J Pain. 2024 Apr 29:104552. doi: 10.1016/j.jpain.2024.104552. Online ahead of print.

ABSTRACT

Bortezomib-induced neuropathic pain (BINP) poses a challenge in multiple myeloma (MM) treatment. Genetic factors play a key role in BINP susceptibility, but research has predominantly focused on Caucasian populations. This research explored novel genetic risk loci and pathways associated with BINP development in Korean MM patients, while evaluating reproducibility of variants from Caucasians. Clinical data and buffy coat samples from 185 MM patients on bortezomib were collected. The cohort was split into discovery and validation cohorts through random stratification of clinical risk factors for BINP. GWAS was performed on the discovery cohort (n=74) with Infinium Global Screening Array-24 v3.0 BeadChip (654,027 SNPs). Relevant biological pathways were identified using pathway scoring algorithm (PASCAL). The top 20 SNPs were validated in the validation cohort (n=111). Previously reported SNPs were validated in the entire cohort (n=185). Pathway analysis of the GWAS results identified 31 relevant pathways, including immune systems and endosomal vacuolar pathways. Among top 20 SNPs from discovery cohort, 16 were replicated, which included intronic variants in ASIC2 and SMOC2, recently implicated in nociception, as well as intergenic variants or long non-coding RNAs. None of the 17 previously reported SNPs remained significant in our cohort (rs2274578, p=0.085). This study represents the first investigation of novel genetic loci and biological pathways associated with BINP occurrence. Our findings, in conjunction with existing Caucasian studies, expand the understanding of personalized risk prediction and disease mechanisms. PERSPECTIVE: This article is the first to explore novel genetic loci and pathways linked to bortezomib-induced neuropathic pain (BINP) in Korean multiple myeloma patients, offering novel insights beyond the existing research focused on Caucasian populations, into personalized risk assessment and therapeutic strategies of BINP.

PMID:38692398 | DOI:10.1016/j.jpain.2024.104552

Nat Commun. 2024 May 1;15(1):3681. doi: 10.1038/s41467-024-48124-4.

ABSTRACT

Defining genetic factors impacting chemotherapy failure can help to better predict response and identify drug resistance mechanisms. However, there is limited understanding of the contribution of inherited noncoding genetic variation on inter-individual differences in chemotherapy response in childhood acute lymphoblastic leukemia (ALL). Here we map inherited noncoding variants associated with treatment outcome and/or chemotherapeutic drug resistance to ALL cis-regulatory elements and investigate their gene regulatory potential and target gene connectivity using massively parallel reporter assays and three-dimensional chromatin looping assays, respectively. We identify 54 variants with transcriptional effects and high-confidence gene connectivity. Additionally, functional interrogation of the top variant, rs1247117, reveals changes in chromatin accessibility, PU.1 binding affinity and gene expression, and deletion of the genomic interval containing rs1247117 sensitizes cells to vincristine. Together, these data demonstrate that noncoding regulatory variants associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to antileukemic agents.

PMID:38693155 | DOI:10.1038/s41467-024-48124-4

J Hypertens. 2024 Apr 12. doi: 10.1097/HJH.0000000000003737. Online ahead of print.

ABSTRACT

Drug allergy and intolerance are increasingly recognized as significant public health concerns, leading to adverse reactions in patients undergoing pharmacological treatments. Multiple drug intolerance syndrome (MDIS), characterized by adverse reactions to at least three different drug classes without a clear immunological mechanism, poses a substantial challenge, particularly in hypertensive patients. Despite its link to suboptimal adherence and uncontrolled blood pressure, MDIS in the context of hypertension remains insufficiently explored. This review synthesizes existing literature on MDIS, emphasizing clinical characteristics, pathogenesis, and psychiatric comorbidity. Furthermore, it delves into MDIS in the context of hypertension, highlighting the importance of a multidisciplinary approach in diagnosis and management, including innovative therapeutic strategies such as novel therapeutic algorithms or renal denervation. The review concludes by emphasizing the necessity for further research and clinical trials to enhance our understanding and address MDIS, especially in hypertensive patients.

PMID:38690922 | DOI:10.1097/HJH.0000000000003737

Reprod Sci. 2024 Apr 30. doi: 10.1007/s43032-024-01573-0. Online ahead of print.

