Cells. 2022 Oct 17;11(20):3267. doi: 10.3390/cells11203267.

ABSTRACT

Major Depressive Disorder (MDD) is a highly prevalent multifactorial psychopathology affected by neurotransmitter levels. Monoamine Oxidase A (MAOA) influences several neural pathways by modulating these levels. This systematic review (per PRISMA protocol and PECOS strategy) endeavors to understand the MAOA uVNTR polymorphism influence on MDD and evaluate its 3R/3R and 3R* genotypic frequencies fluctuation in MDD patients from different populations. We searched the Web of Science, PubMed, Virtual Health Library, and EMBASE databases for eligible original articles that brought data on genotypic frequencies related to the MAOA uVNTR variant in patients with MDD. We excluded studies with incomplete data (including statistical data), reviews, meta-analyses, and abstracts. Initially, we found 43 articles. After removing duplicates and applying the inclusion/exclusion criteria, seven articles remained. The population samples studied were predominantly Asians, with high 3R and 4R allele frequencies. Notably, we observed higher 3R/3R (female) and 3R* (male) genotype frequencies in the healthy control groups and higher 4R/4R (female) and 4R* (male) genotype frequencies in the MDD groups in the majority of different populations. Despite some similarities in the articles analyzed, there is still no consensus on the MAOA uVNTR variant's role in MDD pathogenesis.

PMID:36291132 | DOI:10.3390/cells11203267

Biomedicines. 2022 Oct 13;10(10):2564. doi: 10.3390/biomedicines10102564.

ABSTRACT

Aspirin resistance (AR) is a pressing problem in current ischemic stroke care. Although the role of genetic variations is widely considered, the data still remain controversial. Our aim was to investigate the contribution of genetic features to laboratory AR measured through platelet aggregation with arachidonic acid (AA) and adenosine diphosphate (ADP) in ischemic stroke patients. A total of 461 patients were enrolled. Platelet aggregation was measured via light transmission aggregometry. Eighteen single-nucleotide polymorphisms (SNPs) in ITGB3, GPIBA, TBXA2R, ITGA2, PLA2G7, HMOX1, PTGS1, PTGS2, ADRA2A, ABCB1 and PEAR1 genes and the intergenic 9p21.3 region were determined using low-density biochips. We found an association of rs1330344 in the PTGS1 gene with AR and AA-induced platelet aggregation. Rs4311994 in ADRA2A gene also affected AA-induced aggregation, and rs4523 in the TBXA2R gene and rs12041331 in the PEAR1 gene influenced ADP-induced aggregation. Furthermore, the effect of rs1062535 in the ITGA2 gene on NIHSS dynamics during 10 days of treatment was found. The best machine learning (ML) model for AR based on clinical and genetic factors was characterized by AUC = 0.665 and F1-score = 0.628. In conclusion, the association study showed that PTGS1, ADRA2A, TBXA2R and PEAR1 polymorphisms may affect laboratory AR. However, the ML model demonstrated the predominant influence of clinical features.

PMID:36289824 | DOI:10.3390/biomedicines10102564

Biomedicines. 2022 Oct 12;10(10):2546. doi: 10.3390/biomedicines10102546.

