J Mol Diagn. 2022 Jan 15:S1525-1578(22)00003-4. doi: 10.1016/j.jmoldx.2021.12.001. Online ahead of print.

ABSTRACT

Clinical laboratories offering genome sequencing have the opportunity to return pharmacogenomic findings to patients, providing the added benefit of preemptive testing that could help inform medication selection or dosing throughout the lifespan. Implementation of pharmacogenomic reporting must address several challenges, including inherent limitations in short-read genome sequencing methods, gene and variant selection, standardization of genotype and phenotype nomenclature, and choice of guidelines and drugs to report. An automated pipeline, lmPGX, was developed as an end-to-end solution which produces two versions of a pharmacogenomic report, presenting either Clinical Pharmacogenetics Implementation Consortium or U.S. Food and Drug Administration guidelines for 12 genes. The pipeline was validated for performance using reference samples and pharmacogenetic data from the Genetic Testing Reference Materials Coordination Program. To determine performance and limitations, lmPGX was compared to three additional publicly available pharmacogenomic pipelines. The lmPGX pipeline offers clinical labs an opportunity for seamless integration of pharmacogenomic results with genome reporting.

PMID:35041930 | DOI:10.1016/j.jmoldx.2021.12.001

J Mol Diagn. 2022 Jan 15:S1525-1578(22)00006-X. doi: 10.1016/j.jmoldx.2021.11.008. Online ahead of print.

ABSTRACT

Clinical pharmacogenomic (PGx) testing typically uses targeted genotyping, which only detects variants included in the test design and may vary among laboratories. To evaluate the potential patient impact of genotyping as compared to sequencing, which can detect common and rare variants, an in silico targeted genotyping panel was developed based on the variants most commonly included in clinical tests and applied to a cohort of 10,030 participants who underwent sequencing for CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, DPYD, SLCO1B1, TPMT, UGT1A1, and VKORC1. The results of in silico targeted genotyping were compared to the clinically reported sequencing results. Of the 10,030 participants, 2,780 (28%) had at least one potentially clinically relevant variant/allele identified by sequencing that would not have been detected in a standard targeted genotyping panel. The genes with largest number of participants with variants only detected by sequencing were SLCO1B1, DPYD, and CYP2D6, which impacted 13%, 6.3%, and 3.5% of participants, respectively. DPYD (112 variants) and CYP2D6 (103 variants) had the largest number of unique variants detected only by sequencing. Although targeted genotyping detects the majority of clinically significant PGx variants, sequencing-based approaches are necessary to detect rare variants that collectively impact many patients. However, efforts to establish PGx variant classification systems and nomenclature to accommodate rare variants will be required to adopt sequencing-based PGx.

PMID:35041929 | DOI:10.1016/j.jmoldx.2021.11.008

Mol Biol Rep. 2022 Jan 18. doi: 10.1007/s11033-021-07079-1. Online ahead of print.

ABSTRACT

BACKGROUND: Artemisinin (ART) is an anti-malaria natural compound with a moderate anticancer action. As a metabolite of ART, dihydroartemisinin (DHA) may have stronger anti-colorectal cancer (CRC) bioactivities. However, the effects of DHA and ART on CRC chemoprevention, including adaptive immune regulation, have not been systematically evaluated and compared.

METHODS: Coupled with a newly-established HPLC analytical method, enteric microbiome biotransformation was conducted to identify if the DHA is a gut microbial metabolite of ART. The anti-CRC potential of these compounds was compared using two different human CRC cell lines for cell cycle arrest, apoptotic induction, and anti-inflammation activities. Naive CD4+ T cells were also obtained for testing the compounds on the differentiation of Treg, Th1 and Th17.

RESULTS: Using compound extraction and analytical methods, we observed for the first time that ART completely converted into its metabolites by gut microbiome within 24 h, but no DHA was detected. Although ART did not obviously influence cancer cell growth in the concentration tested, DHA very significantly inhibited the cancer cell growth at relatively low concentrations. DHA included G2/M cell cycle arrest via upregulation of cyclin A and apoptosis. Both ART and DHA downregulated the pro-inflammatory cytokine expression. The DHA significantly promoted Treg cell proliferation, while both ART and DHA inhibited Th1 and Th17 cell differentiation.

