Curr Hypertens Rep. 2021 Sep 6;23(8):40. doi: 10.1007/s11906-021-01157-2.

ABSTRACT

PURPOSE OF HEADING: To review the relationship between intestinal microbes and hypertension and its impact on the efficacy of antihypertensive drugs, and help to address some of these knowledge gaps.

RECENT FINDINGS: Hypertension is associated with cardiovascular diseases and is the most important modifiable risk factor for all-cause morbidity and mortality worldwide. The pathogenesis of hypertension is complex, including factors such as dietary, environmental and genetics. Recently, the studies have shown that the gut microbiota influences the occurrence and development of hypertension through a variety of ways, including affecting the production of short-chain fatty acids, dysfunction of the brain-gut axis, and changes in serotonin content that cause the imbalance of vagus and sympathetic nerve output associated with hypertension. However, patients with hypertension typically take antihypertensive drugs orally on a long-term basis, and most antihypertensive drugs are absorbed by the gastrointestinal tract. Studies have shown that the pharmacokinetics and metabolism of antihypertensive drugs may be influenced by microbiota, or antihypertensive drugs act directly on the intestinal flora to exert efficacy, including regulation of intestinal microbial metabolism, intestinal inflammation, and intestinal sympathetic nervous system disorders. The intestinal flora can affect the pharmacokinetics and metabolism of antihypertensive drugs in the rats, and intestinal microbiota also can be the target "organ" by antihypertensive drugs.

PMID:34487269 | DOI:10.1007/s11906-021-01157-2

Am J Health Syst Pharm. 2021 Sep 6:zxab339. doi: 10.1093/ajhp/zxab339. Online ahead of print.

NO ABSTRACT

PMID:34487145 | DOI:10.1093/ajhp/zxab339

Expert Opin Drug Metab Toxicol. 2021 Sep 6:1-7. doi: 10.1080/17425255.2021.1974397. Online ahead of print.

ABSTRACT

INTRODUCTION: Irinotecan is a cytotoxic agent that is widely used in the treatment of several types of solid tumors. However, although it is generally well tolerated, approximately 20% to 35% of patients develop severe toxicity, particularly delayed-type diarrhea and neutropenia. As the incidence of such toxicities is often associated with the UGT1A1 *28/*28, *6/*28 and *6/*6 genotypes, individualized dosing could reduce these adverse events. Furthermore, prospective trials have shown that patients harboring the UGT1A1 *1/*1 and *1/*28 genotypes can tolerate higher doses of irinotecan, which may in turn impact on a better outcome. Upfront UGT1A1 genotyping could therefore be a usefulness strategy in order to individualize irinotecan dosing, but consensus on the recommended dose based on the UGT1A1 genotype is still lacking.

AREAS COVERED: This review summarizes the results of the main pharmacogenetic studies focused on irinotecan. We provide an overview of current evidence and recommendations for individualized dosing of irinotecan in metastatic colorectal cancer patients.

EXPERT OPINION: Implementation of UGT1A1*28 and UGT1A1*6 genotyping in clinical practice is a first step toward personalizing irinotecan therapy. This approach is likely to improve patient care and reduce healthcare costs. Future large and prospective studies will help to clarify the clinical value of other genetic markers in irinotecan treatment personalization.

PMID:34486919 | DOI:10.1080/17425255.2021.1974397

Pharmacogenomics. 2021 Sep 6. doi: 10.2217/pgs-2021-0041. Online ahead of print.

ABSTRACT

Antiepileptic-mood stabilizers (AED-MS) are often used to treat bipolar disorder (BD). Similar to other mood disorder medications, AED-MS treatment response varies between patients. Identification of biomarkers associated with treatment response may ultimately help with the delivery of individualized treatment and lead to improved treatment efficacy. Here, we conducted a narrative review of the current knowledge of the pharmacogenomics of AED-MS (valproic acid, lamotrigine and carbamazepine) treatment response in BD, including genetic contributions to AED-MS pharmacokinetics. Genes involved in neurotransmitter systems and drug transport have been shown to be associated with AED-MS treatment response. As more studies are conducted, and experimental and analytical methods advance, knowledge of AED-MS pharmacogenomics is expected to grow and contribute to precision medicine in BD.

