BMC Cancer. 2023 Aug 29;23(1):806. doi: 10.1186/s12885-023-11330-2.

ABSTRACT

BACKGROUND: HeberFERON is a co-formulation of α2b and γ interferons, based on their synergism, which has shown its clinical superiority over individual interferons in basal cell carcinomas. In glioblastoma (GBM), HeberFERON has displayed promising preclinical and clinical results. This led us to design a microarray experiment aimed at identifying the molecular mechanisms involved in the distinctive effect of HeberFERON compared to the individual interferons in U-87MG model.

METHODS: Transcriptional expression profiling including a control (untreated) and three groups receiving α2b-interferon, γ-interferon and HeberFERON was performed using an Illumina HT-12 microarray platform. Unsupervised methods for gene and sample grouping, identification of differentially expressed genes, functional enrichment and network analysis computational biology methods were applied to identify distinctive transcription patterns of HeberFERON. Validation of most representative genes was performed by qPCR. For the cell cycle analysis of cells treated with HeberFERON for 24 h, 48 and 72 h we used flow cytometry.

RESULTS: The three treatments show different behavior based on the gene expression profiles. The enrichment analysis identified several mitotic cell cycle related events, in particular from prometaphase to anaphase, which are exclusively targeted by HeberFERON. The FOXM1 transcription factor network that is involved in several cell cycle phases and is highly expressed in GBMs, is significantly down regulated. Flow cytometry experiments corroborated the action of HeberFERON on the cell cycle in a dose and time dependent manner with a clear cellular arrest as of 24 h post-treatment. Despite the fact that p53 was not down-regulated, several genes involved in its regulatory activity were functionally enriched. Network analysis also revealed a strong relationship of p53 with genes targeted by HeberFERON. We propose a mechanistic model to explain this distinctive action, based on the simultaneous activation of PKR and ATF3, p53 phosphorylation changes, as well as its reduced MDM2 mediated ubiquitination and export from the nucleus to the cytoplasm. PLK1, AURKB, BIRC5 and CCNB1 genes, all regulated by FOXM1, also play central roles in this model. These and other interactions could explain a G2/M arrest and the effect of HeberFERON on the proliferation of U-87MG.

CONCLUSIONS: We proposed molecular mechanisms underlying the distinctive behavior of HeberFERON compared to the treatments with the individual interferons in U-87MG model, where cell cycle related events were highly relevant.

PMID:37644431 | DOI:10.1186/s12885-023-11330-2

Cell Death Dis. 2023 Aug 29;14(8):572. doi: 10.1038/s41419-023-05902-0.

NO ABSTRACT

PMID:37644008 | DOI:10.1038/s41419-023-05902-0

Allergy. 2023 Aug 28. doi: 10.1111/all.15869. Online ahead of print.

NO ABSTRACT

PMID:37641395 | DOI:10.1111/all.15869

Diabetes Care. 2023 Aug 28:dc222494. doi: 10.2337/dc22-2494. Online ahead of print.

ABSTRACT

OBJECTIVE: Metformin is the most common treatment for type 2 diabetes (T2D). However, there have been no pharmacogenomic studies for T2D in which a population of color was used in the discovery analysis. This study sought to identify genomic variants associated with metformin response in African American patients with diabetes.

RESEARCH DESIGN AND METHODS: Patients in the discovery set were adult, African American participants from the Diabetes Multi-omic Investigation of Drug Response (DIAMOND), a cohort study of patients with T2D from a health system serving southeast Michigan. DIAMOND participants had genome-wide genotype data and longitudinal electronic records of laboratory results and medication fills. The genome-wide discovery analysis identified polymorphisms correlated to changes in glycated hemoglobin (HbA1c) levels among individuals on metformin monotherapy. Lead associations were assessed for replication in an independent cohort of African American participants from Kaiser Permanente Northern California (KPNC) and in European American participants from DIAMOND.

