Front Genet. 2022 Apr 14;13:864725. doi: 10.3389/fgene.2022.864725. eCollection 2022.

ABSTRACT

Pharmaceuticals are indispensable to healthcare as the burgeoning global population is challenged by diseases. The African continent harbors unparalleled genetic diversity, yet remains largely underrepresented in pharmaceutical research and development, which has serious implications for pharmaceuticals approved for use within the African population. Adverse drug reactions (ADRs) are often underpinned by unique variations in genes encoding the enzymes responsible for their uptake, metabolism, and clearance. As an example, individuals of African descent (14-34%) harbor an exclusive genetic variant in the gene encoding a liver metabolizing enzyme (CYP2D6) which reduces the efficacy of the breast cancer chemotherapeutic Tamoxifen. However, CYP2D6 genotyping is not required prior to dispensing Tamoxifen in sub-Saharan Africa. Pharmacogenomics is fundamental to precision medicine and the absence of its implementation suggests that Africa has, to date, been largely excluded from the global narrative around stratified healthcare. Models which could address this need, include primary human hepatocytes, immortalized hepatic cell lines, and induced pluripotent stem cell (iPSC) derived hepatocyte-like cells. Of these, iPSCs, are promising as a functional in vitro model for the empirical evaluation of drug metabolism. The scale with which pharmaceutically relevant African genetic variants can be stratified, the expediency with which these platforms can be established, and their subsequent sustainability suggest that they will have an important role to play in the democratization of stratified healthcare in Africa. Here we discuss the requirement for African hepatic models, and their implications for the future of pharmacovigilance on the African continent.

PMID:35495161 | PMC:PMC9046844 | DOI:10.3389/fgene.2022.864725

Front Genet. 2022 Apr 14;13:853969. doi: 10.3389/fgene.2022.853969. eCollection 2022.

ABSTRACT

The declared aim of "personalized", "stratified" or "precision" approaches is to place individual variation, as ascertained through genomic and various other biomarkers, at the heart of Scientific Medicine using it to predict risk of disease or response to therapy and to tailor interventions and target therapies so as to maximize benefit and minimize risk for individual patients and efficiency for the health care system overall. It is often contrasted to current practices for which the scientific base is rooted in concepts of a "universal biology" and a "typical" or "average patient" and in which variation is ignored. Yet both approaches equally overlook the hierarchical nature of human variation and the critical importance of differences between populations. Impact of genetic heterogeneity has to be seen within that context to be meaningful and subsequently useful. In Africa such complexity is compounded by the high effective size of its populations, their diverse histories and the diversity of the environmental terrains they occupy, rendering analysis of gene environment interactions including the establishment of phenotype genotype correlations even more cumbersome. Henceforth "Individualized" methods and approaches can only magnify the shortcomings of universal approaches if adopted without due regard to these complexities. In the current perspective we review examples of potential hurdles that may confront biomedical scientists and analysts in genomic medicine in clinical and public health genomics in Africa citing specific examples from the current SARS-COV2 pandemic and the challenges of establishing reference biobanks and pharmacogenomics reference values.

PMID:35495155 | PMC:PMC9047898 | DOI:10.3389/fgene.2022.853969

CPT Pharmacometrics Syst Pharmacol. 2022 May 2. doi: 10.1002/psp4.12793. Online ahead of print.

ABSTRACT

Obesity is an increasingly alarming public health threat, with nearly 20% of children classified as obese in the United States today. Children with obesity are commonly prescribed the opioids fentanyl and methadone, and accurate dosing is critical to reducing the risk of serious adverse events associated with overexposure. However, pharmacokinetic studies in children with obesity are challenging to conduct, so there is limited information to guide fentanyl and methadone dosing in these children. To address this clinical knowledge gap, physiologically-based pharmacokinetic models of fentanyl and methadone were developed in adults and scaled to children with and without obesity to explore the interplay of obesity, age, and pharmacogenomics. These models included key obesity-induced changes in physiology and pharmacogenomic effects. Model predictions captured observed concentrations in children with obesity well, with an overall average fold error of 0.72 and 1.08 for fentanyl and methadone, respectively. Model simulations support a reduced fentanyl dose (1 vs. 2 μg/kg/h) starting at an earlier age (6 years) in virtual children with obesity, highlighting the importance of considering both age and obesity status when selecting an infusion rate most likely to achieve steady-state concentrations within the target range. Methadone dosing simulations highlight the importance of considering genotype in addition to obesity status when possible, as cytochrome P450 (CYP)2B6*6/*6 virtual children with obesity required half the dose to match the exposure of wildtype children without obesity. This physiologically-based pharmacokinetic modeling approach can be applied to explore dosing of other critical drugs in children with obesity.