PMID:34486896 | DOI:10.2217/pgs-2021-0041

Epilepsia Open. 2021 Sep 6. doi: 10.1002/epi4.12536. Online ahead of print.

ABSTRACT

Mesial temporal lobe epilepsy (MTLE) is the most common type of focal epilepsy in adults, and hippocampal sclerosis (HS) is a frequent histopathological feature in patients with MTLE. Pharmacoresistance is present in at least one third of patients with MTLE with HS (MTLE+HS). Several hypotheses have been proposed to explain the mechanisms of pharmacoresistance in epilepsy, including the effect of genetic and molecular factors. In recent years, the increased knowledge generated by high-throughput omic technologies has significantly improved the power of molecular genetic studies to discover new mechanisms leading to disease and response to treatment. In this review, we present and discuss the contribution of different omic modalities to understand the basic mechanisms determining pharmacoresistance in patients with MTLE+HS. We provide an overview and a critical discussion of the findings, limitations, new approaches, and future directions of these studies to improve the understanding of pharmacoresistance in MTLE+HS. However, it is important to point out that, as with other complex traits, pharmacoresistance to anti-seizure medications is likely a multifactorial condition in which gene-gene and gene-environment interactions play an important role. Thus, studies using multidimensional approaches are more likely to unravel these intricate biological processes.

PMID:34486831 | DOI:10.1002/epi4.12536

Front Cardiovasc Med. 2021 Aug 16;8:704175. doi: 10.3389/fcvm.2021.704175. eCollection 2021.

ABSTRACT

Several studies show that statin therapy improves endothelial function by cholesterol-independent mechanisms called "pleiotropic effects." These are due to the inhibition of the RhoA/ROCK kinase pathway, its inhibition being an attractive atheroprotective treatment. In addition, recent work has shown that microRNAs, posttranscriptional regulators of gene expression, can affect the response of statins and their efficacy. For this reason, the objective of this study was to identify by bioinformatic analysis possible new microRNAs that could modulate the pleiotropic effects exerted by statins through the inhibition of ROCK kinases. A bioinformatic study was performed in which the differential expression of miRNAs in endothelial cells was compared under two conditions: Control and treated with simvastatin at 10 μM for 24 h, using a microarray. Seven miRNAs were differentially expressed, three up and four down. Within the up group, the miRNAs hsa-miR-618 and hsa-miR-297 present as a predicted target to ROCK2 kinase. Also, functional and enriched pathway analysis showed an association with mechanisms associated with atheroprotective effects. This work shows an in-silico approach of how posttranscriptional regulation mediated by miRNAs could modulate the pleiotropic effects exerted by statins on endothelial cells, through the inhibition of ROCK2 kinase and its effects.

PMID:34485404 | PMC:PMC8415262 | DOI:10.3389/fcvm.2021.704175

Sci Bull (Beijing). 2021 Aug 28. doi: 10.1016/j.scib.2021.08.017. Online ahead of print.

NO ABSTRACT

PMID:34484849 | PMC:PMC8400453 | DOI:10.1016/j.scib.2021.08.017

Ont Health Technol Assess Ser. 2021 Aug 12;21(13):1-214. eCollection 2021.

ABSTRACT

BACKGROUND: Major depression is a substantial public health concern that can affect personal relationships, reduce people's ability to go to school or work, and lead to social isolation. Multi-gene pharmacogenomic testing that includes decision-support tools can help predict which depression medications and dosages are most likely to result in a strong response to treatment or to have the lowest risk of adverse events on the basis of people's genes.We conducted a health technology assessment of multi-gene pharmacogenomic testing that includes decision-support tools for people with major depression. Our assessment evaluated effectiveness, safety, cost-effectiveness, the budget impact of publicly funding multi-gene pharmacogenomic testing, and patient preferences and values.