CONCLUSIONS: As a metabolite of ART, DHA possessed stronger anti-CRC activities. The DHA significantly inhibited cell growth via cell cycle arrest, apoptosis induction and anti-inflammation actions. The adaptive immune regulation is a related mechanism of actions for the observed effects.

PMID:35040004 | DOI:10.1007/s11033-021-07079-1

Acta Diabetol. 2022 Jan 17. doi: 10.1007/s00592-021-01832-5. Online ahead of print.

ABSTRACT

AIMS: Cataract formation is accelerated by hyperglycemia due to the excessive production of oxidative stress. This study aimed to examine the underlaying role of glutathione peroxidase 1 (GPX1) rs1800668, catalase (CAT) rs1001179 and superoxide dismutase 1 (SOD1) 50 bp Indel promotor region variants in the pathogenesis of cataract in patients with diabetes.

METHODS: A population-based case-control study of n=680 individuals was conducted which comprised of four respective groups: type 2 diabetes mellitus, diabetic cataract, senile cataract patients and controls. Screening of genotypes was performed by allele-specific (AS) and conventional polymerase chain reaction (PCR). Statistical testing was carried out using SPSS© 20.0, MedCal© and SNPStats© software's. Bioinformatics analysis of linkage disequilibrium was done by HaploView© software 7.0.

RESULTS: GPX1 (rs1800668) showed significant association with higher susceptibility of opacification in type 2 diabetes mellitus (χ2=23.0, Adjusted OR=1.63, 95% CI: 1.05-2.49, p<0.001). A protective role was anticipated by CAT variant (rs1001179) for the development of resistance against the pathogenicity of cataract with diabetes (χ2 = 107, Adjusted OR=0.17, 95% CI: 0.10-0.29, p<0.001). Linkage disequilibrium (LD) plot of GPX1 and CAT variants revealed that CTC-CTT haplotypes demonstrated the presence of linkage (D'=1.0) and co-inheritance (LOD=13.84) in patients of diabetic cataract.

CONCLUSIONS: GPX1 (rs1800668) variant may serve as an antioxidant biomarker for the assessment of risk for cataract in type 2 diabetes mellitus. GPX1 enzyme owed an antioxidant activity which can reduce the oxidative stress and hence could develop resistance in cataractogenesis. The findings could be beneficial as a potential target to the future pharmacogenomic studies of cataract prevention and eradication in diabetes mellitus.

PMID:35037135 | DOI:10.1007/s00592-021-01832-5

ACS Omega. 2021 Dec 20;7(1):669-682. doi: 10.1021/acsomega.1c05306. eCollection 2022 Jan 11.

ABSTRACT

A cobalt(III) complex, [Co(L)]Cl (complex 1, where L = 1,8-[N,N-bis{(3-formyl-2-hydroxy-5-methyl)benzyl}]-1,4,8,11-tetraaza-5,5,7,12,12,14-hexamethylcyclotetradecane) with distorted octahedral geometry has been synthesized and characterized using various spectroscopic techniques. The structure of the ligand has remarkably rich hydrogen intermolecular interactions such as H···H, H···C/C···H, and H···O/O···H that vary with the presence of the metal ion, and the structure of complex 1 has Cl···H interactions; this result has been proved by Hirshfeld surface and two-dimensional (2D) fingerprint maps analyses. The complex exhibits a quasi-reversible Co(III)/Co(II) redox couple with E 1/2 = -0.76 V. Calf thymus DNA (CT DNA) binding abilities of the ligand and complex 1 were confirmed by spectroscopic and electrochemical analyses. According to absorption studies, the ligand and complex 1 bind to CT DNA via intercalative binding mode, with intrinsic binding strengths of 1.41 × 103 and 8.64 × 103 M-1, respectively. A gel electrophoresis assay shows that complex 1 promotes the pUC19 DNA cleavage under dark and light irradiation conditions. Complex 1 has superior antimicrobial activity than the ligand. The cytotoxicity of complex 1 was tested against MDA-MB-231 breast cancer cells with values of IC50 of 1.369 μg mL-1 in the dark and 0.9034 μg mL-1 after light irradiation. Besides, cell morphological studies confirmed the morphological changes with AO/EB dual staining, reactive oxygen species (ROS) staining, mitochondria staining, and Hoechst staining on MDA-MB-231 cancer cells by fluorescence microscopy. Complex 1 was found to be a potent antiproliferative agent against MDA-MB-231 cells, and it can induce mitochondrial-mediated and caspase-dependent apoptosis with activation of downregulated caspases. The biotoxicity assay of complex 1 on the development of Artemia nauplii was evaluated at an IC50 value of 200 μg mL-1 and with excellent biocompatibility.