PMID:35491971 | DOI:10.1002/psp4.12793

Hum Genet. 2022 Apr 30:1-8. doi: 10.1007/s00439-022-02452-x. Online ahead of print.

ABSTRACT

Genomic medicine aims to improve health using the individual genomic data of people to inform care. While clinical utility of genomic medicine in many monogenic, Mendelian disorders is amply demonstrated, clinical utility is less evident in polygenic traits, e.g., coronary artery disease or breast cancer. Polygenic risk scores (PRS) are subsets of individual genotypes designed to capture heritability of common traits, and hence to allow the stratification of risk of the trait in a population. We systematically reviewed the PubMed database for unequivocal evidence of clinical utility of polygenic risk scores, using stringent inclusion and exclusion criteria. While we identified studies demonstrating clinical validity in conditions where medical intervention based on a PRS is likely to benefit patient outcome, we did not identify a single study demonstrating unequivocally such a benefit, i.e. clinical utility. We conclude that while the routine use of PRSs hold great promise, translational research is still needed before they should enter mainstream clinical practice.

PMID:35488921 | PMC:PMC9055005 | DOI:10.1007/s00439-022-02452-x

Int J Infect Dis. 2022 Apr 27:S1201-9712(22)00253-3. doi: 10.1016/j.ijid.2022.04.052. Online ahead of print.

ABSTRACT

OBJECTIVES: To compare the unbound plasma meropenem concentrations at mid-dosing intervals (Cmid, 50%fT), end-dosing intervals (Ctrough, 100%fT), and proportions of patients achieving 50%fT and 100%fT above MIC (50%fT>MIC and 100%fT>MIC) between extended infusion (EI) and intermittent bolus (IB) administration in a therapeutic drug monitoring (TDM) program in children.

METHODS: A prospective observational study was conducted in children aged 1 month to 18 years receiving meropenem every 8 h by either EI or IB. Meropenem Cmid, Ctrough, and proportions of patients achieving 50%fT>MIC and 100%fT>MIC were compared.

RESULTS: TDM data from 72 patients with a median age (IQR) of 12 months (3-37) were used. Meropenem dose was 120 and 60 mg/kg/day in EI and IB groups, respectively. Geometric mean (95% CI) Cmid of EI versus IB was 17.3 mg/L (13.7-21.8) versus 3.4 mg/L (1.7-6.7) (P<0.001). Geometric mean (95% CI) Ctrough of EI versus IB was 2.3 mg/L (1.6-3.4) versus 0.8 mg/L (0.4-1.5) (P=0.005). Greater proportions of patients achieving 50%fT>MIC and 100%fT>MIC were observed in the EI group.

CONCLUSIONS: A meropenem dose of 20 mg/kg/dose given by IB should not be used in critically ill children, even if they are not suspected of having a CNS infection. A dose of 40 mg/kg/dose given by EI resulted in higher Cmid, Ctrough, and proportions of patients achieving 50%fT>MIC and 100%fT>MIC.

PMID:35489632 | DOI:10.1016/j.ijid.2022.04.052

Clin Transl Sci. 2022 Apr 30. doi: 10.1111/cts.13294. Online ahead of print.