METHODS: We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Cochrane Risk of Bias Tool and the Risk of Bias Assessment Tool for Nonrandomized studies (RoBANS) and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria.We performed a systematic literature search of the economic evidence to review published cost-effectiveness studies on multi-gene pharmacogenomic testing that includes a decision-support tool in people with major depression. We developed a state-transition model and conducted a probabilistic analysis to determine the incremental cost of multi-gene pharmacogenomic testing versus treatment as usual per quality-adjusted life-year (QALY) gained for people with major depression who had inadequate response to one or more antidepressant medications. In the reference case (with GeneSight-guided care), we considered a 1-year time horizon with an Ontario Ministry of Health perspective. We also estimated the 5-year budget impact of publicly funding multi-gene pharmacogenomic testing for people with major depression in Ontario.To contextualize the potential value of multi-gene pharmacogenomic testing that includes decision-support tools, we spoke with people who have major depression and their families.

RESULTS: We included 14 studies in the clinical evidence review that evaluated six multi-gene pharmacogenomic tests. Although all tests included decision-support tools, they otherwise differed greatly, as did study design, populations included in studies, and outcomes reported. Little or no improvement was observed on change in HAM-D17 depression score compared with treatment as usual for any test evaluated (GRADE: Low-Very Low). GeneSight- and NeuroIDgenetix-guided medication selection led to statistically significant improvements in response (GRADE: Low-Very Low) and remission (GRADE: Low-Very Low), while treatment guided by CNSdose led to significant improvement in remission rates (GRADE: Low), but the study did not report on response. Results were inconsistent and uncertain for the impact of Neuropharmagen, and no significant improvement was observed for Genecept or another unspecified test for either response or remission (GRADE: Low-Very Low). Neuropharmagen may reduce adverse events and CNSDose may reduce intolerability to medication, while no difference was observed in adverse events with GeneSight, Genecept, or another unspecified test (GRADE: Moderate-Very Low). No studies reported data on suicide, treatment adherence, relapse, recovery, or recurrence of depression symptoms.Our review included four model-based economic studies and found that multi-gene pharmacogenomic testing was associated with greater effectiveness and cost savings than treatment as usual, over long-term (i.e., 3-,5-year and lifetime) time horizons. Since none of the included studies was fully applicable to the Ontario health care system, we conducted a primary economic evaluation.Our reference case analysis over the 1-year time horizon found that multi-gene pharmacogenomic testing (with GeneSight) was associated with additional QALYs (0.03, 95% credible interval [CrI]: 0.005; 0.072) and additional costs ($1,906, 95% Crl: $688; $3,360). An incremental cost-effectiveness ratio was $60,564 per QALY gained. The probability of the intervention being cost-effective (vs. treatment as usual) was 36.8% at a willingness-to-pay amount of $50,000 per QALY (i.e., moderately likely not to be cost-effective), rising to 70.7% at a willingness-to-pay amount of $100,000 per QALY (i.e., moderately likely to be cost-effective). Evidence informing economic modeling of the reference case with GeneSight and other multi-gene pharmacogenomic tests was of low to very low quality, implying considerable uncertainty or low confidence in the effectiveness estimates. The price of the test, efficacy of the intervention on remission, time horizon, and analytic perspective were major determinants of the cost-effectiveness results. If the test price were assumed to be $2,162 (compared with $2,500 in the reference case), the intervention would be cost-effective at a willingness-to-pay amount of $50,000 per QALY; moreover, if the price decreased to $595, the intervention would be cost saving (or dominant) compared with treatment as usual.At an increasing uptake of 1% per year and a test price of $2,500, the annual budget impact of publicly funding multi-gene pharmacogenomic testing in Ontario over the next 5 years ranged from an additional $3.5 million in year 1 (at uptake of 1%) to $16.8 million in year 5. The 5-year budget impact was estimated at about $52 million.People with major depression and caregivers generally supported multi-gene pharmacogenomic testing because they believed it could provide guidance that fit their values. They hoped such guidance would speed symptom relief, would reduce side effects and help inform their medication choices. Some patients expressed concerns over maintaining confidentiality of test results and the possibility that physicians would sacrifice patient-centred care to follow pharmacogenomic guidance.