PMID:35036733 | PMC:PMC8756598 | DOI:10.1021/acsomega.1c05306

Am J Transl Res. 2021 Dec 15;13(12):13328-13335. eCollection 2021.

ABSTRACT

Intersubject variability in drug response, whether related to efficacy or toxicity, is well recognized clinically. Over the years, drug selection from our pharmacologic armamentarium has moved from providers' preferred choices to more personalized treatments as clinicians' decisions are guided by data from clinical trials. Since the advent of more accessible and affordable pharmacogenomic (PGx) testing, the promise of precise pharmacotherapy has been made. Results have accumulated in the literature with numerous examples demonstrating the value of PGx to improve drug response or prevent drug toxicity. Unfortunately, limited availability of reimbursement policies has dampened the enthusiasm of providers and organizations. The clinical application of PGx knowledge remains difficult for most clinicians under real-world conditions in patients with numerous chronic conditions and polypharmacy. This may be due to phenoconversion, a condition where there is a discrepancy between the genotype-predicted phenotype and the observed phenotype. This condition complicates the interpretation of PGx results and may lead to inappropriate recommendations and clinical decision making. For this reason, regulatory agencies have limited the transfer of information from PGx laboratories directly to consumers, especially recommendations about the use of certain drugs. This mini-review presents cases (mexiletine, propafenone, clopidogrel, warfarin, codeine, procainamide) from historical observations where drug response was modified by phenoconversion. The cases illustrate, from decades ago, that we are still in great need of advanced clinical decision systems that cope with conditions associated with phenoconversion, especially in patients with polypharmacy.

PMID:35035679 | PMC:PMC8748136

J Oncol. 2022 Jan 6;2022:9529681. doi: 10.1155/2022/9529681. eCollection 2022.