ABSTRACT

Response to metformin, first-line therapy for type 2 diabetes mellitus (T2DM), exists interindividual variation. Considering that transporters belonging to the solute carrier (SLC) superfamily are determinants of metformin pharmacokinetics, we evaluated the effects of promoter variants in organic cation transporter 1 (OCT1) (SLC22A1 rs628031), OCT2 (SLC22A2 rs316019), multidrug and toxin extrusion protein 1 (MATE1) (SLC47A1 rs2289669), and MATE2 (SLC47A2 rs12943590) on the variation in metformin response. The glucose-lowering effects and improvement of insulin resistance of metformin were assessed in newly diagnosed, treatment-naive type 2 diabetic patients of Han nationality in Chaoshan China (n = 93) receiving metformin. Fasting plasma glucose (FPG), fasting insulin (FINS), glycated hemoglobin A1 (HbA1C), homeostasis model assessment-insulin sensitivity (HOMA-IS), and homeostasis model assessment-insulin resistance (HOMA-IR) were the main metformin efficacy measurements. There were significant correlations between both SLC47A1 rs2289669 and SLC47A2 rs12943590 and the efficacy of metformin in individuals with T2DM. In normal weight T2DM patients, significant associations between the AA and GG genotypes of the rs2289669 variant of SLC47A1 and a greater reduction in FINS and HOMA-IR were detected. A significant correlation was observed between the AG genotype of the rs12943590 polymorphism of SLC47A2 and a greater reduction in HOMA-IR. Gene-environment interaction analysis showed that in the FINS interaction model, the second-order of dose30_g-SLC47A2 rs12943590 was statistically significant. The variants of SLC47A1 rs2289669 and SLC47A2 rs12943590 could be predictors of insulin resistance in type 2 diabetic patients treated with metformin. The second-order interaction of dose30_g-SLC47A2 rs12943590 may have a significant effect on FINS in patients with T2DM on metformin treatment. These findings suggest that promoter variants of SLC47A1 and SLC47A2 are important determinants of metformin transport and response in type 2 diabetes mellitus.

PMID:36289808 | DOI:10.3390/biomedicines10102546

Biomedicines. 2022 Sep 30;10(10):2445. doi: 10.3390/biomedicines10102445.

ABSTRACT

Digital technologies are shifting the paradigm of medicine in a way that will transform the healthcare industry. Conventional medical approaches focus on treating symptoms and ailments for large groups of people. These approaches can elicit differences in treatment responses and adverse reactions based on population variations, and are often incapable of treating the inherent pathophysiology of the medical conditions. Advances in genetics and engineering are improving healthcare via individualized treatments that include gene and cell therapies, pharmacogenetics, disease detection, and diagnostics. This paper highlights ways that artificial intelligence can help usher in an age of personalized medicine.

PMID:36289707 | DOI:10.3390/biomedicines10102445

Ter Arkh. 2022 Jun 17;94(5):610-615. doi: 10.26442/00403660.2022.05.201495.

ABSTRACT

AIM: To evaluate the possible association of CYP2C8 gene polymorphisms with the clinical efficacy and safety of ketorolac in relation to postoperative pain.

MATERIALS AND METHODS: The study included 107 patients after video laparoscopic cholecystectomy, who received ketorolac (30 mg 2.0 w/m 3 r/d) as postoperative pain relief. All patients were genotyped for CYP2C8. The pain syndrome was assessed using the visual analog scale, the McGill pain questionnaire. The profile of adverse reactions was assessed by the dynamics of red blood counts, as a possible trigger for the development of gastrointestinal bleeding according to the method of global assessment of triggers (Global Trigger Tool GTT).

RESULTS: According to visual analog scale data: in carriers of the genotype CYP2C8*3 (rs10509681) and CYP2C8*3 (rs11572080) after 12, 24, 36, 48 hours the intensity of pain syndrome is lower than in carriers of the wild type (p0.05). According to the McGill pain questionnaire, there were no statistically significant differences in pain intensity between the two groups.

CONCLUSION: In carriers of the genotype CYP2C8*3 (rs10509681) and CYP2C8*3 (rs11572080), the effectiveness of anesthesia with ketorolac is higher than in carriers of the wild type. Carriage of the genotype CYP2C8*3 (rs10509681) and CYP2C8*3 (rs10509681) does not affect the risk of developing adverse reactions after ketorolac anesthesia.

PMID:36286958 | DOI:10.26442/00403660.2022.05.201495

Ter Arkh. 2022 Feb 15;94(2):200-208. doi: 10.26442/00403660.2022.02.201371.

ABSTRACT

AIM: To study the polymorphic markers CYP2D6*4 (G1846A, rs3892097), CYP2D6*6 (T1707del, rs5030655), CYP2D6*10 (C100T, rs1065852), CYP2D6*41 (G2988A, rs28371725) and CYP2D6*3 (A2549del, rs4986774) role in treatment optimization of portal hypertension with propranolol in patients with liver cirrhosis (LC).