CONCLUSIONS: Multi-gene pharmacogenomic testing that includes decision-support tools to guide medication selection for depression varies widely. Differences between individual tests must be considered, as clinical utility observed with one test might not apply to other tests. Overall, effectiveness was inconsistent among the six multi-gene pharmacogenomic tests we identified. Multi-gene pharmacogenomic tests may result in little or no difference in improvement in depression scores compared with treatment as usual, but some tests may improve response to treatment or remission from depression. The impact on adverse events is uncertain. The evidence, however, is uncertain, and therefore our confidence that these observed effects reflect the true effects is low to very low.For the management of major depression in people who had inadequate response to at least one medication, some multi-gene pharmacogenomic tests that include decision support tools are associated with additional costs and QALYs over the 1-year time horizon, and maybe be cost-effective at the willingness-to-pay amount of $100,000 per QALY. Publicly funding multi-gene pharmacogenomic testing in Ontario would result in additional annual costs of between $3.5 million and $16.8 million, with a total budget impact of about $52 million over the next 5 years.People with major depression and caregivers generally supported multi-gene pharmacogenomic testing because they believed it could provide guidance that fit their values. They hoped such guidance would speed symptom relief, would reduce side and help inform their medication choices. Some patients expressed concerns over maintaining confidentiality of test results and the possibility that physicians would sacrifice patient-centred care to follow pharmacogenomic guidance.

PMID:34484487 | PMC:PMC8382305

Front Genet. 2021 Aug 17;12:698825. doi: 10.3389/fgene.2021.698825. eCollection 2021.

ABSTRACT

Background: The triad of drug efficacy, toxicity and resistance underpins the risk-benefit balance of all therapeutics. The application of pharmacogenomics has the potential to improve the risk-benefit balance of a given therapeutic via the stratification of patient populations based on DNA variants. A growth in the understanding of the particulars of the mitochondrial genome, alongside the availability of techniques for its interrogation has resulted in a growing body of literature examining the impact of mitochondrial DNA (mtDNA) variation upon drug response. Objective: To critically evaluate and summarize the available literature, across a defined period, in a systematic fashion in order to map out the current landscape of the subject area and identify how the field may continue to advance. Methods: A systematic review of the literature published between January 2009 and December 2020 was conducted using the PubMed database with the following key inclusion criteria: reference to specific mtDNA polymorphisms or haplogroups, a core objective to examine associations between mtDNA variants and drug response, and research performed using human subjects or human in vitro models. Results: Review of the literature identified 24 articles reporting an investigation of the association between mtDNA variant(s) and drug efficacy, toxicity or resistance that met the key inclusion criteria. This included 10 articles examining mtDNA variations associated with antiretroviral therapy response, 4 articles examining mtDNA variants associated with anticancer agent response and 4 articles examining mtDNA variants associated with antimicrobial agent response. The remaining articles covered a wide breadth of medications and were therefore grouped together and referred to as "other." Conclusions: Investigation of the impact of mtDNA variation upon drug response has been sporadic to-date. Collective assessment of the associations identified in the articles was inconclusive due to heterogeneous methods and outcomes, limited racial/ethnic groups, lack of replication and inadequate statistical power. There remains a high degree of idiosyncrasy in drug response and this area has the potential to explain variation in drug response in a clinical setting, therefore further research is likely to be of clinical benefit.

PMID:34484295 | PMC:PMC8416105 | DOI:10.3389/fgene.2021.698825

Front Pharmacol. 2021 Aug 13;12:729474. doi: 10.3389/fphar.2021.729474. eCollection 2021.