ABSTRACT

There are limited comparison data throughout the dosing interval for generic versus brand metoprolol extended-release (ER) tablets. We compared the pharmacokinetics (PK) and pharmacodynamics (PD) of brand name versus two generic formulations (Drugs 1 and 2) of metoprolol ER tablets with different time to maximum concentration (Tmax ) in adults with hypertension. Participants were randomized to equal drug doses (50-150 mg/day) administered in one of two sequences (Brand-Drug1-Brand-Drug2 or Brand-Drug2-Brand-Drug1) and completed 24-hour PK, digital heart rate (HR), ambulatory blood pressure (BP) and HR studies after taking each formulation for ≥7 days. Metoprolol concentrations were determined by LC-MS/MS, with non-compartmental analysis performed to obtain PK parameters in Phoenix WinNonlin. Heart rate variability (HRV) low-to-high frequency ratio was determined per quartile over the 24-hour period. Thirty-six participants completed studies with the brand name and at least one generic product. Among 30 participants on the 50 mg dose, the primary PK endpoints of area under the concentration-time curve and maximum concentration were similar between products; Tmax was 6.1±3.6 for the brand versus 3.5±4.9 for Drug 1 (p=0.019) and 9.6±3.2 for Drug 2 ( p<0.001). Among all 36 participants, 24-hour BP and HR were similar between products. Mean 24-hr HRV low-to-high ratio was also similar for Drug 1 (2.04±1.35), Drug 2 (1.86±1.35), and Brand (2.04±1.77), but was more sustained over time for the brand versus Drug 1 (drug×quartile interaction p=0.017). Differences in Tmax between metoprolol ER products following repeated doses may have implications for drug effects on autonomic balance over the dosing interval.

PMID:35488487 | DOI:10.1111/cts.13294

Clin Pharmacol Ther. 2022 Apr 30. doi: 10.1002/cpt.2627. Online ahead of print.

ABSTRACT

Enabled by a plethora of new technologies, research in membrane transporters has exploded in the past decade. The goal of this state-of-the-art manuscript is to describe recent advances in research on membrane transporters that are particularly relevant to drug discovery and development. This review covers advances in basic, translational and clinical research that has led to an increased understanding of membrane transporters at all levels. At the basic level, we describe the available crystal structures of membrane transporters in both the Solute Carrier (SLC) and ATP Binding Cassette (ABC) Superfamilies, which has been enabled by the development of cryogenic electron microscopy (cryo-EM) methods. Next, we describe new research on lysosomal and mitochondrial transporters as well as recently deorphaned transporters in the SLC superfamily. The translational section includes a summary of proteomic research which has led to a quantitative understanding of transporter levels in various cell types and tissues and new methods to modulate transporter function such as allosteric modulators and targeted protein degraders of transporters. The section ends with a review of the effect of the gut microbiome on modulation of transporter function followed by a presentation of 3D cell cultures, which will enable in vivo predictions of transporter function. In the clinical section, we describe new genomic and pharmacogenomic research, highlighting important polymorphisms in transporters that are clinically relevant to many drugs. Finally, we describe new clinical tools, which are becoming increasingly available to enable precision medicine, with the application of tissue-derived small extracellular vesicles and real-world biomarkers.

PMID:35488474 | DOI:10.1002/cpt.2627

Pharmacogenomics. 2022 Apr 29. doi: 10.2217/pgs-2022-0010. Online ahead of print.

ABSTRACT

Aims: To investigate the role of MYBBP1A gene and rs3809849 in pancreatic cancer (PANC1) and lymphoblastic leukemia (NALM6) cell lines and their response to asparaginase treatment. Materials & methods: The authors applied CRISPR-Cas9 to produce MYBBP1A knock-out (KO) and rs3809849 knock-in (KI) cell lines. The authors also interrogated rs3809849's impact on PANC1 cells through allele-specific overexpression. Results: PANC1 MYBBP1A KO cells exhibited lower proliferation capacity (p ≤ 0.05), higher asparaginase sensitivity (p = 0.01), reduced colony-forming potential (p = 0.001), cell cycle blockage in S phase, induction of apoptosis and remarkable morphology changes suggestive of an epithelial-mesenchymal transition. Overexpression of the wild-type (but not the mutant) allele of MYBBP1A-rs3809849 in PANC1 cells increased asparaginase sensitivity. NALM6 MYBBP1A KO displayed resistance to asparaginase (p < 0.0001), whereas no effect for rs3809849 KI was noted. Conclusions: MYBBP1A is important for regulating various cellular functions, and it plays, along with its rs3809849 polymorphism, a tissue-specific role in asparaginase treatment response.