MATERIALS AND METHODS: The study included 60 patients with LC who received propranolol therapy at a daily dose of 30 mg for 14 days. The efficacy of treatment was assessed by ultrasonography measuring the linear blood flow velocity of portal vein. Genotyping of CYP2D6*4, CYP2D6*6, CYP2D6*10, CYP2D6*41 and CYP2D6*3 was carried out by real-time polymerase chain reaction. Evaluation of the CYP2D6 activity was carried out by determining the ratio of pinoline and its metabolite concentration in morning urine using high performance liquid chromatography with mass spectrometry.

RESULTS: Positive hemodynamics in the form of any increase in the mean linear blood flow velocity of the portal vein compared to baseline was observed in 41 patients. Portal vein mean linear blood flow rate increased from 10.43.9 to 14.74.3 cm/s (p0.001). Of these, 29 patients showed an increase in this indicator by 20% from the initial one with a dynamic of 5.5 cm/s (p0.001). The regression analysis constructed by us revealed the presence of a statistically significant effect of the CYP2D6 gene polymorphic marker G1846A carriage on the propranolol therapeutic effect (p0.05). There was no statistically significant effect of polymorphic markers T1707del, C100T, G2988A, and A2549del of the CYP2D6 gene (p0.05). No convincing reliable dependence of CYP2D6 activity on the severity of LC was revealed (p0.05).

CONCLUSION: An association was found between CYP2D6 gene polymorphic marker G1846A carriage and the hemodynamic effect of propranolol in patients with LC of the Russian population. There is a more significant positive dynamics of manifestations of portal hypertension on the background of propranolol therapy in carriers of the homozygous GG CYP2D6*4 genotype, in contrast to patients with the heterozygous GA genotype. Based on the results of the study, an algorithm has been developed for personalizing the treatment of patients with LC with nonselective b-adrenergic blockers using the method of CYP2D6 genotyping. Carriage of polymorphic markers T1707del, C100T, G2988A and A2549del gene CYP2D6 does not affect the effectiveness of propranolol therapy in patients with LC.

PMID:36286743 | DOI:10.26442/00403660.2022.02.201371

Ter Arkh. 2021 Nov 15;93(11):1334-1339. doi: 10.26442/00403660.2021.11.201220.

ABSTRACT

AIM: Find the prevalence of CYP2C8*3 (rs10509681; rs11572080), PTGS-1 (rs10306135; rs12353214) and PTGS-2 (rs20417) alleles and genotypes in four ethnic groups among Laks, Avars, Dargins and Kumyks.

MATERIALS AND METHODS: The study involved 400 volunteers from four ethnic groups living in Republic of Dagestan: 100 participants from each group. Carriage of polymorphic markers was determined by reverse transcription polymerase chain reaction.

RESULTS: Minor allele frequency of the CYP2C8 (rs10509681) was 5.5% in Avars, 10% in Dargins, Laks and Kumyks 6.5% both; CYP2C8 (rs11572080) was 5.5% in Avars, 9.5% in Dargins, 6.5% in Laks, 8.5% in Kumyks; PTGS-1 (rs10306135) in Avars 10.5%, in Dargins 13.0%, in Laks 9.5% and Kumyks 7.5%; PTGS-1 (rs12353214) in Avars 9.0%, in Dargins 4.5%, in Laks 7.5%, in Kumyks 8.0%; PTGS-2 (rs20417) in Avars 1.0%, in Dargins 2.5%, in Laks 3.5%, in Kumyks 5.0%. There were no significant differences between groups.

CONCLUSION: The study of CYP2C8 and PTGS-1 and 2 gene polymorphisms is promising for predicting the effectiveness and safety of non-steroidal anti-inflammatory drug therapy, due to the high prevalence of these polymorphisms in ethnic groups in the North Caucasus.

PMID:36286656 | DOI:10.26442/00403660.2021.11.201220

Pharmacogenomics. 2022 Oct 26. doi: 10.2217/pgs-2022-0026. Online ahead of print.