ABSTRACT

Cuproptosis is a recently discovered mode of cell death that has garnered attention due to its association with various diseases. However, the intricate genetic relationship between cuproptosis and ovarian aging has remained largely unexplored. This study aimed to bridge this knowledge gap by leveraging data sets related to ovarian aging and cuproptosis. Through comprehensive bioinformatics analyses, facilitated by R software, we uncovered FDX1 as a potential cuproptosis-related gene with relevance to ovarian aging. To gain insights into FDX1's role, we conducted spatial transcriptome analyses in the ovaries of both young and aged female mice. These experiments revealed a significant reduction in FDX1 expression in the aging group compared to the young group. To substantiate these findings at the genetic level, we turned to clinical infertility biopsies. Impressively, we observed consistent results in biopsies from elderly infertile patients, reinforcing the link between FDX1 and ovarian aging. Moreover, we delved into the pharmacogenomics of ovarian cell lines and discovered that FDX1 expression levels were intricately associated with heightened sensitivity to specific small molecule drugs. This observation suggests that modulating FDX1 could potentially be a strategy to influence drug responses in ovarian-related therapies. In sum, this study marks a pioneering effort in identifying FDX1 as a cuproptosis-related gene implicated in ovarian aging. These findings hold substantial promise, not only in shedding light on the underlying mechanisms of ovarian aging but also in positioning FDX1 as a potential diagnostic biomarker and therapeutic target. With further research, FDX1 could play a pivotal role in advancing precision medicine and therapies for ovarian-related conditions.

PMID:38689081 | DOI:10.1007/s43032-024-01573-0

Dent Med Probl. 2024 Mar-Apr;61(2):257-268. doi: 10.17219/dmp/155811.

ABSTRACT

BACKGROUND: The screw-retrievable cement-retained (SRCR) design combines the benefits of both screwand cement-retained implant-supported restorations. This concept has sparked interest in implant dentistry. However, there is a lack of research on fracture behaviors and clinical performance of such restorations.

OBJECTIVES: The aim of the present article was to review the current literature on the fracture loads and fracture modes of SRCR implant restorations - in vitro studies, and also studies demonstrating the clinical performance of such design.

MATERIAL AND METHODS: A literature search was conducted from January 2000 to June 2022, using 6 databases to identify studies on fracture load and clinical performance that fulfilled the eligibility criteria. Thirty-eight studies met the inclusion criteria (22 in vitro and16 in vivo). The in vivo studies comprised case reports/series/letters (9), clinical techniques (2), retrospective/prospective studies (3), and randomized controlled trials (RCTs) (2).

RESULTS: The reviewed articles reported the effects of the SRCR design on the fracture risk if screw access channels were filled or unfilled, with regard to their diameter, and the preparation before or after glazing. The effect of the type of material used in the construction on the fracture modes SRCR restorations was also reported. The long-term clinical data was mainly retrospective and referred to metal-ceramic constructions. Limited long-term clinical data was available for all-ceramic materials and high-performance polymers (HPPs).

CONCLUSIONS: Screw-retrievable cement-retained implant restorations appear to have potential in the monolithic design. If the SRCR construction is metal-ceramic or made of a veneered material, special design and abutment selection should be considered. High-performance polymers may be recommended as a substitute for posterior implant restoration.

PMID:38686968 | DOI:10.17219/dmp/155811

Pharmacotherapy. 2024 Apr 30. doi: 10.1002/phar.2923. Online ahead of print.

ABSTRACT

BACKGROUND: Major bleeding occurs annually in 1%-3% of patients on vitamin K antagonists (VKAs), despite close monitoring. Genetic variants in proteins involved in VKA response may affect this risk.

AIM: To determine the association of genetic variants (cytochrome P450 enzymes 2C9 [CYP2C9] and 4F2 [CYP4F2], gamma-glutamyl carboxylase [GGCX]) with major bleeding in VKA users, separately and combined, including vitamin K epoxide reductase complex subunit-1 (VKORC1).

METHODS: A case-cohort study was established within the BLEEDS cohort, which includes 16,570 patients who initiated VKAs between 2012 and 2014. We selected all 326 major bleeding cases that occurred during 17,613 years of follow-up and a random subcohort of 978 patients. We determined variants in CYP2C9, CYP4F2, GGCX, VKORC1 and evaluated the interaction between variant genotypes. Hazard ratios for major bleeding with 95% confidence intervals (95% CI) were estimated by weighted Cox regression.