RESULTS: The discovery set consisted of 447 African American participants, whereas the replication sets included 353 African American KPNC participants and 466 European American DIAMOND participants. The primary analysis identified a variant, rs143276236, in the gene ARFGEF3, which met the threshold for genome-wide significance, replicated in KPNC African Americans, and was still significant in the meta-analysis (P = 1.17 × 10-9). None of the significant discovery variants replicated in European Americans DIAMOND participants.

CONCLUSIONS: We identified a novel and biologically plausible genetic variant associated with a change in HbA1c levels among African American patients on metformin monotherapy. These results highlight the importance of diversity in pharmacogenomic studies.

PMID:37639712 | DOI:10.2337/dc22-2494

Front Pharmacol. 2023 Aug 10;14:1237446. doi: 10.3389/fphar.2023.1237446. eCollection 2023.

ABSTRACT

CYP2D6 analysis prior to the prescription of pimozide is required above a certain dose by the Food and Drug Administration in order to detect individuals with the poor metabolizer status. This precautionary measure aims to prevent the occurrence of serious adverse drug reactions. This study presents a case of a patient diagnosed with schizophrenia spectrum disorder. The patient suffered re-admission in the psychiatry ward because of severe secondary symptoms due to the antipsychotic drug pimozide, previously prescribed on a first admission. In order to assess the patient's medication profile, real-time PCR was performed to analyze the main genes responsible for its metabolization, namely, CYP2D6 and CYP3A4. The pharmacogenetic study revealed that the patient is a poor metabolizer for CYP2D6, presenting deletion of both copies of the gene (diplotype *5/*5). Fortunately, the symptomatology disappeared after the withdrawal of the responsible drug. In conclusion, abiding by the pharmacogenetic clinical practice guidelines and the pharmacogenetic analysis of CYP2D6 when prescribing pimozide would have probably saved the patient from the consequences of severe side effects and the health system expenditure. There is an important need for more training in the pharmacogenetic field for specialists in psychiatry.

PMID:37637419 | PMC:PMC10448185 | DOI:10.3389/fphar.2023.1237446

Pharmaceutics. 2023 Aug 3;15(8):2085. doi: 10.3390/pharmaceutics15082085.

ABSTRACT

The pharmacokinetic variability of nifedipine widely observed in the clinic cannot be fully explained by pharmacogenomics. As a new factor affecting drug metabolism, how the gut microbiota affects the pharmacokinetics of nifedipine needs to be explored. Spontaneously hypertensive rats (SHRs) have been commonly used in hypertension-related research and served as the experimental groups; Wistar rats were used as control groups. In this study, the bioavailability of nifedipine decreased by 18.62% (p < 0.05) in the SHRs compared with the Wistar rats. Changes in microbiota were associated with the difference in pharmacokinetics. The relative abundance of Bacteroides dorei was negatively correlated with AUC0-t (r = -0.881, p = 0.004) and Cmax (r = -0.714, p = 0.047). Analysis of serum bile acid (BA) profiles indicated that glycoursodeoxycholic acid (GUDCA) and glycochenodeoxycholic acid (GCDCA) were significantly increased in the SHRs. Compared with the Wistar rats, the expressions of CYP3A1 and PXR were upregulated and the enzyme activity of CYP3A1 increased in the SHRs. Spearman's rank correlation revealed that Bacteroides stercoris was negatively correlated with GUDCA (r = -0.7126, p = 0.0264) and GCDCA (r = -0.6878, p = 0.0339). Moreover, GUDCA was negatively correlated with Cmax (r = -0.556, p = 0.025). In primary rat hepatocytes, GUDCA could induce the expressions of PXR target genes CYP3A1 and Mdr1a. Furthermore, antibiotic treatments in SHRs verified the impact of microbiota on the pharmacokinetics of nifedipine. Generally, gut microbiota affects the pharmacokinetics of nifedipine through microbial biotransformation or by regulating the enzyme activity of CYP3A1.

PMID:37631299 | DOI:10.3390/pharmaceutics15082085

Pharmaceutics. 2023 Jul 28;15(8):2034. doi: 10.3390/pharmaceutics15082034.