ABSTRACT

Aims: To describe the diversity of pharmacogenomic variants affecting warfarin metabolism in Sri Lankans. Materials & methods: Genotype data were filtered out from an anonymized database of 400 Sri Lankans, and minor allele frequencies (MAF) were calculated. Variants of CYP2C9, VKORC1 and CYP4F2 genes were studied. Results: Overall, CYP2C9*2 and CYP2C9*3 alleles had MAFs of 2.25% (95% CI: 0.80-3.70) and 10.38% (95% CI: 7.50-13.50), respectively. CYP2C9*11 and CYP2C9*14 alleles had MAFs of 0.13% (95% CI: 0-0.74) and 2.50% (95% CI: 0.97-4.03), respectively. MAFs of VKORC1 variants rs7294, rs9934438, rs8050894 and rs2884737 were 47.25% (95% CI: 42.36-52.14), 10.13% (95% CI: 7.28-13.22), 9.88% (95% CI: 7.06-12.94) and 4.88% (95% CI: 2.86-7.14), respectively. MAF of CYP4F2 variant rs2108622 was 45.63% (95% CI: 40.87-50.63). Conclusion: Compared with other populations, the frequencies of some studied variants were significantly different in Sri Lankans, and these are likely to account for variability in warfarin dosage requirements.

PMID:36285665 | DOI:10.2217/pgs-2022-0026

Pharmacogenomics. 2022 Oct 26. doi: 10.2217/pgs-2022-0145. Online ahead of print.

ABSTRACT

Tweetable abstract The pharmaco-omics revolution has started and, as a wild stream, sooner or later, will expand and dramatically improve drug discovery and individual response to pharmacotherapy. Hopefully, we will all be ready to follow the stream.

PMID:36285650 | DOI:10.2217/pgs-2022-0145

Hepatol Int. 2022 Oct 25. doi: 10.1007/s12072-022-10437-1. Online ahead of print.

NO ABSTRACT

PMID:36284080 | DOI:10.1007/s12072-022-10437-1

Breast. 2022 Oct 15;66:157-161. doi: 10.1016/j.breast.2022.10.005. Online ahead of print.

ABSTRACT

BACKGROUND: Gastric pH changes by proton-pump-inhibitors (PPIs) were found to affect progression-free survival (PFS) in metastatic breast cancer (mBC) patients treated with palbociclib. The current study was aimed at investigating whether the same effect could occur in patients treated with ribociclib.

PATIENTS AND METHODS: Patients with hormone-positive/HER-2-negative mBC candidates for first-line treatment with ribociclib were enrolled in this retrospective-cohort study. Patients were classified as "no concomitant PPIs" or "concomitant PPIs"; PPI administration covered the entire or not less than 2/3 of treatment with ribociclib. All clinical interventions were made according to clinical practice.

RESULTS: A total of 128 patients were consecutively enrolled in the study; 78 belonged to the "no concomitant PPIs" group and 50 to the "concomitant PPIs" group. One hundred and six patients were endocrine-sensitive and received ribociclib and letrozole, while 22 were endocrine-resistant and were treated with ribociclib and fulvestrant. The most prescribed PPI was lansoprazole. According to PFS, patients taking PPIs had a PFS almost superimposable to those assuming ribociclib and endocrine therapy alone (35.3 vs. 49.2 months, p = 0.594). No difference in PFS was observed in estrogen-sensitive or estrogen-resistant mBC in the presence or absence of concomitant PPI treatment (p = 0.852). No correlation with adverse events was found including grade>2 hematological toxicities.

CONCLUSIONS: The present study supports the hypothesis that the concomitant use of PPIs does not compromise the efficacy of ribociclib in a real-life setting.

PMID:36283134 | DOI:10.1016/j.breast.2022.10.005

Medicine (Baltimore). 2022 Oct 21;101(42):e31277. doi: 10.1097/MD.0000000000031277.

ABSTRACT

BACKGROUND: Based on network pharmacology and molecular docking, this study discusses the potential mechanism of Gancao Xiexin decoction in the treatment of Behçet disease (BD) to provide a more reliable theoretical basis for the treatment of BD.