RESULTS: Genotype was determined in 256 cases and 783 subcohort members. Phenprocoumon was the most prescribed VKA for both cases and the subcohort (78% and 75%, respectively). Patients with major bleeding were slightly older than subcohort patients. CYP4F2-TT carriership was associated with a 1.6-fold (95% CI 0.9-2.8) increased risk of major bleeding compared with CC-alleles, albeit not statistically significant. For the CYP2C9 and GGCX variants instead, the major bleeding risk was around unity. Carrying at least two variant genotypes in CYP2C9 (poor metabolizer), CYP4F2-TT, and VKORC1-AA was associated with a 4.0-fold (95%CI 1.4-11.4) increased risk, while carriers of both CYP4F2-TT and VKORC1-AA had a particularly increased major bleeding risk (hazard ratio 6.7, 95% CI 1.5-29.8) compared with carriers of CC alleles in CYP4F2 and GG in VKORC1. However, the number of major bleeding cases in carriers of multiple variants was few (8 and 5 patients, respectively).

CONCLUSIONS: CYP4F2 polymorphism was associated with major bleeding, especially in combination with VKORC1 genetic variants. These variants could be considered to further personalize anticoagulant treatment.

PMID:38686648 | DOI:10.1002/phar.2923

Front Immunol. 2024 Apr 15;15:1392099. doi: 10.3389/fimmu.2024.1392099. eCollection 2024.

ABSTRACT

BACKGROUND: Asparaginase (ASNase) is a crucial part of acute leukemia treatment, but immune responses to the agent can reduce its effectiveness and increase the risk of relapse. Currently, no reliable and validated biomarker predicts ASNase-induced hypersensitivity reactions during therapy. We aimed to identify predictive biomarkers and determine immune cells responsible for anaphylaxis using a murine model of ASNase hypersensitivity.

METHODS: Our preclinical study uses a murine model to investigate predictive biomarkers of ASNase anaphylaxis, including anti-ASNase antibody responses, immune complex (IC) levels, ASNase-specific binding to leukocytes or basophils, and basophil activation.

RESULTS: Our results indicate that mice immunized to ASNase exhibited dynamic IgM, IgG, and IgE antibody responses. The severity of ASNase-induced anaphylaxis was found to be correlated with levels of IgG and IgE, but not IgM. Basophils from immunized mice were able to recognize and activate in response to ASNase ex vivo, and the extent of recognition and activation also correlated with the severity of anaphylaxis observed. Using a multivariable model that included all biomarkers significantly associated with anaphylaxis, independent predictors of ASNase-induced hypersensitivity reactions were found to be ASNase IC levels and ASNase-specific binding to leukocytes or basophils. Consistent with our multivariable analysis, we found that basophil depletion significantly protected mice from ASNase-induced hypersensitivity reactions, supporting that basophils are essential and can be used as a predictive marker of ASNase-induced anaphylaxis.

CONCLUSIONS: Our study demonstrates the need for using tools that can detect both IC- and IgE-mediated hypersensitivity reactions to mitigate the risk of ASNase-induced hypersensitivity reactions during treatment.

PMID:38686384 | PMC:PMC11057047 | DOI:10.3389/fimmu.2024.1392099

Cureus. 2024 Mar 30;16(3):e57241. doi: 10.7759/cureus.57241. eCollection 2024 Mar.

ABSTRACT

Diabetes, hypertension, obesity, and chronic kidney disease (CKD) are major public health challenges globally, contributing significantly to morbidity and mortality. The co-occurrence and interplay among these conditions exacerbate health outcomes, highlighting the need for an integrated understanding and approach to management. This narrative review aims to explore the complex relationships between diabetes, hypertension, obesity, and CKD, elucidating their collective impact on health. It discusses the epidemiological trends, underlying pathophysiological mechanisms, genetic predispositions, current treatment strategies, and the future direction of research and therapy. An extensive review of current literature was conducted, focusing on the epidemiology, pathophysiology, risk factors, diagnosis, and treatment of diabetes, hypertension, obesity, and CKD. Additionally, the review delves into the genetic and molecular biology underlying these conditions, the potential for personalized medicine, and the importance of a multidisciplinary approach to care. The review identifies key areas where these conditions intersect, enhancing disease progression and complicating management. It highlights the role of genetic and environmental factors in disease etiology, the critical need for personalized treatment strategies, and the gaps in current management approaches. Innovations in pharmacotherapy, monitoring technologies, and the potential of pharmacogenomics are discussed as avenues for advancing patient care. Diabetes, hypertension, obesity, and CKD are intricately linked, necessitating an integrated, patient-centered approach to care that goes beyond traditional treatment modalities. Future research should focus on collaborative models and interdisciplinary strategies to address the multifaceted challenges posed by these conditions. Emphasizing personalized medicine and leveraging technological advancements offer promising pathways to improve outcomes and reduce the global health burden of these metabolic disorders.