PMID:35485735 | DOI:10.2217/pgs-2022-0010

J Chemother. 2022 Apr 28:1-3. doi: 10.1080/1120009X.2022.2068850. Online ahead of print.

ABSTRACT

Ceftobiprole (CFB), especially in combination, could be a promising alternative treatment for infective endocarditis. A main determinant of clinical response to antibiotic treatment is drug concentration at the infected site. Data on CFB and Daptomycin (DPT) heart valve penetration are lacking.Here we report a clinical case of CFB and DPT treatment combination for endocarditis. Then, we measured CFB and DPT concentrations in a native infected valve to verify their pharmacokinetic penetration and relationship with pharmacodynamic microbiological markers.The isolated microorganism was a MRSA with CFB and DPT MIC < 2 mg/L and <1 mg/L, respectively. The CFB and DPT plasma concentrations were 36.2 and 14.1 mg/L, respectively and the extrapolated concentration, based on each half-life, at the operatory time were 16.4 and 19.1 mg/L for CFB and DPT, respectively; the corresponding median CFB and DPT valve concentrations were 2.26 (IQR 2.14-2.69) and 12.9 µg/g (IQR 5.69-20.9), respectively; the estimated tissue/plasma ratios for CFB and DTP were 0.14 and 0.67, respectively.The association of CFB and DPT showed a good efficacy in this single endocarditis clinical case, confirmed by plasma and tissue PK/PD data.This report shows the first data on CFB valve tissue penetration, and it needs to be confirmed in other patient valve tissues. Moreover, relative studies of correlation with clinical efficacy are needed.

PMID:35484923 | DOI:10.1080/1120009X.2022.2068850

CNS Spectr. 2022 Apr;27(2):236-237. doi: 10.1017/S1092852922000372.

ABSTRACT

INTRODUCTION: Adverse drug reactions (ADRs) are associated with increased morbidity, mortality, and resource utilization. Drug interactions (DDIs) are among the most common causes of ADRs, and estimates have cited that up to 22% of patients take interacting medications. DDIs are often due to the propensity for agents to induce or inhibit enzymes responsible for the metabolism of concomitantly administered drugs. However, this phenomenon is further complicated by genetic variants of such enzymes. The aim of this study is to quantify and describe potential drug-drug, drug-gene, and drug-drug-gene interactions in a community-based patient population.

METHODS: A regional pharmacy with retail outlets in Arkansas provided deidentified prescription data from March 2020 for 4761 individuals. Drug-drug and drug-drug-gene interactions were assessed utilizing the logic incorporated into GenMedPro, a commercially available digital gene-drug interaction software program that incorporates variants of 9 pharmacokinetic (PK) and 2 pharmacodynamic (PD) genes to evaluate DDIs and drug-gene interactions. The data were first assessed for composite drug-drug interaction risk, and each individual was stratified to a risk category using the logic incorporated in GenMedPro. To calculate the frequency of potential drug-gene interactions, genotypes were imputed and allocated to the cohort according to each gene's frequency in the general population. Potential genotypes were randomly allocated to the population 100 times in a Monte Carlo simulation. Potential drug-drug, gene-drug, or gene-drug-drug interaction risk was characterized as minor, moderate, or major.

RESULTS: Based on prescription data only, the probability of a DDI of any impact (mild, moderate, or major) was 26% [95% CI: 0.248-0.272] in the population. This probability increased to 49.6% [95% CI: 0.484-0.507] when simulated genetic polymorphisms were additionally assessed. When assessing only major impact interactions, there was a 7.8% [95% CI: 0.070-0.085] probability of drug-drug interactions and 10.1% [95% CI: 0.095-0.108] probability with the addition of genetic contributions. The probability of drug-drug-gene interactions of any impact was correlated with the number of prescribed medications, with an approximate probability of 77%, 85%, and 94% in patients prescribed 5, 6, or 7+ medications, respectively. When stratified by specific drug class, antidepressants (19.5%), antiemetics (21.4%), analgesics (16%), antipsychotics (15.6%), and antiparasitics (49.7%) had the highest probability of major drug-drug-gene interaction.