METHODS: The effective components and action targets of Gancao Xiexin decoction were obtained by searching the traditional Chinese medicine systems pharmacology database and analysis platform database, and the genome annotation database platform (GeneCards) database Search BD related targets in Online Mendelian inheritance in man database, pharmacogenetics and pharmacogenomics knowledge base database, therapeutic target database and drugbank database, Venny analysis tool was used to overlap drug targets and disease targets; The "active drug active ingredient target gene" network was constructed with the help of Cytoscape 3.8.2 software, and the protein-protein interaction (PPI) network was constructed with string database; R language was used for Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of genes and genomes (KEGG) pathway enrichment analysis; Target prediction based on pubchemp platform.

RESULTS: A total of 163 active components were identified, with 730 corresponding targets, including 56 common targets of the active components and BD. GO enrichment analysis yielded 1126 entries for biological processes (BP), 17 entries for cellular components, and 89 entries for molecular functions. The significant items of BP enrichment mainly included reaction to lipopolysaccharide, reaction to bacteria-derived molecules, exogenous apoptosis signal pathways, and biological metabolism processes of reactive oxygen species. KEGG pathway enrichment analysis identified 118 significantly enriched pathways. The molecular docking technology verified that its effective components can effectively bind to the corresponding BD related target proteins.

CONCLUSION: Gancao Xiexin decoction synergistically treats BD through multi-component, multi-target, and multi-channel mechanisms, which provides a basis for further study of the active components and mechanism of Gancao Xiexin decoction.

PMID:36281148 | DOI:10.1097/MD.0000000000031277

Eur Psychiatry. 2022 Oct 25:1-19. doi: 10.1192/j.eurpsy.2022.2333. Online ahead of print.

NO ABSTRACT

PMID:36281033 | DOI:10.1192/j.eurpsy.2022.2333

Nat Commun. 2022 Oct 24;13(1):6323. doi: 10.1038/s41467-022-33144-9.

ABSTRACT

Statins, a family of FDA-approved cholesterol-lowering drugs that inhibit the rate-limiting enzyme of the mevalonate metabolic pathway, have demonstrated anticancer activity. Evidence shows that dipyridamole potentiates statin-induced cancer cell death by blocking a restorative feedback loop triggered by statin treatment. Leveraging this knowledge, we develop an integrative pharmacogenomics pipeline to identify compounds similar to dipyridamole at the level of drug structure, cell sensitivity and molecular perturbation. To overcome the complex polypharmacology of dipyridamole, we focus our pharmacogenomics pipeline on mevalonate pathway genes, which we name mevalonate drug-network fusion (MVA-DNF). We validate top-ranked compounds, nelfinavir and honokiol, and identify that low expression of the canonical epithelial cell marker, E-cadherin, is associated with statin-compound synergy. Analysis of remaining prioritized hits led to the validation of additional compounds, clotrimazole and vemurafenib. Thus, our computational pharmacogenomic approach identifies actionable compounds with pathway-specific activities.

PMID:36280687 | DOI:10.1038/s41467-022-33144-9

Biomed Pharmacother. 2022 Oct 21;156:113899. doi: 10.1016/j.biopha.2022.113899. Online ahead of print.

ABSTRACT

Cannabinoid derivates have been largely used for different medical purpose. In the literature, several methods capable of separating THC and its principles metabolites are described, although Δ8- and Δ9-THC separation has not been completely achieved. THC metabolism has not been fully understood and metabolites plasma distribution in healthy and pathological patients remains to further deepen. The aim of this study was the validation of UHPLC-MS/MS method for the quantification of 10 cannabinoids in human plasma, as important tool for improving clinical efficacy of cannabis administration. Obtained results were in accordance with recommendations of ICH Harmonised Guideline for bioanalytical method validation, showing a good linearity, optimal accuracy as well as satisfactory results in terms of intra-day and inter-day precision and matrix effect. Furthermore, blood sampling study was performed to investigate the better collection method. Optimal separation of Δ-9-tetrahydrocannabinol (Δ9-THC), Δ8-tetrahydrocannabinol (Δ8-THC) was obtained. The present method showed optimal linearity and satisfactory results in terms of specificity and selectivity. Recovery was between 92.0% and 96.5% for all analytes. The matrix-effect showed good performance; no carry over was observed. Cannabinoid metabolites present in higher plasma concentrations were: 11-Hydroxy-Δ9-tetrahydrocannabinol, 11-Nor-9carboxy-Δ9-tetrahydrocannabinol and THC-COOH-glucuronide. Method performance makes it suitable for routine purposes and a potential tool for therapeutic ranges definition. The present work will be used to test several samples in a long-term clinical study, paving the way for further future works.