ABSTRACT

Antipsychotics (APs) are associated with weight gain and other metabolic abnormalities such as hyperglycemia, dyslipidemia and metabolic syndrome. This translational study aimed to uncover the underlying molecular mechanisms and identify the key genes involved in AP-induced metabolic effects. An integrative gene expression analysis was performed in four different mouse tissues (striatum, liver, pancreas and adipose) after risperidone or olanzapine treatment. The analytical approach combined the identification of the gene co-expression modules related to AP treatment, gene set enrichment analysis and protein-protein interaction network construction. We found several co-expression modules of genes involved in glucose and lipid homeostasis, hormone regulation and other processes related to metabolic impairment. Among these genes, EP300, which encodes an acetyltransferase involved in transcriptional regulation, was identified as the most important hub gene overlapping the networks of both APs. Then, we explored the genetically predicted EP300 expression levels in a cohort of 226 patients with first-episode psychosis who were being treated with APs to further assess the association of this gene with metabolic alterations. The EP300 expression levels were significantly associated with increases in body weight, body mass index, total cholesterol levels, low-density lipoprotein cholesterol levels and triglyceride concentrations after 6 months of AP treatment. Taken together, our analysis identified EP300 as a key gene in AP-induced metabolic abnormalities, indicating that the dysregulation of EP300 function could be important in the development of these side effects. However, more studies are needed to disentangle the role of this gene in the mechanism of action of APs.

PMID:34483940 | PMC:PMC8414590 | DOI:10.3389/fphar.2021.729474

Focus (Am Psychiatr Publ). 2021 Jan;19(1):76-85. doi: 10.1176/appi.focus.19107. Epub 2021 Jan 25.

ABSTRACT

(Reprinted with permission from Am J Geriatr Psychiatry 2020; 28:933-945).

PMID:34483773 | PMC:PMC8412149 | DOI:10.1176/appi.focus.19107

Pharmgenomics Pers Med. 2021 Aug 28;14:1069-1080. doi: 10.2147/PGPM.S322743. eCollection 2021.

ABSTRACT

BACKGROUND: Annually, 10% of warfarin patients will likely need to stop warfarin prior to elective surgery to achieve a baseline international normalization ratio (INR) level (INR ≤ 1.2) at the time of the procedure. This study explores the influence of genetic and non-genetic factors on INR normalization in the Arab (major part of Near Eastern) population in preprocedural warfarin management.

METHODS: An observational prospective cohort study was designed to recruit Arab patients taking warfarin and scheduled for an elective procedure. Two INR readings were recorded. DNA extraction and genotyping of variants in CYP2C9*2, CYP2C9*3, CYP4F2*3, VKORC1*2, and FII (rs5896) and FVII (rs3093229) genes using real-time polymerase chain reaction were performed.

RESULTS: Data from 116 patients were included in the analysis. CYP2C9 and VKORC1 genetic variants carriers required lower maintenance dose compared to non-carriers. The analysis showed that ciprofloxacin, antiplatelet medications, and INR index (INR at visit 1) are the only factors associated with the INR decline rate. Also, the proportion of CYP2C9*3 carriers with normal INR (≤1.2) on the day of surgery was significantly lower than those with wild-type genotype (28% vs 60%, p=0.013). In addition, heparin bridging, INR target, and Sudanese nationality are significant predictors of INR normalization (≤1.2) on the day of the procedure.

CONCLUSION: Despite the confirmed effect of genetic factors on warfarin maintenance dose, the study was not able to find a significant effect of any genetic factor on the rate of INR normalization possibly due to the small sample size. Index INR and interacting medications showed to be significant predictors of INR decline rate.

PMID:34483679 | PMC:PMC8409603 | DOI:10.2147/PGPM.S322743

Ind Psychiatry J. 2021 Jan-Jun;30(1):4-5. doi: 10.4103/ipj.ipj_119_21. Epub 2021 Jun 24.

NO ABSTRACT

PMID:34483516 | PMC:PMC8395549 | DOI:10.4103/ipj.ipj_119_21

Anal Chim Acta. 2021 Sep 15;1178:338829. doi: 10.1016/j.aca.2021.338829. Epub 2021 Jul 5.