CONCLUSIONS: In a community-based population of outpatients, the probability of drug-drug interaction risk increases when genetic polymorphisms are attributed to the population. These data suggest that pharmacogenetic testing may be useful in predicting drug interactions, drug-gene interactions, and severity of interactions when proactively evaluating patient medication profiles.

FUNDING: Genomind, Inc.

PMID:35477626 | DOI:10.1017/S1092852922000372

Pharmacogenomics J. 2022 Apr 28. doi: 10.1038/s41397-022-00279-3. Online ahead of print.

ABSTRACT

No biomarkers are available to predict toxicities induced by VEGFR TKIs. This study aimed to identify markers of toxicities induced by these drugs using a discovery-validation approach. The discovery set included 140 sorafenib-treated cancer patients (TARGET study) genotyped for SNPs in 56 genes. The most significant SNPs associated with grade ≥2 hypertension, diarrhea, dermatologic toxicities, and composite toxicity (any one of the toxicities) were tested for association with grade ≥2 toxicity in a validation set of 201 sorafenib-treated patients (Alliance/CALGB 80802). The validated SNP was tested for association with grade ≥2 toxicity in 107 (LCCC 1029) and 82 (Italian cohort) regorafenib-treated patients. SNP-toxicity associations were evaluated using logistic regression, and a meta-analysis between the studies was performed by inverse variance. Variant rs4864950 in KDR increased the risk of grade ≥2 composite toxicity in TARGET, Alliance/CALGB 80802, and the Italian cohort (meta-analysis p = 6.79 × 10-4, OR = 2.01, 95% CI 1.34-3.01). We identified a predictor of toxicities induced by VEGFR TKIs. CLINICALTRIALS.GOV IDENTIFIER: NCT00073307 (TARGET), NCT01015833 (Alliance/CALGB 80802), and NCT01298570 (LCCC 1029).

PMID:35484400 | DOI:10.1038/s41397-022-00279-3

Transl Psychiatry. 2022 Apr 28;12(1):173. doi: 10.1038/s41398-022-01942-w.

ABSTRACT

Risperidone is routinely used in the clinical management of schizophrenia, but the treatment response is highly variable among different patients. The genetic underpinnings of the treatment response are not well understood. We performed a pharmacogenomic study of the treatment response to risperidone in patients with schizophrenia by using a SNP microarray -based genome-wide association study (GWAS) and whole exome sequencing (WES)-based GWAS. DNA samples were collected from 189 patients for the GWAS and from 222 patients for the WES after quality control in multiple centers of China. Antipsychotic response phenotypes of patients who received eight weeks of risperidone treatment were quantified with percentage change on the Positive and Negative Syndrome Scale (PANSS). The GWAS revealed a significant association between several SNPs and treatment response, such as three GRM7 SNPs (rs141134664, rs57521140, and rs73809055). Gene-based analysis in WES revealed 13 genes that were associated with antipsychotic response, such as GPR12 and MAP2K3. We did not identify shared loci or genes between GWAS and WES, but association signals tended to cluster into the GPCR gene family and GPCR signaling pathway, which may play an important role in the treatment response etiology. This study may provide a research paradigm for pharmacogenomic research, and these data provide a promising illustration of our potential to identify genetic variants underlying antipsychotic responses and may ultimately facilitate precision medicine in schizophrenia.

PMID:35484098 | DOI:10.1038/s41398-022-01942-w

Respir Med. 2022 Apr 9;197:106849. doi: 10.1016/j.rmed.2022.106849. Online ahead of print.

ABSTRACT

BACKGROUND: Critical inhaler technique errors have been associated with lower treatment efficacy in chronic obstructive pulmonary disease (COPD). We aimed to assess and follow-up critical inhaler technique errors, and to investigate their association with COPD symptoms and exacerbations.