PMID:38686257 | PMC:PMC11056813 | DOI:10.7759/cureus.57241

Front Genet. 2024 Apr 15;15:1407559. doi: 10.3389/fgene.2024.1407559. eCollection 2024.

NO ABSTRACT

PMID:38686024 | PMC:PMC11056498 | DOI:10.3389/fgene.2024.1407559

Am J Psychiatry. 2024 Apr 30:appiajp20230657. doi: 10.1176/appi.ajp.20230657. Online ahead of print.

ABSTRACT

OBJECTIVE: In this review, the authors update the 2018 position statement of the American Psychiatric Association Council of Research Workgroup on Biomarkers and Novel Treatments on pharmacogenomic (PGx) tools for treatment selection in depression.

METHODS: The literature was reviewed for new clinical trials and meta-analyses, published from 2017 to 2022, of studies using PGx tools for treatment selection in depression. The blinding and control conditions, as well as primary and secondary outcomes and post hoc analyses, were summarized.

RESULTS: Eleven new clinical trials and five meta-analyses were identified; all studies had primary outcome measures related to speed or efficacy of treatment response. Three trials (27%) demonstrated efficacy on the primary outcome measure with statistical significance; the three studies used different PGx tools; one study was open-label and the other two were small single-blind trials. Five trials (45%) did not detect efficacy with statistical significance on either primary or secondary outcome measures. Only one trial (9%) used adverse events as a primary outcome measure. All studies had significant limitations; for example, none adopted a fully blinded study design, only two studies attempted to blind the treating clinician, and none incorporated measures to estimate the effectiveness of the blinds or the influence of lack of blinding on the study results.

CONCLUSIONS: The addition of these new data do not alter the recommendations of the 2018 report, or the advice of the U.S. Food and Drug Administration, that the evidence does not support the use of currently available combinatorial PGx tools for treatment selection in major depressive disorder. Priority efforts for future studies and the development and testing of effective tools include fully blinded study designs, inclusion of promising genetic variants not currently included in any commercially available tests, and investigation of other uses of pharmacogenomics, such as estimating the likelihood of rare adverse drug effects, rather than increasing the speed or magnitude of drug response.

PMID:38685859 | DOI:10.1176/appi.ajp.20230657

Sr Care Pharm. 2024 May 1;39(5):168. doi: 10.4140/TCP.n.2024.168.

NO ABSTRACT

PMID:38685623 | DOI:10.4140/TCP.n.2024.168

Sr Care Pharm. 2024 May 1;39(5):173-177. doi: 10.4140/TCP.n.2024.173.

ABSTRACT

Traditional definitions of polypharmacy may largely not account for the market proliferation of herbal and dietary supplements, cannabis products, or incorporate the new science of pharmacogenomics (PGx). Polypharmacy is encountered by most pharmacists providing patient care in many settings. The "polypharmacist" can assist patients and providers with solving medication-related problems (MRPs) in this new and challenging environment of supplements and cannabis products by utilizing traditional pharmacology and pharmacokinetic principles, including PGx, broadly across many medical disciplines. One may encounter polypharmacy more in the geriatric population, though in an age of supplements and cannabis proliferation, polypharmacy is increasingly being encountered at younger ages. Not only is polypharmacy training at best fragmented in pharmacy curricula, but it may also not account for the above-mentioned products that may use the same metabolic pathways to increase drug interactions and adverse drug reactions (ADRs) regarding prescription medications. Polypharmacy being more formally prioritized in pharmacist training may better prepare pharmacists for commonly encountered polypharmacy and can be a viable model of practice.

PMID:38685622 | DOI:10.4140/TCP.n.2024.173

J Allergy Clin Immunol Pract. 2024 Apr 27:S2213-2198(24)00422-7. doi: 10.1016/j.jaip.2024.04.037. Online ahead of print.