ABSTRACT

Dermatologic diseases are the fourth most frequent nonfatal common illness, yet they have a psychological, economical, and professional burden that is comparable to or larger than other chronic conditions. From a survey in China of 6 provinces, the overall prevalence of psoriasis with squamous cell carcinoma was 0.47%. According to the current investigation, the outburst of skin disease was not associated with gender, but mainly with the climate of the environment; that is, dry cold weather will more likely to induce psoriasis. Approximately 3% of people around the world have psoriasis, which is near the most common autoimmune skin disease in adults. By simple estimation, there are at least two hundred million psoriasis patients in the world. Therefore, it is not just a simple health problem in a country or a region but a serious global challenge. Of note, about half of the adult patients had been reported to be sick in their childhood and they mostly fell ill around 10 years old. Actinic keratosis is perhaps the most common, followed by squamous cell carcinoma and, to a lesser extent, acne vulgaris, psoriasis, and hidradenitis suppurativa, as well as dermatitis herpetiformis. 5-Fluorouracil (5-FU) 0.5 percent is used topically to treat actinic keratosis and squamous cell carcinoma with good outcomes, while it might cause significant toxicity in certain patients. Dapsone, a Valosin-containing protein, is a medication that is often used to treat inflammatory skin disorders like psoriatic arthritis, but it can occasionally cause hemolytic anemia. Furthermore, biologic medications for the treatment of moderate-to-severe psoriasis and multiple squamous cell carcinoma have proven to be successful and safe; nevertheless, a small percentage of patients do not react to biologic treatment in the long term or do not respond at all. Based on the data from the China Food and Drug Administration, the majority of chemical drugs are utilized as the topical formulations, while Chinese medicines are mainly delivered by an oral route, suggesting that the market for topical preparations of Chinese medicine to treat skin diseases like psoriasis is worth exploration. This large interindividual diversity in response could be caused by changes in genes that encode proteins implicated in the disease's pathologic environment or the medication's mechanism of action. Pharmacogenetics is the study of the association between genetic differences and medication response, which is valuable for identifying nonresponsive patients and those who are more likely to suffer toxicity as a result of treatment. This study highlights the pharmacogenetic recommendations for dermatology therapies that have the strongest evidence at this time, highlighting those that have been incorporated in clinical practice guides. Pharmacogenetic clinical guidelines for multiple squamous cell carcinoma and psoriasis vulgaris were found in this investigation. Here, for multiple squamous cell carcinoma trichohyalin-like 1 (TCHHL1), 5-fluorouracil (5-FU) 0.5% is recommended. Along with that dapsone, Valosin-containing protein can be recommended for treating the psoriasis vulgaris. We made some clinical trials over the two diseases, and from the result obtained, we hypothesize that the suggested drug may be a novel therapeutic target in treating the multiple squamous cell carcinoma with psoriasis vulgaris.

PMID:35035485 | PMC:PMC8758264 | DOI:10.1155/2022/9529681

Pharmacogenomics J. 2022 Jan 17. doi: 10.1038/s41397-021-00255-3. Online ahead of print.

ABSTRACT

Azathioprine (AZA) and its metabolite, mercaptopurine (6-MP), are widely used immunosuppressant drugs. Polymorphisms in genes implicated in AZA/6-MP metabolism, reportedly, could account in part for their potential toxicity. In the present study we performed a systematic review and a meta-analysis, comprising 30 studies and 3582 individuals, to investigate the putative genetic association of two inosine triphosphatase (ITPA) polymorphisms with adverse effects in patients treated with AZA/6-MP. We found that rs1127354 is associated with neutropenia in general populations and in children (OR: 2.39, 95%CI: 1.97-2.90, and OR: 2.43, 95%CI: 2.12-2.79, respectively), and with all adverse effects tested herein in adult populations (OR: 2.12, 95%CI: 1.22-3.69). We also found that rs7270101 is associated with neutropenia and leucopenia in all-ages populations (OR: 2.93, 95%CI: 2.36-3.63, and OR: 2.82, 95%CI: 1.76-4.50, respectively) and with all adverse effects tested herein in children (OR: 1.74, 95%CI: 1.06-2.87). Stratification according to background disease, in combination with multiple comparisons corrections, verified neutropenia to be associated with both polymorphisms, in acute lymphoblastic leukemia (ALL) patients. These findings suggest that ITPA polymorphisms could be used as predictive biomarkers for adverse effects of thiopurine drugs to eliminate intolerance in ALL patients and clarify dosing in patients with different ITPA variants.

PMID:35034963 | DOI:10.1038/s41397-021-00255-3

Adv Protein Chem Struct Biol. 2022;128:361-396. doi: 10.1016/bs.apcsb.2021.08.002. Epub 2021 Oct 13.