METHODS: COPD-diagnosed primary and secondary care outpatients (n = 310) demonstrated inhaler technique with inhaler devices they were currently using. Critical errors in opening, positioning and loading the inhaler device, and exhalation through dry-powder inhalers were assessed and corrected, and the assessment was repeated one year later. COPD Assessment Test, the modified Medical Research Council dyspnoea scale and history of exacerbations were collected at both visits.

RESULTS: The proportion of patients making ≥1 critical inhaler technique error was lower at follow-up in the total population (46% vs 37%, p = 0.01) and among patients with unchanged device models (46% vs 35%, p = 0.02), but not among patients with a new inhaler device model (46% vs 41%, p = 0.56). Not positioning the device correctly was the most common critical error at both visits (30% and 22%). Seventy-four percent of the patients had unchanged COPD treatment from baseline to follow-up. Treatment escalation, de-escalation, and switch was observed in 14%, 11%, and 1% of the patients, respectively. No association was found between critical errors and COPD symptoms or exacerbations.

CONCLUSIONS: Assessment and correction of inhaler technique was associated with a decrease in critical inhaler technique errors. This effect was most pronounced in patients using the same device models throughout the follow-up period.

PMID:35483167 | DOI:10.1016/j.rmed.2022.106849

Hum Genet. 2022 Apr 28. doi: 10.1007/s00439-022-02456-7. Online ahead of print.

NO ABSTRACT

PMID:35482087 | DOI:10.1007/s00439-022-02456-7

Open Med (Wars). 2022 Apr 7;17(1):694-701. doi: 10.1515/med-2021-0371. eCollection 2022.

ABSTRACT

This study aimed to investigate the possible influence of genetic and non-genetic factors on the incidence of clopidogrel adverse drug reactions (ADRs) in cardiology patients, including the most important CYP2C19 alleles, namely *2 and *17, as well as compliance, dose, drug interactions, and clinical factors. A total of 102 clopidogrel-treated adult Caucasian patients hospitalized at the Cardiology Department of the Clinical Center of Montenegro were enrolled in the study. Data on clinical outcomes of interest were obtained by intensive monitoring ADRs during hospitalization and one year after hospital discharge. Genotyping for CYP2C19*2 and *17 was conducted using the real-time polymerase chain reaction method. ADRs were characterized using the Rawlins and Thompson classification and the World Health Organization criteria. Causality was assessed using the Naranjo probability scale. ADRs to clopidogrel were observed in 9 of 102 patients (8.8%). The observed frequencies of CYP2C19*2 and *17 were 13.2 and 25.5%, respectively. Our study, which is the first to report the frequency of CYP2C19 polymorphism in the Montenegrin population, as well as to link the pharmacovigilance of clopidogrel with CYP2C19 gene variability, shows that the incidence of ADRs of clopidogrel in cardiac patients is high and depends on CYP2C19 polymorphisms, comedication/drug interactions, and gastrointestinal comorbidity.

PMID:35480401 | PMC:PMC8990878 | DOI:10.1515/med-2021-0371

Front Med (Lausanne). 2022 Apr 11;9:869912. doi: 10.3389/fmed.2022.869912. eCollection 2022.

ABSTRACT

AIMS: To assess whether MTHFR rs1801131 and rs1801133 SNPs are associated with concomitant psoriatic arthritis (PsA) and investigate the efficacy and hepatotoxicity of MTX in patients with psoriasis in the Han Chinese population.

METHODS: This prospective, single-arm, interventional study recruited a total of 309 patients with psoriasis, 163 with psoriatic arthritis and 146 without psoriatic arthritis, who completed a 12-week MTX treatment and 1,031 healthy controls. Patients' characteristics including age, gender, disease duration, height, weight, smoking status, alcohol consumption, medical history, disease severity and liver function test results were accessed and recorded. Single nucleotide polymorphism (SNP) genotyping of rs1801131 and rs1801133 in the MTHFR gene was performed.