ABSTRACT

During the development of an oral solid form of a drug substance, a thorough understanding of the critical material attributes is necessary, as the physical properties of the active pharmaceutical ingredient (API) can profoundly influence the drug product's manufacturability, critical quality attributes, and bioavailability. The objective of this study was to validate the manufacturing process of the drug Linezolid from three different sources at both the pilot and industrial scale and to identify differences in critical material attributes between the API manufacturers. Furthermore, the scalability factor between the pilot and industrial scale and the suitability of a process for direct compression were also evaluated. In the present study, the different sources of API were characterized by SeDeM methodology, particle size distribution, and scanning electron microscopy determinations. The statistical analysis revealed that no statistically significant differences were found for any of the parameters under study for the same API source analyzed on both scales. On the other hand, for most of the parameters evaluated, statistical differences were observed between the different sources. It was concluded that SeDeM was able to successfully validate the API manufacturing process, assess scalability, and distinguish between sources. Therefore, it could be highly valuable in the formulation phase to select the best API source.

PMID:37631248 | DOI:10.3390/pharmaceutics15082034

Pharmaceutics. 2023 Jul 26;15(8):2024. doi: 10.3390/pharmaceutics15082024.

ABSTRACT

Psoriasis is a chronic, immune-mediated and inflammatory skin disease. Although various biological drugs are available for psoriasis treatment, some patients have poor responses or do not respond to treatment. The aim of the present study was to highlight the molecular mechanism of responsiveness to current biological drugs for psoriasis treatment. To this end, we reviewed previously published articles that reported genes associated with treatment response to biological drugs in psoriasis, and gene ontology analysis was subsequently performed using the Cytoscape platform. Herein, we revealed a statistically significant association between NF-kappaB signaling (p value = 3.37 × 10-9), regulation of granulocyte macrophage colony-stimulating factor production (p value = 6.20 × 10-6), glial cell proliferation (p value = 2.41 × 10-5) and treatment response in psoriatic patients. To the best of our knowledge, we are the first to directly associate glial cells with treatment response. Taken together, our study revealed gene ontology (GO) terms, some of which were previously shown to be implicated in the molecular pathway of psoriasis, as novel GO terms involved in responsiveness in psoriatic disease patients.

PMID:37631238 | DOI:10.3390/pharmaceutics15082024

Life (Basel). 2023 Jul 26;13(8):1627. doi: 10.3390/life13081627.

ABSTRACT

Tacrolimus (TAC) is a narrow-therapeutic-range immunosuppressant drug used after organ transplantation. A therapeutic failure is possible if drug levels are not within the therapeutic range after the first year of treatment. Pharmacogenetic variants and drug-drug interactions (DDIs) are involved. We describe a patient case of a young man (16 years old) with a renal transplant receiving therapy including TAC, mycophenolic acid (MFA), prednisone and omeprazole for prophylaxis of gastric and duodenal ulceration. The patient showed great fluctuation in TAC blood concentration/oral dose ratio, as well as pharmacotherapy adverse effects (AEs) and frequent diarrhea episodes. Additionally, decreased kidney function was found. A pharmacotherapeutic follow-up, including pharmacogenetic analysis, was carried out. The selection of the genes studied was based on the previous literature (CYP3A5, CYP3A4, POR, ABCB1, PXR and CYP2C19). A drug interaction with omeprazole was reported and the nephrologist switched to rabeprazole. A lower TAC concentration/dose ratio was achieved, and the patient's condition improved. In addition, the TTT haplotype of ATP Binding Cassette Subfamily B member 1 (ABCB1) and Pregnane X Receptor (PXR) gene variants seemed to affect TAC pharmacotherapy in the studied patient and could explain the occurrence of long-term adverse effects post-transplantation. These findings suggest that polymorphic variants and co-treatments must be considered in order to achieve the effectiveness of the immunosuppressive therapy with TAC, especially when polymedicated patients are involved. Moreover, pharmacogenetics could influence the drug concentration at the cellular level, both in lymphocyte and in renal tissue, and should be explored in future studies.