ABSTRACT

Rapid, convenient, sensitive and simultaneous detection of distinct enzymes is urgently needed for diagnosis, therapeutics and prognostic of related diseases. Here, a new strategy for simultaneous monitoring γ-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) activity has been fabricated based on dual-emission carbon dots (CDs). CDs were prepared by solvothermal treatment of Actinidia chinensis, which presents two fluorescent emissions at 471 nm (blue channel) and 671 nm (red channel). GGT and ALP activity can be detected based on inner filter effect (IFE) and static quenching effect (SQE) of blue and red channels of CDs, respectively. Linear ranges were 2.5-90 U L-1 and 5-200 U L-1, and limit of detection (LOD) were 0.71 U L-1 and 1.2 U L-1 for GGT and ALP, respectively. Developed CDs can monitor GGT and ALP activity in human serum samples with satisfied recoveries (99.3%-108.6% for GGT, 98.4%-105.4% for ALP). Furthermore, the combination of CDs to sense GGT and ALP activity with OR logic gate can predict human health status. The design and application of dual-emission CDs can also be extended as promising tools to detect multianalytes using different channel signals.

PMID:34482874 | DOI:10.1016/j.aca.2021.338829

Mol Oncol. 2021 Sep 4. doi: 10.1002/1878-0261.13096. Online ahead of print.

ABSTRACT

Testicular germ cell tumors (TGCTs) are aggressive but sensitive to cisplatin-based chemotherapy. Alternative therapies are needed for tumors refractory to cisplatin with hypomethylating agents providing one possibility. The mechanisms of cisplatin hypersensitivity and resistance in TGCTs remain poorly understood. Recently, it has been shown that TGCTs, even those resistant to cisplatin, are hypersensitive to very low doses of hypomethylating agents including 5-aza deoxy-cytosine (5-aza) and guadecitabine. We undertook a pharmacogenomic approach in order to better understand mechanisms of TGCT hypomethylating agent hypersensitivity by generating a panel of acquired 5-aza resistant TGCT cells and contrasting these to previously generated acquired isogenic cisplatin resistant cells from the same parent. Interestingly, there was a reciprocal relationship between cisplatin and 5-aza sensitivity, with cisplatin resistance associated with increased sensitivity to 5-aza and 5-aza resistance associated with increased sensitivity to cisplatin. Unbiased transcriptome analysis revealed 5-aza resistant cells strongly downregulated polycomb target gene expression, the exact opposite of the finding for cisplatin resistant cells which upregulated polycomb target genes. This was associated with a dramatic increase in H3K27me3 and decrease in DNMT3B levels in 5-aza resistant cells, the exact opposite changes seen in cisplatin resistant cells. Evidence is presented that reciprocal regulation of polycomb and DNMT3B may be initiated by changes in DNMT3B levels as DNMT3B knockdown alone in parental cells resulted in increased expression of H3K27me3, EZH2 and BMI1, conferred 5-aza resistance and cisplatin sensitization, and mediated genome-wide repression of polycomb target gene expression. Finally, genome-wide analysis revealed that 5-aza resistant, cisplatin resistant and DNMT3B knockdown cells alter the expression of a common set of polycomb target genes. This study highlights that reciprocal epigenetic changes mediated by DNMT3B and polycomb may be a key driver of the unique cisplatin and 5-aza hypersensitivity of TGCTs and suggests that distinct epigenetic vulnerabilities may exist for pharmacological targeting of TGCTs.

PMID:34482638 | DOI:10.1002/1878-0261.13096

Biochem Biophys Res Commun. 2021 Aug 31;576:59-65. doi: 10.1016/j.bbrc.2021.08.091. Online ahead of print.