PMID:36279720 | DOI:10.1016/j.biopha.2022.113899

Pharmacogenomics J. 2022 Oct 22. doi: 10.1038/s41397-022-00295-3. Online ahead of print.

ABSTRACT

The study aimed to conduct a meta-analysis of studies comparing pharmacogenetically guided dosing of antidepressants with empiric standard of care. Publications referring to genotype-guided antidepressant therapy were identified via PubMed, Google Scholar, Scopus, Web of Science, Embase, and Cochrane databases from the inception of the databases to 2021. In addition, bibliographies of all articles were manually searched for additional references not identified in primary searches. Studies comparing clinical outcomes between two groups of patients who received antidepressant treatment were included in meta-analysis. Analysis of the data revealed statistically significant differences between the experimental group receiving pharmacogenetically guided dosing and the empirically treated controls. Specifically, genotype-guided treatment significantly improved response and remission of patients after both eight and twelve weeks of therapy, whereas no effect on the development of adverse drug reactions was observed. This meta-analysis indicates that the use of preemptive genotyping to guide dosing of antidepressants might increase treatment efficacy.

PMID:36273107 | DOI:10.1038/s41397-022-00295-3

Clin Transl Sci. 2022 Oct 21. doi: 10.1111/cts.13396. Online ahead of print.

ABSTRACT

This study conducted a pairwise comparison of antihypertensive and metabolic effects of hydrochlorothiazide (HCTZ) and chlorthalidone (CTD) at 25 mg/day in the same individuals to address the clinical dilemma on preferred thiazide for hypertension (HTN) management. We included 15 African American (AA) and 35 European American (EA) patients with HTN treated with HCTZ and CTD as part of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, respectively. Mean reduction in systolic/diastolic blood pressure (SBP/DBP) with HCTZ versus CTD was 8/5 versus 16/8 mmHg among EA patients (p < 1.0e-5 SBP, p = 0.002 DBP) and 11/8 versus 20/11 mmHg among AA patients (p = 0.03 SBP, p = 0.22 DBP). While CTD showed clinically meaningful benefit over HCTZ in two-thirds of participants with respect to SBP reduction and half of EA patients with respect to DBP reduction, a majority of AA patients (53%) showed similar DBP reduction with both thiazides. Sixty percent of AA patients and 29% of EA patients attained blood pressure (BP) <140/90 mmHg with both thiazides. Mean potassium (K+) reduction was greater with CTD compared to HCTZ both in EA patients (mean difference = 0.35, p = 0.0002) and AA patients (0.49, p = 0.043). While 31% of AA patients developed severe hypokalemia on CTD, <5% of others developed severe hypokalemia. Although 46% of AA patients on CTD required K+ supplementation, only 6%-11% of others required supplementation. Overall, in the majority of EA patients, CTD was superior to HCTZ, whereas among AA patients, it was superior in a minority, and was associated with significant potassium-related risk, suggesting that guideline preferences for CTD over HCTZ are reasonable in EA patients but may be less reasonable in AA patients, particularly if the target is <140/90 mmHg.

PMID:36271676 | DOI:10.1111/cts.13396

Biomed Pharmacother. 2022 Nov;155:113787. doi: 10.1016/j.biopha.2022.113787. Epub 2022 Oct 6.