PMID:37629484 | DOI:10.3390/life13081627

Int J Mol Sci. 2023 Aug 19;24(16):12966. doi: 10.3390/ijms241612966.

ABSTRACT

Alzheimer's disease (AD) is the most common neurodegenerative disease, with a complex genetic background. Apart from rare, familial cases, a combination of multiple risk loci contributes to the susceptibility of the disease. Genome-wide association studies (GWAS) have identified numerous AD risk loci. Changes in cerebrospinal fluid (CSF) biomarkers and imaging techniques can detect AD-related brain changes before the onset of clinical symptoms, even in the presence of preclinical mild cognitive impairment. In this study, we aimed to assess the associations between SNPs in well-established GWAS AD risk loci and CSF biomarker levels or cognitive test results in Slovenian patients with cognitive decline. The study included 82 AD patients, 28 MCI patients with pathological CSF biomarker levels and 35 MCI patients with normal CSF biomarker levels. Carriers of at least one polymorphic TOMM40 rs157581 C allele had lower Aβ42 (p = 0.033) and higher total tau (p = 0.032) and p-tau181 levels (p = 0.034). Carriers of at least one polymorphic T allele in SORCS1 rs1358030 had lower total tau (p = 0.019), while polymorphic SORCS1 rs1416406 allele was associated with lower total tau (p = 0.013) and p-tau181 (p = 0.036). In addition, carriers of at least one polymorphic T allele in BCHE rs1803274 had lower cognitive test scores (p = 0.029). The study findings may contribute to the identification of genetic markers associated with AD and MCI and provide insights into early disease diagnostics.

PMID:37629144 | DOI:10.3390/ijms241612966

Int J Mol Sci. 2023 Aug 11;24(16):12696. doi: 10.3390/ijms241612696.

ABSTRACT

Improper drug prescription is a main cause of both drug-related harms (inefficacy and toxicity) and ineffective spending and waste of the healthcare system's resources. Nowadays, strategies to support an improved, informed prescription process may benefit from the adequate use of pharmacogenomic testing. Using next-generation sequencing, we analyzed the genomic profile for three major cytochromes P450 (CYP2C9, CYP2C19, CYP2D6) and studied the frequencies of dysfunctional isozymes (e.g., poor, intermediate, or rapid/ultra-rapid metabolizers) in a cohort of 298 Italian subjects. We found just 14.8% of subjects with a fully normal set of cytochromes, whereas 26.5% of subjects had combined cytochrome dysfunction (more than one isozyme involved). As improper drug prescription is more frequent, and more burdening, in polytreated patients, since drug-drug interactions also cause patient harm, we discuss the potential benefits of a more comprehensive PGX testing approach to support informed drug selection in such patients.

PMID:37628884 | DOI:10.3390/ijms241612696

Genes (Basel). 2023 Jul 27;14(8):1535. doi: 10.3390/genes14081535.

ABSTRACT

Cerebral cavernous malformations (CCMs) are relatively common in the central nervous system. They occur in two forms, sporadic and familial (FCCMs). Three genes are recognized to be associated with FCCM, including CCM1, CCM2, and CCM3, the latter also called PDCD10. In this article, we describe a single-nucleotide variant in the PDCD10 gene in a 23-year-old Polish female with CCM. The NM_007217.4 (PDCD10): c.395+1G>A variant destroys the canonical splice donor site following exon 6. This is the first reported genetically characterized case of CCM (FCCM) in Poland.

PMID:37628586 | DOI:10.3390/genes14081535

Cancers (Basel). 2023 Aug 12;15(16):4077. doi: 10.3390/cancers15164077.