ABSTRACT

HER1-and HER2-targeted drugs are effective in cancer therapy, especially against lung, breast and colon malignancies; however, resistance of cancer cells to HER1-and HER2-targeted therapies is becoming a serious problem. The avidity/affinity constant (KA) and growth inhibitory effect of anti-HER3 rat monoclonal antibodies (mAb, Ab1∼Ab6) in the presence of therapeutic mAb or low-molecular-weight inhibitors against HER family proteins were analyzed by flow cytometry-based Scatchard plots (Splot) and cell proliferation assay. The KA of Ab3 and Ab6, but not Ab1 or Ab4, split into dual (high and low) modes of KA, and Ab6 exhibited greater anti-proliferative effects against LS-174T colon cancer cells in the presence of Pertuzumab (anti-HER2 mAb). A high KA by Ab6 and Ab6-mediated increased growth inhibition were observed against NCI-H1838 lung or BT474 breast cancer cells, respectively, in the presence of Panitumumab (anti-HER1 mAb) or Perutuzumab. A high KA by Ab6 and Ab6-mediated increased anti-proliferative effects against NCI-H1838 or BT474 were also respectively observed in the presence of Erlotinib (HER1 inhibitor) or Lapatinib (HER1/HER2 inhibitor). In HER1-knockout (KO) NCI-H1838, the reactivity and KA of Ab4 increased compared with in parent NCI-H1838. In HER1-KO or HER3-KO SW1116 colon cancer cells, dual modes of KA with Pertuzumab were noted, and the combination Ab6 and Pertuzumab promoted growth inhibition of HER1-KO, but not of parent SW1116.

PMID:34482024 | DOI:10.1016/j.bbrc.2021.08.091

Basic Clin Pharmacol Toxicol. 2021 Sep 4. doi: 10.1111/bcpt.13654. Online ahead of print.

ABSTRACT

Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity that affects 30-40% of patients undergoing cancer treatment. Although multiple mechanisms of chemotherapy-induced neurotoxicity have been described in preclinical models, these have not been translated into widely effective strategies for the prevention or treatment of CIPN. Predictive biomarkers to inform therapeutic approaches are also lacking. Recent studies have examined genetic risk factors associated with CIPN susceptibility. This review provides an overview of the clinical and pathologic features of CIPN and summarizes efforts to identify target pathways through genetic and functional studies. Structurally and mechanistically diverse chemotherapeutics are associated with CIPN; however, the current review is focused on microtubule targeting agents since these are the focus of most pharmacogenetic association and functional studies of CIPN. Genome-wide pharmacogenetic association studies are useful tools to identify not only causative genes and genetic variants but also genetic networks implicated in drug response or toxicity and have been increasingly applied to investigations of CIPN. Induced pluripotent stem cell-derived models of human sensory neurons are especially useful to understand the mechanistic significance of genomic findings. Combined genetic and functional genomic efforts to understand CIPN hold great promise for developing therapeutic approaches for its prevention and treatment.

PMID:34481421 | DOI:10.1111/bcpt.13654

J Anal Toxicol. 2021 Sep 5:bkab096. doi: 10.1093/jat/bkab096. Online ahead of print.

ABSTRACT

Tramadol (TR) metabolism is mainly dependent on the enzymatic activity of CYP2D6, which is controlled by genetic polymorphisms. Individuals are classified as poor (PMs), intermediate (IMs), extensive (EMs) or ultrarapid metabolizers (UMs) according to their genotype or phenotype. The determination of the metabolic phenotype for CYP2D6 can be of utmost importance in forensic and clinical contexts that involve TR intake. The present study aimed to describe CYP2D6 genetic variants in cases of TR-related deaths and to assess which metabolic ratio(s) (MRs) would allow to determine CYP2D6 phenotype without having to perform genetic analyses. Forty-eight postmortem blood samples were selected from TR-related death cases previously analyzed in a forensic context in North of France between 2013 and 2019. Initial available data included blood concentrations of TR and its two main metabolites (M1& M2) determined using a LC-MS/MS method. TR metabolism was expressed as various MRs comprising TR/M1, TR/M2 and M2/M1. After DNA extraction, sequencing was used for genetic variant detections that affect CYP2D6 activity/expression. In the present study, the allelic variants with the higher frequency were CYP2D6*1 (68%), followed by *4 (21%). The most frequent phenotype is EMs (59.6%), followed by IMs (23.4%), PMs (12.8%), and UMs (6.4%). There was no significant correlation between each calculated MR and the genotypically-predicted phenotypes, except for M2/M1 which appears related to the PM phenotype. The observed distribution of CYP2D6 genetic variants in this TR-related death population was similar to that found in the general Caucasian population. The present study displayed that the blood M2/M1 ratio could be the best-correlated tramadol MR to the PM phenotype, and could thus be used in forensic contexts where genetic analyses are not possible or poorly informative. For the other phenotypes, especially the UM phenotype, genetic analysis appears to be the only reliable method to predict the CYP2D6 phenotype.