ABSTRACT

G protein-coupled receptors (GPCRs) are membrane proteins that play a central role in cell signaling and constitute one of the largest classes of drug targets. The molecular mechanisms underlying GPCR function have been characterized by several experimental and computational methods and provide an understanding of their role in physiology and disease. Population variants arising from nsSNPs affect the native function of GPCRs and have been implicated in differential drug response. In this chapter, we provide an overview on GPCR structure and activation, with a special focus on the β2-adrenergic receptor (β2-AR). First, we discuss the current understanding of the structural and dynamic features of the wildtype receptor. Subsequently, the population variants identified in this receptor from clinical and large-scale genomic studies are described. We show how computational approaches such as bioinformatics tools and molecular dynamics simulations can be used to characterize the variant receptors in comparison to the wildtype receptor. In particular, we discuss three examples of clinically important variants and discuss how the structure and function of these variants differ from the wildtype receptor at a molecular level. Overall, the chapter provides an overview of structure and function of GPCR variants and is a step towards the study of inter-individual differences and personalized medicine.

PMID:35034724 | DOI:10.1016/bs.apcsb.2021.08.002

Clin Pharmacol Ther. 2022 Jan 16. doi: 10.1002/cpt.2526. Online ahead of print.

ABSTRACT

CYP2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 genotype impacts clopidogrel active metabolite formation. CYP2C19 intermediate and poor metabolizers who receive clopidogrel experience reduced platelet inhibition and increased risk for major adverse cardiovascular and cerebrovascular events. This guideline is an update to the 2013 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of clopidogrel based on CYP2C19 genotype and includes expanded indications for CYP2C19 genotype-guided antiplatelet therapy, increased strength of recommendation for CYP2C19 intermediate metabolizers, updated CYP2C19 genotype to phenotype translation, and evidence from an expanded literature review (updates at www.cpicpgx.org).

PMID:35034351 | DOI:10.1002/cpt.2526

Clin Pharmacol Ther. 2022 Jan 16. doi: 10.1002/cpt.2527. Online ahead of print.

ABSTRACT

SLCO1B1 genotype is known to influence patient adherence to statin therapy, in part by increasing the risk for statin-associated musculoskeletal symptoms (SAMS). The SLCO1B1*5 allele has previously been associated with simvastatin discontinuation and SAMS. Prior analyses of the relationship between SLCO1B1*5 and atorvastatin muscle side effects have been inconclusive due to insufficient power. We now quantify the impact of SLCO1B1*5 on atorvastatin discontinuation and SAMS in a large observational cohort using electronic medical record (EMR) data from a single health care system. In our study cohort (n = 1,627 patients exposed to atorvastatin during the course of routine clinical care), 56% (n = 912 of 1,627 patients) discontinued atorvastatin and 18% (n = 303 of 1,627 patients) developed SAMS. A univariate model revealed that SLCO1B1*5 increased the likelihood that patients would stop atorvastatin during routine care (Odds Ratio 1.2, 95% confidence interval [C.I.]: 1.1 - 1.5, p = 0.04). A multivariate Cox proportional hazards model further demonstrated that this same variant was associated with time to atorvastatin discontinuation (Hazard Ratio 1.2, C.I. 1.1 - 1.4, p = 0.004). Additional time-to-event analyses also revealed that SCLO1B1*5 was associated with SAMS (Hazard Ratio 1.4, C.I. 1.1 - 1.7, p = 0.02). Atorvastatin discontinuation was associated with SAMS (Odds Ratio 1.67, p = 0.0001) in our cohort.

PMID:35034348 | DOI:10.1002/cpt.2527

Pathol Res Pract. 2022 Jan 10;230:153760. doi: 10.1016/j.prp.2022.153760. Online ahead of print.

ABSTRACT

Next-generation sequencing (NGS) has been increasingly popular in genomics studies over the last decade, as new sequencing technology has been created and improved. Recently, NGS started to be used in clinical oncology to improve cancer therapy through diverse modalities ranging from finding novel and rare cancer mutations, discovering cancer mutation carriers to reaching specific therapeutic approaches known as personalized medicine (PM). PM has the potential to minimize medical expenses by shifting the current traditional medical approach of treating cancer and other diseases to an individualized preventive and predictive approach. Currently, NGS can speed up in the early diagnosis of diseases and discover pharmacogenetic markers that help in personalizing therapies. Despite the tremendous growth in our understanding of genetics, NGS holds the added advantage of providing more comprehensive picture of cancer landscape and uncovering cancer development pathways. In this review, we provided a complete overview of potential NGS applications in scientific and clinical oncology, with a particular emphasis on pharmacogenomics in the direction of precision medicine treatment options.