ABSTRACT

The CYP3A5*1 polymorphism, which increases the metabolic activity of CYP3A5, has been associated with a poor prognosis for asthma. In addition, individuals with this allele have a reduced response to corticosteroid treatment.

PMID:38685478 | DOI:10.1016/j.jaip.2024.04.037

J Control Release. 2024 Apr 27:S0168-3659(24)00270-0. doi: 10.1016/j.jconrel.2024.04.041. Online ahead of print.

ABSTRACT

Scramblase Xk-related protein 8 (Xkr8) regulates the externalization of phosphatidylserine (PS) during apoptosis and holds a pivotal role in fostering tumor immunosuppression. Targeting Xkr8 in conjunction with chemotherapy demonstrated a novel avenue for amplifying antitumor immune response and overcoming chemo-immune resistance. Here we further evaluated this strategy by using a clinically relevant orthotopic model and elucidated the mechanism through in-depth single-cell RNA sequencing (scRNA-seq). We found that Xkr8 knockdown exhibited the potential to lead to immunogenic cell death (ICD) by impeding the normal clearance of apoptotic cells. Co-delivery of Xkr8 small interference RNA (siRNA) and a prodrug conjugate of 5-fluorouracil (5-Fu) and oxoplatin (FuOXP) showed remarkable therapeutic efficacy in an orthotopic pancreatic tumor model with increased infiltration of proliferative NK cells and activated macrophages in the tumor microenvironment (TME). Single-cell trajectory analysis further unveiled that tumor infiltrating CD8+ T cells are differentiated favorably to cytotoxic over exhausted phenotype after combination treatment. Our study sheds new light on the impact of Xkr8 knockdown on TME and solidifies the rationale of combining Xkr8 knockdown with chemotherapy to treat various types of cancers.

PMID:38685385 | DOI:10.1016/j.jconrel.2024.04.041

Malar J. 2024 Apr 29;23(1):125. doi: 10.1186/s12936-024-04930-1.

ABSTRACT

BACKGROUND: Despite efforts made to reduce morbidity and mortality associated with malaria, especially in sub-Saharan Africa, malaria continues to be a public health concern that requires innovative efforts to reach the WHO-set zero malaria agenda. Among the innovations is the use of artemisinin-based combination therapy (ACT) that is effective against Plasmodium falciparum. Generic artemether-lumefantrine (AL) is used to treat uncomplicated malaria after appropriate diagnosis. AL is metabolized by the cytochrome P450 family of enzymes, such as CYP2B6, CYP3A4 and CYP3A5, which can be under pharmacogenetic influence. Pharmacogenetics affecting AL metabolism, significantly influence the overall anti-malarial activity leading to variable therapeutic efficacy. This study focused on generic AL drugs used in malarial treatment as prescribed at health facilities and evaluated pharmacogenomic influences on their efficacy.

METHODS: Patients who have been diagnosed with malaria and confirmed through RDT and microscopy were recruited in this study. Blood samples were taken on days 1, 2, 3 and 7 for parasite count and blood levels of lumefantrine, artemisinin, desbutyl-lumefantrine (DBL), and dihydroartemisinin (DHA), the active metabolites of lumefantrine and artemether, respectively, were analysed using established methods. Pharmacogene variation analysis was undertaken using iPLEX microarray and PCR-RFLP.

RESULTS: A total of 52 patients completed the study. Median parasite density from day 1 to 7 ranged from 0-2666/μL of blood, with days 3 and 7 recording 0 parasite density. Highest median plasma concentration for lumefantrine and desbutyl lumefantrine, which are the long-acting components of artemisinin-based combinations, was 4123.75 ng/mL and 35.87 ng/mL, respectively. Day 7 plasma lumefantrine concentration across all generic ACT brands was ≥ 200 ng/mL which potentially accounted for the parasitaemia profile observed. Monomorphism was observed for CYP3A4 variants, while there were observed variations in CYP2B6 and CYP3A5 alleles. Among the CYP3A5 genotypes, significant differences in genotypes and plasma concentration for DBL were seen on day 3 between 1/*1 versus *1/*6 (p = 0.002), *1/*3 versus *1/*6 (p = 0.006) and *1/*7 versus *1/*6 (p = 0.008). Day 7 plasma DBL concentrations showed a significant difference between *1/*6 and *1/*3 (p = 0.026) expressors.