ABSTRACT

Several studies have suggested that single nucleotide polymorphisms (SNPs) related to vitamin D metabolism may affect CRC carcinogenesis and survival. The aim of this study was to evaluate the influence of 13 SNPs involved in the vitamin D metabolic pathway on CRC survival. We conducted an observational retrospective cohort study, which included 127 Caucasian CRC patient from the south of Spain. SNPs in VDR, CYP27B1, CYP2R1, CYP24A1, and GC genes were analyzed by real-time polymerase chain reaction. Progression-free survival (PFS) and overall survival (OS) were assessed. Cox regression analysis adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2-4), lymph node involvement, adjuvant chemotherapy, and no family history of CRC showed that the VDR ApaI (p = 0.036), CYP24A1 rs6068816 (p < 0.001), and GC rs7041 (p = 0.006) were associated with OS in patients diagnosed with CRC, and CYP24A1 rs6068816 (p < 0.001) was associated with PFS adjusted for metastasis, age of diagnosis, stage (IIIB, IV or IVB), ECOG score (2-4), lymph node involvement, adjuvant chemotherapy, and no primary tumor resection. The rest of the SNPs showed no association with CRC survival. Thus, the SNPs mentioned above may have a key role as prognostic biomarkers of CRC.

PMID:37627104 | DOI:10.3390/cancers15164077

Cells. 2023 Aug 16;12(16):2077. doi: 10.3390/cells12162077.

ABSTRACT

Mortality from myocardial infarction (MI) has declined over recent decades, which could be attributed in large part to improved treatment methods. Early reperfusion is the cornerstone of current MI treatment. However, reoxygenation via restored blood flow induces further damage to the myocardium, leading to ischemia-reperfusion injury (IRI). While experimental studies overwhelmingly demonstrate that females experience greater functional recovery from MI and decreased severity in the underlying pathophysiological mechanisms, the outcomes of MI with subsequent reperfusion therapy, which is the clinical correlate of myocardial IRI, are generally poorer for women compared with men. Distressingly, women are also reported to benefit less from current guideline-based therapies compared with men. These seemingly contradicting outcomes between experimental and clinical studies show a need for further investigation of sex-based differences in disease pathophysiology, treatment response, and a sex-specific approach in the development of novel therapeutic methods against myocardial IRI. In this literature review, we summarize the current knowledge on sex differences in the underlying pathophysiological mechanisms of myocardial IRI, including the roles of sex hormones and sex chromosomes. Furthermore, we address sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics of current drugs prescribed to limit myocardial IRI. Lastly, we highlight ongoing clinical trials assessing novel pharmacological treatments against myocardial IRI and sex differences that may underlie the efficacy of these new therapeutic approaches.

PMID:37626887 | DOI:10.3390/cells12162077

Cells. 2023 Aug 10;12(16):2037. doi: 10.3390/cells12162037.

ABSTRACT

RECQ5, a member of the conserved RECQ helicase family, is the sole human RECQ homolog that has not been linked to a hereditary developmental syndrome. Nonetheless, dysregulation of RECQ5 has emerged as a significant clinical concern, being linked to cancer predisposition, cardiovascular disease, and inflammation. In cells, RECQ5 assumes a crucial role in the regulation of DNA repair pathways, particularly in the repair of DNA double-strand breaks and inter-strand DNA crosslinks. Moreover, RECQ5 exhibits a capacity to modulate gene expression by interacting with transcription machineries and their co-regulatory proteins, thus safeguarding against transcription-induced DNA damage. This review aims to provide an overview of the multifaceted functions of RECQ5 and its implications in maintaining genomic stability. We will discuss the potential effects of clinical variants of RECQ5 on its cellular functions and their underlying mechanisms in the pathogenesis of cancer and cardiovascular disease. We will review the impact of RECQ5 variants in the field of pharmacogenomics, specifically their influence on drug responses, which may pave the way for novel therapeutic interventions targeting RECQ5 in human diseases.

PMID:37626846 | DOI:10.3390/cells12162037

Biomedicines. 2023 Aug 18;11(8):2304. doi: 10.3390/biomedicines11082304.