PMID:35033746 | DOI:10.1016/j.prp.2022.153760

Pharmacol Res. 2022 Jan 13:106087. doi: 10.1016/j.phrs.2022.106087. Online ahead of print.

ABSTRACT

Inter-individual variability in pharmacokinetics and drug response is heavily influenced by single-nucleotide variants (SNVs) and copy-number variations (CNVs) in genes with importance for drug disposition. Nowadays, a plethora of studies implement next generation sequencing to capture rare and novel pharmacogenomic (PGx) variants that influence drug response. To address these issues, we present a comprehensive end-to-end analysis workflow, beginning from targeted PGx panel re-sequencing to in silico analysis pipelines and in vitro validation assays. Specifically, we show that novel pharmacogenetic missense variants that are predicted or putatively predicted to be functionally deleterious, significantly alter protein activity levels of CYP2D6 and CYP2C19 proteins. We further demonstrate that variant priorization pipelines tailored with functional in vitro validation assays provide supporting evidence for the deleterious effect of novel PGx variants. The proposed workflow could provide the basis for integrating next-generation sequencing for PGx testing into routine clinical practice.

PMID:35033648 | DOI:10.1016/j.phrs.2022.106087

Trials. 2022 Jan 15;23(1):37. doi: 10.1186/s13063-022-05999-2.

ABSTRACT

INTRODUCTION: Hypertension is one of the most important risk factors for cardiovascular disease, and its control rates remain low worldwide. The most effective strategy is that patients with hypertension should be diagnosed and treated early. Preliminary studies showed that the Bushen Jiangya granule (BSJY) could suppress ventricular hypertrophy and inflammatory responses, lower blood pressure, and protect the target organs of hypertension. We designed a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of BSJY in patients with low-to-medium risk hypertension.

METHODS AND ANALYSIS: This trial is a one-center, randomized, double-blind, placebo-controlled study. A total of 260 participants will be randomized in a 1:1 ratio to an experimental group (BSJY plus amlodipine) and a control group (placebo plus amlodipine). The trial cycle will last 8 weeks. The primary outcome is the change in 24-h average systolic and diastolic blood pressure. The secondary outcomes include heart rate variability, pharmacogenomic evaluation, improvement in TCM syndrome, and serum pro-inflammatory/anti-inflammatory cytokines between the two groups. The safety of medication will also be evaluated. All the data will be recorded in electronic case report forms and analyzed by SPSS V.22.0.

ETHICS AND DISSEMINATION: This study has been approved by the Research Ethics Committee of Guang'anmen Hospital, China Academy of Chinese Medical Sciences in Beijing, China (No. 2019-186-KY-01). The participants are volunteers, understand the process of this trial, and sign an informed consent. The results of this study will be disseminated to the public through peer-reviewed journals and academic conferences.

DISCUSSION: We hypothesize that patients with low-to-medium-risk hypertension will benefit from BSJY. If successful, this study will provide evidence-based recommendations for clinicians.

TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiMCTR1900002876. Registered in November 2019.

PMID:35033168 | DOI:10.1186/s13063-022-05999-2

Diabetes Res Clin Pract. 2022 Jan 12:109193. doi: 10.1016/j.diabres.2022.109193. Online ahead of print.

ABSTRACT

AIMS: To examine the predictive factors associated with the progression of different prediabetic status to diabetes.

METHODS: A two-year retrospective cohort study was conducted on 5741 participants aged 40 years or older. Finally, 1685 participants with prediabetes defined by IFG (impaired fasting glucose), IGT (impaired glucose tolerance) and CGI (combined IFG and IGT) were included. Logistic regression model was used to evaluate the risk of prediabetes progression to diabetes.