CONCLUSIONS: The study findings show that CYP2B6 and CYP3A5 pharmacogenetic variations may lead to higher plasma exposure of AL metabolites.

PMID:38685044 | DOI:10.1186/s12936-024-04930-1

BMJ Open. 2024 Apr 29;14(4):e081990. doi: 10.1136/bmjopen-2023-081990.

ABSTRACT

OBJECTIVES: Pharmacovigilance databases play a critical role in monitoring drug safety. The duplication of reports in pharmacovigilance databases, however, undermines their data integrity. This scoping review sought to provide a comprehensive understanding of duplication in pharmacovigilance databases worldwide.

DESIGN: A scoping review.

DATA SOURCES: Reviewers comprehensively searched the literature in PubMed, Web of Science, Wiley Online Library, EBSCOhost, Google Scholar and other relevant websites.

ELIGIBILITY CRITERIA: Peer-reviewed publications and grey literature, without language restriction, describing duplication and/or methods relevant to duplication in pharmacovigilance databases from inception to 1 September 2023.

DATA EXTRACTION AND SYNTHESIS: We used the Joanna Briggs Institute guidelines for scoping reviews and conformed with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. Two reviewers independently screened titles, abstracts and full texts. One reviewer extracted the data and performed descriptive analysis, which the second reviewer assessed. Disagreements were resolved by discussion and consensus or in consultation with a third reviewer.

RESULTS: We screened 22 745 unique titles and 156 were eligible for full-text review. Of the 156 titles, 58 (47 peer-reviewed; 11 grey literature) fulfilled the inclusion criteria for the scoping review. Included titles addressed the extent (5 papers), prevention strategies (15 papers), causes (32 papers), detection methods (25 papers), management strategies (24 papers) and implications (14 papers) of duplication in pharmacovigilance databases. The papers overlapped, discussing more than one field. Advances in artificial intelligence, particularly natural language processing, hold promise in enhancing the efficiency and precision of deduplication of large and complex pharmacovigilance databases.

CONCLUSION: Duplication in pharmacovigilance databases compromises risk assessment and decision-making, potentially threatening patient safety. Therefore, efficient duplicate prevention, detection and management are essential for more reliable pharmacovigilance data. To minimise duplication, consistent use of worldwide unique identifiers as the key case identifiers is recommended alongside recent advances in artificial intelligence.

PMID:38684275 | DOI:10.1136/bmjopen-2023-081990

J Clin Pharmacol. 2024 Apr 29. doi: 10.1002/jcph.2446. Online ahead of print.

ABSTRACT

Human genetic variation (polymorphisms) in genes coding proteins involved in the absorption, distribution, metabolism, and elimination (ADME) of drugs can have a strong effect on drug exposure and downstream efficacy and safety outcomes. Vamorolone, a dissociative steroidal anti-inflammatory drug for treating Duchenne muscular dystrophy (DMD), primarily undergoes oxidation by CYP3A4 and CYP3A5 and glucuronidation by UDP-glucuronosyltransferases. This work assesses the pharmacokinetics (PKs) of vamorolone and sources of interindividual variability (IIV) in 81 steroid-naïve boys with DMD aged 4 to <7 years old considering the genetic polymorphisms of CYPS3A4 (CYP3A4*22, CYP3A4*1B), CYP3A5 (CYP3A5*3), and UGT1A1 (UGT1A1*60) utilizing population PK modeling. A one-compartment model with zero-order absorption (Tk0, duration of absorption), linear clearance (CL/F), and volume (V/F) describes the plasma PK data for boys with DMD receiving a wide range of vamorolone doses (0.25-6 mg/kg/day). The typical CL/F and V/F values of vamorolone were 35.8 L/h and 119 L, with modest IIV. The population Tk0 was 3.14 h yielding an average zero-order absorption rate (k0) of 1.16 mg/kg/h with similar absorption kinetics across subjects at the same vamorolone dose (i.e., no IIV on Tk0). The covariate analysis showed that none of the genetic covariates had any significant impact on the PKs of vamorolone in boys with DMD. Thus, the PKs of vamorolone is very consistent in these young boys with DMD.

PMID:38682893 | DOI:10.1002/jcph.2446

Cancer. 2024 Apr 29. doi: 10.1002/cncr.35343. Online ahead of print.