ABSTRACT

Research into early predictors of effective weight loss could help determine more effective therapeutic interventions. In this study, 106 subjects with class I obesity, genotyped with the fat mass and obesity-associated (FTO) rs9930506 gene variant, were enrolled into a 12-week weight loss program (WLP). Anthropometric and body composition measurements were controlled with bioelectrical impedance analysis (BIA) at baseline and after 4 and 12 weeks. Biopsies of abdominal subcutaneous adipose tissue (AT) and venous blood samples were collected to monitor changes in interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa B (NF-κB) mRNA levels in white blood cells (WBCs) and to assess if changes in WBC gene expression reflected changes in adipose tissue. The FTO rs9930506 variant had no effect on weight loss and no reduction in proinflammatory transcripts in WBCs or AT. Changes in anthropometric parameters were associated with changes in carbohydrate metabolism. A linear regression model showed that initial weight loss (after 4 weeks of the WLP) was the most predictive factor of weight loss success after 12 weeks of the WLP. Changes in plasma lipids or proinflammatory transcript levels in WBCs or AT were not associated with weight loss effectiveness. However, the gene expression in WBCs did reflect changes occurring in subcutaneous AT.

PMID:37626800 | DOI:10.3390/biomedicines11082304

Biomedicines. 2023 Aug 16;11(8):2282. doi: 10.3390/biomedicines11082282.

ABSTRACT

Polymorphism in cytochrome P450 (CYP) 2C9 enzyme is known to cause significant inter-individual differences in drug response and occurrence of adverse drug reactions. Different alleles of the CYP2C9 gene have been identified, but the notable alleles responsible for reduced enzyme activity are CYP2C9*2 and CYP2C9*3. No pharmacogenetic data are available on CYP2C9*2 and CYP2C9*3 alleles in the Pakistani population. In Pakistan, pharmacogenetics, which examines the relationship between genetic factors and drug response, are in the early stages of development. We, for the first time, investigated the association between the CYP2C9 variant alleles CYP2C9*2 and CYP2C9*3 and the incidence of hypoglycaemia in patients with Type 2 diabetes mellitus (T2DM) receiving sulphonylurea medications. A total of n = 400 individuals of Pashtun ethnicity were recruited from 10 different districts of Khyber Pakhtunkhwa, Pakistan to participate in the study. The study participants were divided into two distinct groups: the case group (n = 200) and the control group (n = 200). The case group consisted of individuals with T2DM who were receiving sulphonylurea medications and experienced hypoglycaemia with it, whereas the control group included individuals with T2DM who were receiving sulphonylurea medication but did not experience sulphonylurea-induced hypoglycaemia (SIH). Blood samples were obtained from study participants following informed consent. DNA was isolated from whole blood samples using a Wiz-Prep DNA extraction kit. Following DNA isolation, CYP2C9 alleles were genotyped using MassARRAY sequencing platform at the Centre of Genomics at the Rehman Medical Institute (RMI). The frequency of CYP2C9*2 (low-activity allele) was more frequent in the diabetic patients with SIH compared to the control group (17.5% vs. 6.0%, p = 0.021). The frequency of its corresponding genotype CYP2C9*1/*2 was higher in cases compared to the control group (10% vs. 6% with p = 0.036); the same was true for genotype CYP2C9*2/*2 (7% vs. 3.5% with p = 0.028). Logistic regression analysis evidenced potential association of CYP2C9*2 allele and its genotypes with SIH. When adjusted for confounding factors such as age, weight, sex, mean daily dose of sulphonylurea, and triglyceride level, the association between the CYP2C9*2 allele and hypoglycaemia remained consistent. Confounding factors played no role in SIH (insignificant p-value) because both groups (cases and controls) were closely matched in term of age, weight, sex, mean daily dose of sulphonylurea, and triglyceride levels. Our study suggests that genetic information about a patient's CYP2C9 gene/enzyme can potentially assist physicians in prescribing the most suitable and safest drug, based on their genetic make-up.

PMID:37626778 | DOI:10.3390/biomedicines11082282

Biomedicines. 2023 Aug 1;11(8):2157. doi: 10.3390/biomedicines11082157.