RESULTS: Of the 1685 subjects with prediabetes at baseline, 212 (12.6%) subjects progressed to diabetes and 1473 (87.4%) subjects did not. Logistic regression analysis demonstrated that people with CGI were associated with an increased risk of progressing to diabetes compared to those with IFG (OR, 95% CI: 3.127, 2.047-4.776). Moreover, males, obese people, people with increased BMI and WHR (Waist/ Hip ratio), and hypertension were positively associated with the progression to diabetes, while HOMA-β was negatively associated with the progression to diabetes.

CONCLUSIONS: Subjects with CGI are prone to progressed to diabetes compared to those with IFG or IGT in middle-aged and older person in China. More attention should be paid to male and obese prediabetic subjects, and measures should be taken to control the increase in their BMI and WHR.

PMID:35032561 | DOI:10.1016/j.diabres.2022.109193

Expert Opin Drug Metab Toxicol. 2022 Jan 14. doi: 10.1080/17425255.2021.2029403. Online ahead of print.

ABSTRACT

INTRODUCTION: : Therapeutic drug monitoring (TDM) of the anticancer drug fluorouracil (5FU) as a method to support dose adjustments has been researched and discussed extensively. Despite manifold evidence of the advantages of 5FU-TDM, traditional body surface area (BSA)-guided dosing is still widely applied.

AREAS COVERED: : This review covers the latest evidence on 5FU-TDM based on a literature search in PubMed between June and September 2021. It particularly highlights new approaches of implementing 5FU-TDM into precision medicine by combining TDM with pharmacogenetic testing and/or pharmacometric models. This review further discusses remaining obstacles in order to incorporate 5FU-TDM into clinical routine.

EXPERT OPINION: : New data on 5FU-TDM further strengthen the advantages compared to BSA-guided dosing as it is able to reduce pharmacokinetic variability and thereby improve treatment efficacy and safety. Interprofessional collaboration has the potential to overcome the remaining barriers for its implementation. Pre-emptive pharmacogenetic testing followed by 5FU-TDM can further improve 5FU exposure in a substantial proportion of patients. Developing a model framework integrating pharmacokinetics and pharmacodynamics of 5FU will be crucial to fully advance into the precision medicine era. Model applications can potentially support clinicians in dose finding before starting chemotherapy. Additionally, TDM provides further assistance in continuously improving model predictions.

PMID:35029518 | DOI:10.1080/17425255.2021.2029403

Artif Organs. 2022 Jan 14. doi: 10.1111/aor.14161. Online ahead of print.

ABSTRACT

BACKGROUND: Hemodialysis (HD) using super high-flux dialyzer (HD + SHF) comparably removed uremic toxins to high-volume postdilution online hemodiafiltration (olHDF). Integration of hemoperfusion (HP) to HD + SHF (HD + SHF + HP) might provide superior uremic toxin removing capability to high-volume postdilution olHDF.

METHOD: The present study was conducted in thrice-a-week HD patients to compare the efficacy in removing indoxyl sulfate (IS), beta-2 microglobulin (β2 M), and urea between high-volume postdilution ol-HDF and HD + SHF + HP, comprising HD + SHF as the main treatment plus HD + SHF + HP 1/week in the first 4 weeks and 1/2 weeks in the second 4 weeks.

RESULTS: Ten prevalent HD patients with blood flow rate (BFR) above 400 ml/min were randomized into two sequences of 8-week treatment periods of HD + SHF + HP and later high-volume postdilution olHDF or vice versa. When compared with high-volume postdilution olHDF (convective volume of 26.02 ± 1.8 L/session), HD + SHF + HP provided comparable values of percentage reduction ratio of IS (52.0 ± 11.7 vs. 56.3 ± 7.5%, p = 0.14) and β2 M (83.7 ± 4.9 vs. 84.0 ± 4.3%, p = 0.37) and slightly lower urea reduction ratio. Despite greater dialysate albumin loss (p = 0.008), there was no significant change in serum albumin level in HD + SHF + HP group.