ABSTRACT

BACKGROUND: Genetic polymorphisms of molecules are known to cause individual differences in the therapeutic efficacy of anticancer drugs. However, to date, germline mutations (but not somatic mutations) for anticancer drugs have not been adequately studied. The objective of this study was to investigate the association between germline polymorphisms of gemcitabine metabolic and transporter genes with carbohydrate antigen 19-9 (CA 19-9) response (decrease ≥50% from the pretreatment level at 8 weeks) and overall survival (OS) in patients with metastatic pancreatic cancer who receive gemcitabine-based chemotherapy.

METHODS: This multicenter, prospective, observational study enrolled patients with metastatic pancreatic cancer patients who were receiving gemcitabine monotherapy or gemcitabine plus nanoparticle albumin-bound paclitaxel combination chemotherapy. Thirteen polymorphisms that may be involved in gemcitabine responsiveness were genotyped, and univariate and multivariate logistic regression analyses were used to determine the association of these genotypes with CA 19-9 response and OS. The significance level was set at 5%.

RESULTS: In total, 180 patients from 11 hospitals in Japan were registered, and 159 patients whose CA 19-9 response could be assessed were included in the final analysis. Patients who had a CA 19-9 response had significantly longer OS (372 vs. 241 days; p = .007). RRM1 2464A>G and RRM2 175T>G polymorphisms suggested a weak association with CA 19-9 response and OS, but it was not statistically significant. COX-2 -765G>C polymorphism did not significantly correlate with CA 19-9 response but was significantly associated with OS (hazard ratio, 2.031; p = .019).

CONCLUSIONS: Genetic polymorphisms from the pharmacokinetics of gemcitabine did not indicate a significant association with efficacy, but COX-2 polymorphisms involved in tumor cell proliferation might affect OS.

PMID:38682652 | DOI:10.1002/cncr.35343

Pharmacoepidemiol Drug Saf. 2024 May;33(5):e5796. doi: 10.1002/pds.5796.

ABSTRACT

PURPOSE: Use of real-world data (RWD) for external controls added to single-arm trials (SAT) is increasingly prevalent in regulatory submissions. Due to inherent differences in the data-generating mechanisms, biases can arise. This paper aims to illustrate how to use quantitative bias analysis (QBA).

METHODS: Advanced non-small cell lung cancer (NSCLC) serves as an example, where many small subsets of patients with molecular tumor subtypes exist. First, some sources of bias that may occur in oncology when comparing RWD to SAT are described. Second, using a hypothetical immunotherapy agent, a dataset is simulated based on expert input for survival analysis of advanced NSCLC. Finally, we illustrate the impact of three biases: missing confounder, misclassification of exposure, and outcome evaluation.

RESULTS: For each simulated scenario, bias was induced by removing or adding data; hazard ratios (HRs) were estimated applying conventional analyses. Estimating the bias-adjusted treatment effect and uncertainty required carefully selecting the bias model and bias factors. Although the magnitude of each biased and bias-adjusted HR appeared moderate in all three hypothetical scenarios, the direction of bias was variable.

CONCLUSION: These findings suggest that QBA can provide an intuitive framework for bias analysis, providing a key means of challenging assumptions about the evidence. However, the accuracy of bias analysis is itself dependent on correct specification of the bias model and bias factors. Ultimately, study design should reduce bias, but QBA allows us to evaluate the impact of unavoidable bias to assess the quality of the evidence.

PMID:38680093 | DOI:10.1002/pds.5796

Cell Rep. 2024 Apr 27;43(5):114160. doi: 10.1016/j.celrep.2024.114160. Online ahead of print.

ABSTRACT

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) recapitulate numerous disease and drug response phenotypes, but cell immaturity may limit their accuracy and fidelity as a model system. Cell culture medium modification is a common method for enhancing maturation, yet prior studies have used complex media with little understanding of individual component contribution, which may compromise long-term hiPSC-CM viability. Here, we developed high-throughput methods to measure hiPSC-CM maturation, determined factors that enhanced viability, and then systematically assessed the contribution of individual maturation medium components. We developed a medium that is compatible with extended culture. We discovered that hiPSC-CM maturation can be sub-specified into electrophysiological/EC coupling, metabolism, and gene expression and that induction of these attributes is largely independent. In this work, we establish a defined baseline for future studies of cardiomyocyte maturation. Furthermore, we provide a selection of medium formulae, optimized for distinct applications and priorities, that promote measurable attributes of maturation.

PMID:38678564 | DOI:10.1016/j.celrep.2024.114160