehensive Review of the Human Data
by Navid Neyshaburinezhad, Hengameh Ghasim, Mohammadreza Rouini, Youssef Daali and Yalda H. Ardakani
J. Pers. Med. 2021, 11(8), 804; https://doi.org/10.3390/jpm11080804 - 18 Aug 2021
Cited by 9 | Viewed by 4315
Abstract
Genetic polymorphisms in cytochrome P450 genes can cause alteration in metabolic activity of clinically important medicines. Thus, single nucleotide variants (SNVs) and copy number variations (CNVs) in CYP genes are leading factors of drug pharmacokinetics and toxicity and form pharmacogenetics biomarkers for drug [...] Read more.
Genetic polymorphisms in cytochrome P450 genes can cause alteration in metabolic activity of clinically important medicines. Thus, single nucleotide variants (SNVs) and copy number variations (CNVs) in CYP genes are leading factors of drug pharmacokinetics and toxicity and form pharmacogenetics biomarkers for drug dosing, efficacy, and safety. The distribution of cytochrome P450 alleles differs significantly between populations with important implications for personalized drug therapy and healthcare programs. To provide a meta-analysis of CYP allele polymorphisms with clinical importance, we brought together whole-genome and exome sequencing data from 800 unrelated individuals of Iranian population (100 subjects from 8 major ethnics of Iran) and 63,269 unrelated individuals of five major human populations (EUR, AMR, AFR, EAS and SAS). By integrating these datasets with population-specific linkage information, we evolved the frequencies of 140 CYP haplotypes related to 9 important CYP450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5) giving a large resource for major genetic determinants of drug metabolism. Furthermore, we evaluated the more frequent Iranian alleles and compared the dataset with the Caucasian race. Finally, the similarity of the Iranian population SNVs with other populations was investigated. Full article
(This article belongs to the Special Issue Personalized Medicine: Pharmacokinetics)
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19 pages, 885 KiB  
Review
Drug-Drug Interactions Leading to Adverse Drug Reactions with Rivaroxaban: A Systematic Review of the Literature and Analysis of VigiBase
by Silvia Fernandez, Camille Lenoir, Caroline Flora Samer and Victoria Rollason
J. Pers. Med. 2021, 11(4), 250; https://doi.org/10.3390/jpm11040250 - 30 Mar 2021
Cited by 15 | Viewed by 5156
Abstract
Rivaroxaban has become an alternative to vitamin K antagonists, which are considered to be at higher risk of drug-drug interactions (DDI) and more difficult to use. However, DDI do occur. We systematically reviewed studies that evaluated them and analysed DDI and subsequent adverse [...] Read more.
Rivaroxaban has become an alternative to vitamin K antagonists, which are considered to be at higher risk of drug-drug interactions (DDI) and more difficult to use. However, DDI do occur. We systematically reviewed studies that evaluated them and analysed DDI and subsequent adverse drug reactions (ADR) reported in spontaneous reports and VigiBase. We systematically searched articles that explored DDI with rivaroxaban up to 20 August 2018 via Medline, Embase and Google Scholar. Data from VigiBase came from spontaneous reports recovered up to 2 January 2018, where Omega was used to detect signals and identify potential interactions in terms of triplets with two drugs and one ADR. We identified 31 studies and 28 case reports. Studies showed significant variation in the pharmacokinetic for rivaroxaban, and an increased risk of haemorrhage or thromboembolic events due to DDI was highlighted in case reports. From VigiBase, a total of 21,261 triplets were analysed and the most reported was rivaroxaban–aspirin–gastrointestinal haemorrhage. In VigiBase, only 34.8% of the DDI reported were described or understood, and most were pharmacodynamic DDI. These data suggest that rivaroxaban should be considered to have significant potential for DDI, especially with CYP3A/P-gp modulators or with drugs that impair haemostasis. Full article
(This article belongs to the Special Issue Personalized Medicine: Pharmacokinetics)
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Other

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24 pages, 642 KiB  
Systematic Review
Genetic Predictors for Sinusoidal Obstruction Syndrome—A Systematic Review
by Nicolas Waespe, Sven Strebel, Simona Jurkovic Mlakar, Maja Krajinovic, Claudia Elisabeth Kuehni, Tiago Nava and Marc Ansari
J. Pers. Med. 2021, 11(5), 347; https://doi.org/10.3390/jpm11050347 - 26 Apr 2021
Cited by 6 | Viewed by 3345
Abstract
Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication after hematopoietic stem cell transplantation (HSCT) or antineoplastic treatment without HSCT. Genetic variants were investigated for their association with SOS, but the evidence is inconclusive. We performed a systematic literature review to identify genes, [...] Read more.
Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication after hematopoietic stem cell transplantation (HSCT) or antineoplastic treatment without HSCT. Genetic variants were investigated for their association with SOS, but the evidence is inconclusive. We performed a systematic literature review to identify genes, gene variants, and methods of association analyses of genetic markers with SOS. We identified 23 studies after HSCT and 4 studies after antineoplastic treatment without HSCT. One study (4%) performed whole-exome sequencing (WES) and replicated the analysis in an independent cohort, 26 used a candidate-gene approach. Three studies included >200 participants (11%), and six were of high quality (22%). Variants in 34 genes were tested in candidate gene studies after HSCT. Variants in GSTA1 were associated with SOS in three studies, MTHFR in two, and CPS1, CTH, CYP2B6, GSTM1, GSTP1, HFE, and HPSE in one study each. UGT2B10 and LNPK variants were identified in a WES analysis. After exposure to antineoplastic agents without HSCT, variants in six genes were tested and only GSTM1 was associated with SOS. There was a substantial heterogeneity of populations within and between studies. Future research should be based on sufficiently large homogenous samples, adjust for covariates, and replicate findings in independent cohorts. Full article
(This article belongs to the Special Issue Personalized Medicine: Pharmacokinetics)
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