ABSTRACT

Epithelial ovarian cancer (EOC) is a significant cause of cancer-related mortality in women. Despite advances in diagnosis and treatment, EOC remains a challenging disease to manage, and the 5-year survival rate is still poor. The role of hormone receptors (HRs) in EOC carcinogenesis and prognosis has been actively explored; however, the role of hormone therapy (HT) in the treatment of these tumors is not well established. Most available data on HT mainly come from retrospective series and small early clinical trials. Several of these studies suggest that HT may have a role in adjuvant, maintenance therapy, or in the case of recurrent disease, especially for some subtypes of EOC (e.g., low-grade serous EOC). Furthermore, HT has recently been combined with targeted therapies, but most studies evaluating these combinations are still ongoing. The main aim of this review is to provide an overview of the progress made in the last decade to characterize the biological and prognostic role of HRs for EOC and the developments in their therapeutic targeting through HT.

PMID:37626654 | DOI:10.3390/biomedicines11082157

Pharmacogenomics J. 2023 Aug 26. doi: 10.1038/s41397-023-00313-y. Online ahead of print.

ABSTRACT

Epilepsy treatment is challenging due to heterogeneous syndromes, different seizure types and higher inter-individual variability. Identification of genetic variants predicting drug efficacy, tolerability and risk of adverse-effects for anti-seizure medications (ASMs) is essential. Here, we assessed the clinical actionability of known genetic variants, based on their functional and clinical significance and estimated their diagnostic predictability. We performed a systematic PubMed search to identify articles with pharmacogenomic (PGx) information for forty known ASMs. Functional annotation of the identified genetic variants was performed using different in silico tools, and their clinical significance was assessed using the American College of Medical Genetics (ACMG) guidelines for variant pathogenicity, level of evidence (LOE) from PharmGKB and the United States-Food and drug administration (US- FDA) drug labelling with PGx information. Diagnostic predictability of the replicated genetic variants was evaluated by calculating their accuracy. A total of 270 articles were retrieved with PGx evidence associated with 19 ASMs including 178 variants across 93 genes, classifying 26 genetic variants as benign/ likely benign, fourteen as drug response markers and three as risk factors for drug response. Only seventeen of these were replicated, with accuracy (up to 95%) in predicting PGx outcomes specific to six ASMs. Eight out of seventeen variants have FDA-approved PGx drug labelling for clinical implementation. Therefore, the remaining nine variants promise for potential clinical actionability and can be improvised with additional experimental evidence for clinical utility.

PMID:37626111 | DOI:10.1038/s41397-023-00313-y

Cancer Chemother Pharmacol. 2023 Aug 25. doi: 10.1007/s00280-023-04581-0. Online ahead of print.

ABSTRACT

BACKGROUND: Imatinib is presently the first-line choice for the treatment of chronic myeloid leukemia. However, there are limited real-world data on Chinese patients to support individualized medicine. This work aims to characterize population pharmacokinetics in Chinese patients with chronic myeloid leukemia, investigate the effects of several covariates on imatinib exposure, and provide support for personalized medicine and dose reduction.

METHODS: A total of 230 patients with chronic myeloid leukemia were enrolled, and 424 steady-state concentration measurements were taken to perform the population pharmacokinetic analysis and Monte Carlo simulations with Phoenix NLME software. The effects of the demographic, biological, and pharmacogenetic (ten SNP corresponding to CYP3A4, CYP3A5, ABCB1, ABCG2, SCL22A1 and POR) covariates on clearance were evaluated.

RESULTS: A one-compartmental model best-described imatinib pharmacokinetics. The hemoglobin and the estimated glomerular filtration rate (< 85 mL⋅min-1⋅1.73 m2) were associated with imatinib clearance. The genetic polymorphisms related to pharmacokinetics were not found to have a significant effect on the clearance of imatinib. The final model estimates of parameters are: ka (h-1) = 0.329; Vd/F (L) = 270; CL/F (L⋅h-1) = 7.60.

CONCLUSIONS: Key covariates in the study population accounting for variability in imatinib exposure are hemoglobin and the estimated glomerular filtration rate. There is some need for caution when treating patients with moderate-to-severe renal impairment and significant hemoglobin changes.

PMID:37624393 | DOI:10.1007/s00280-023-04581-0