CONCLUSIONS: HD + SHF + HP could not provide superior efficacy in removing uremic toxins to high-volume postdilution olHDF. The use of low BFR of 200 ml/min during the first 2 h of HD + SHF + HP session, according to the instruction of manufacturer, might impair the efficacy of the HD + SHF part in removing uremic toxins.

PMID:35028951 | DOI:10.1111/aor.14161

Semin Oncol. 2021 Dec 13:S0093-7754(21)00074-9. doi: 10.1053/j.seminoncol.2021.11.004. Online ahead of print.

ABSTRACT

BACKGROUND: Fluoropyrimidine chemotherapy is used across many tumor types and settings. The incidence of severe adverse events (SAEs) is around 20%. Mortality is 0.5%-1%. Dihydropyrimidine dehydrogenase (DPD) plays a key role in fluoropyrimidine inactivation. Key DPYD mutations are linked to a high risk of SAEs. Pretreatment DPD screening was mandated by EMA guidelines in April 2020 and widely adopted thereafter. Uncertainty remains regarding optimal dosing practice.

METHODS: We retrospectively examined records of all 23 patients with DPYD mutation who started chemotherapy between April and November 2020. Our center tests for the mutations considered clinically actionable by Clinical Pharmacogenetics Implementation Consortium and uses the Gene Activity Score (GAS) to guide dose reduction.

RESULTS: Most patients started on a 50% dose. One started on 100% and experienced mild diarrhea after cycle 2; DPD was tested belatedly, subsequent cycles were reduced to 50% and he remained well. Three patients receiving chemo-radiotherapy started on 76% dose; 50% was felt to be subtherapeutic. One of them had no toxicities; another had grade 2 nausea and a hospital attendance with non-neutropenic fever; the third was admitted for 6 weeks with pancolitis. Seven patients did not have toxicities above grade 1 and no hospital attendances. Five patients had further dose reductions. None had dose escalation.

CONCLUSION: As our experience shows, patients with DPD deficiency are heterogeneous. Worryingly, SAEs occur despite dose reduction according to GAS. Others had minimal toxicity and may be under-dosed by GAS. There are clearly many factors at play other than the 4 DPYD variants. The DPD result must be available and inform first cycle dosing. Dose should be cautiously titrated up if tolerated; this was not done at our center due to clinician caution. Further research is needed to guide this. Patients should be reviewed frequently, counselled regarding their DPD status, and empowered to seek advice promptly when they feel unwell.

PMID:35027218 | DOI:10.1053/j.seminoncol.2021.11.004

Metabolism. 2022 Jan 10:155121. doi: 10.1016/j.metabol.2021.155121. Online ahead of print.

NO ABSTRACT

PMID:35026232 | DOI:10.1016/j.metabol.2021.155121

Lancet Gastroenterol Hepatol. 2022 Feb;7(2):171-185. doi: 10.1016/S2468-1253(21)00223-5.

ABSTRACT

Therapeutic drug monitoring (TDM) has emerged as a useful tool for optimising the use of biologics, and in particular anti-tumour necrosis factor (anti-TNF) therapy, in inflammatory bowel disease (IBD). However, challenges remain and are hindering the widespread implementation of TDM in clinical practice. These barriers include identification of the optimal drug concentration to target, the lag time between sampling and results, and the proper interpretation of anti-drug antibody titres among different assays. Solutions to overcome these barriers include the harmonisation of TDM assays and the use of point-of-care testing. Other unmet needs include well designed prospective studies and randomised controlled trials focusing on proactive TDM, particularly during induction therapy. Future studies should also investigate the utility of TDM for biologics other than anti-TNF therapies in both IBD and other immune-mediated inflammatory diseases such as rheumatoid arthritis and psoriasis, and the use of pharmacokinetic modelling dashboards and pharmacogenetics towards individual personalised medicine.

PMID:35026171 | DOI:10.1016/S2468-1253(21)00223-5