ABSTRACT

Tumor-infiltrating immune cells (TIICs) play a critical role in breast cancer (BC) prognosis, but little is known regarding the efficacy of endocrine therapy in patients with ER-positive BC with diverse immunological phenotypes. To investigate whether TIICs affect survival after endocrine therapy in patients with different BC molecular subtypes, data were gathered from six studies totaling 1900 samples. CIBERSORTx was used to analyze the invasion of 22 immune cell subpopulations using a bulk gene expression profile. The relationships of immune-related metagenes and immune cell subsets with survival (distant metastasis-free survival, relapse-free survival, and overall survival) were studied using Cox regression models with cell proportions modeled in quartiles. The immune score and IGHG3 and LCK gene activity were linked to a better prognosis. Among the immune cells, monocytes, resting CD4+ memory T cells and plasma cells were correlated with prolonged survival, while neutrophils, Tregs, M0 macrophages, and M2 macrophages were associated with an unfavorable prognosis. Similar effects were reported for the luminal A subtype. In the luminal B subtype, γδ T cells and eosinophils were favorable prognostic factors. Covariate-adjusted multivariate Cox regression analysis revealed that high proportions of resting CD4+ memory T cells and resting dendritic cells were correlated with a good prognosis. Meanwhile, neutrophils were associated with an unfavorable prognosis. Understanding how monocytes and macrophages interact in the tumor microenvironment may be a promising study focus. Comprehensive research on the cellular immune response in tumors could help facilitate the development of new treatments.

PMID:36271565 | DOI:10.1016/j.biopha.2022.113787

Pharm Res. 2022 Oct 21. doi: 10.1007/s11095-022-03407-7. Online ahead of print.

ABSTRACT

PURPOSE: Voriconazole is an essential antifungal drug whose complex pharmacokinetics with high interindividual variability impedes effective and safe therapy. By application of the minimally-invasive sampling technique microdialysis, interstitial space fluid (ISF) concentrations of VRC and its potentially toxic N-oxide metabolite (NO) were assessed to evaluate target-site exposure for further elucidating VRC pharmacokinetics.

METHODS: Plasma and ISF samples of a clinical trial with an approved VRC dosing regimen were analyzed for VRC and NO concentrations. Concentration-time profiles, exposure assessed as area-under-the-curve (AUC) and metabolic ratios of four healthy adults in plasma and ISF were evaluated regarding the impact of multiple dosing and CYP2C19 genotype.

RESULTS: VRC and NO revealed distribution into ISF with AUC values being ≤2.82- and 17.7-fold lower compared to plasma, respectively. Intraindividual variability of metabolic ratios was largest after the first VRC dose administration while interindividual variability increased with multiple dosing. The CYP2C19 genotype influenced interindividual differences with a maximum 6- and 24-fold larger AUCNO/AUCVRC ratio between the intermediate and rapid metabolizer in plasma and ISF, respectively. VRC metabolism was saturated/auto-inhibited indicated by substantially decreasing metabolic concentration ratios with increasing VRC concentrations and after multiple dosing.

CONCLUSION: The feasibility of the simultaneous microdialysis of VRC and NO in vivo was demonstrated and provided new quantitative insights by leveraging distribution and metabolism processes of VRC in humans. The exploratory analysis suggested substantial dissimilarities of VRC and NO pharmacokinetics in plasma and ISF. Ultimately, a thorough understanding of target-site pharmacokinetics might contribute to the optimization of personalized VRC dosing regimens.

PMID:36271205 | DOI:10.1007/s11095-022-03407-7

Support Care Cancer. 2022 Oct 21. doi: 10.1007/s00520-022-07404-9. Online ahead of print.

ABSTRACT

Studies suggest wide heterogeneity in pain management response. Improved methods of pain pharmacotherapy are urgently needed to improve clinical response and safety profile of analgesics. The study or application of how genetics influence response to medications is called pharmacogenomics (PGx). PGx testing is a tool that may support more precise selection and dosing of pain medicines. PGx guidelines exist for drug-gene interactions with high levels of evidence and can be applied in clinical practice for more precise care in patients with cancer. The Clinical Pharmacogenetics Implementation Consortium (CPIC) is a publicly funded international consortium of experts who curate published PGx data and create peer-reviewed guidelines on how to translate PGx results into actionable prescribing decisions. Given the immense need to improve pain management, it is important to increase awareness and consider application of CPIC guidelines to pain management strategies. This commentary concisely describes how PGx can be used to aid in more precise applications of pain pharmacotherapy based on the CPIC guidelines.

PMID:36271058 | DOI:10.1007/s00520-022-07404-9