PMID:34480795 | DOI:10.1093/jat/bkab096

Eur J Clin Pharmacol. 2021 Sep 4. doi: 10.1007/s00228-021-03206-w. Online ahead of print.

ABSTRACT

BACKGROUND: Body surface area (BSA)-based dosing of irinotecan (IR) does not account for its pharmacokinetic (PK) and pharmacodynamic (PD) variabilities. Functional hepatic nuclear imaging (HNI) and excretory/metabolic/PD pharmacogenomics have shown correlations with IR disposition and toxicity/efficacy. This study reports the development of a nonlinear mixed-effect population model to identify pharmacogenomic and HNI-related covariates that impact on IR disposition to support dosage optimization.

METHODS: Patients had advanced colorectal cancer treated with IR combination therapy. Baseline blood was analysed by Affymetrix DMET™ Plus Array and, for PD, single nucleotide polymorphisms (SNPs) by Sanger sequencing. For HNI, patients underwent 99mTc-IDA hepatic imaging, and data was analysed for hepatic extraction/excretion parameters. Blood was taken for IR and metabolite (SN38, SN38G) analysis on day 1 cycle 1. Population modelling utilised NONMEM version 7.2.0, with structural PK models developed for each moiety. Covariates include patient demographics, HNI parameters and pharmacogenomic variants.

RESULTS: Analysis included (i) PK data: 32 patients; (ii) pharmacogenomic data: 31 patients: 750 DMET and 22 PD variants; and (iii) HNI data: 32 patients. On initial analysis, overall five SNPs were identified as significant covariates for CLSN38. Only UGT1A3_c.31 T > C and ABCB1_c.3435C > T were included in the final model, whereby CLSN38 reduced from 76.8 to 55.1%.

CONCLUSION: The identified UGT1A3_c.31 T > C and ABCB1_c.3435C > T variants, from wild type to homozygous, were included in the final model for SN38 clearance.

PMID:34480602 | DOI:10.1007/s00228-021-03206-w

Pharmacogenomics J. 2021 Sep 3. doi: 10.1038/s41397-021-00253-5. Online ahead of print.

ABSTRACT

Urine drug testing (UDT) is a tool for monitoring drug use, including oxycodone. While variation in cytochrome P450 (CYP) genes is known to alter oxycodone metabolism, its impact on UDT results of oxycodone and its metabolites has not been well-studied. Here, multivariate analysis was performed on retrospective UDT results of 90,379 specimens collected from 14,684 genotyped patients prescribed oxycodone. Genetic variation in CYP2D6 and CYP2C19 had a significant impact on oxymorphone/oxycodone ratios, with a 6.9-fold difference between CYP2D6 ultrarapid metabolizers (UMs) and poor metabolizers (PMs; p < 10-300) and a 1.6-fold difference between CYP2C19 UMs and PMs (p = 1.50 × 10-4). CYP2D6 variation also significantly impacted noroxycodone/oxycodone ratios (p = 6.95 × 10-38). Oxycodone-positive specimens from CYP2D6 PMs were ~5-fold more likely to be oxymorphone-negative compared to normal metabolizers. These findings indicate that multivariate analysis of UDT data may be used to reveal the real-world impact of genetic and non-genetic factors on drug metabolism.

PMID:34480108 | DOI:10.1038/s41397-021-00253-5