RESULTS: The rs1801133 CC genotype was more frequent in patients with PsA than those with PsO and healthy controls (42.3% vs. 28.8% vs. 33.1%, p < 0.05). The 90% reduction from baseline PASI score (PASI 90) response rates to MTX were significantly higher in patients with the rs1801133 TT genotype than those with the CT and CC genotype (33.96% vs. 19.31% vs. 14.41%, OR = 2.76, p = 0.006). The rs1801133 CT+TT genotype was more frequent in PsA patients with abnormal liver function than in those with normal liver function (p < 0.05). In addition, patients with the rs1801131 CT genotype had lower PASI 75 response rates to MTX (OR = 0.49, p = 0.01), and lower risk of ALT elevation (OR = 0.46, p = 0.04).

CONCLUSIONS: This study provided some evidence for MTHFR polymorphism association with the risk of PsA and the efficacy and hepatotoxicity of the low-dose MTX in the Chinese population. Given the relatively small sample size and potentially missed diagnosis of PsA, the results from this study warrant further investigation.

PMID:35479943 | PMC:PMC9035632 | DOI:10.3389/fmed.2022.869912

Gut. 2022 Apr 27:gutjnl-2021-326784. doi: 10.1136/gutjnl-2021-326784. Online ahead of print.

ABSTRACT

The COVID-19 pandemic has raised considerable concerns that patients with inflammatory bowel disease (IBD), particularly those treated with immunosuppressive therapies, may have an increased risk of SARS-CoV-2 acquisition, develop worse outcomes following COVID-19, and have suboptimal vaccine response compared with the general population. In this review, we summarise data on the risk of COVID-19 and associated outcomes, and latest guidance on SARS-CoV-2 vaccines in patients with IBD. Emerging evidence suggests that commonly used medications for IBD, such as corticosteroids but not biologicals, were associated with adverse outcomes to COVID-19. There has been no increased risk of de novo, or delayed, IBD diagnoses, however, an overall decrease in endoscopy procedures has led to a rise in the number of missed endoscopic-detected cancers during the pandemic. The impact of IBD medication on vaccine response has been a research priority recently. Data suggest that patients with IBD treated with antitumour necrosis factor (TNF) medications had attenuated humoral responses to SARS-CoV-2 vaccines, and more rapid antibody decay, compared with non-anti-TNF-treated patients. Reassuringly, rates of breakthrough infections and hospitalisations in all patients who received vaccines, irrespective of IBD treatment, remained low. International guidelines recommend that all patients with IBD treated with immunosuppressive therapies should receive, at any point during their treatment cycle, three primary doses of SARS-CoV-2 vaccines with a further booster dose as soon as possible. Future research should focus on our understanding of the rate of antibody decay in biological-treated patients, which patients require additional doses of SARS-CoV-2 vaccine, the long-term risks of COVID-19 on IBD disease course and activity, and the potential risk of long COVID-19 in patients with IBD.

PMID:35477864 | DOI:10.1136/gutjnl-2021-326784

Pharmacogenomics. 2022 Apr 28. doi: 10.2217/pgs-2022-0016. Online ahead of print.

ABSTRACT

Autism spectrum disorder (ASD) is a global challenge that may disrupts family and social life significantly. There is robust evidence for the association of a pharmacokinetic gene variant (e.g., CYP2D6) with risperidone-induced hyperprolactinemia in ASD. Association of a pharmacodynamic gene variant (e.g., DRD2) with risperidone-induced hyperprolactinemia in ASD is also evident from multiple studies. In addition to genetic factors, dose, duration and drug-drug interactions of risperidone might also increase the serum prolactin level. There are several difficulties, such as reimbursement, knowledge and education of healthcare providers, in implementing risperidone pharmacogenomics into clinical practice. However, preparation of national and international pharmacogenomics-based dosing guidelines of risperidone may advance precision medicine of ASD.

PMID:35477330 | DOI:10.2217/pgs-2022-0016

JCO Precis Oncol. 2022 Apr;6:e2200015. doi: 10.1200/PO.22.00015.

ABSTRACT

PURPOSE: In GI cancers, anaplastic lymphoma kinase (ALK) rearrangements are extremely less frequent than in non-small-cell lung cancer but may be important to offer personalized strategies of treatment in selected patients. Data about the activity and efficacy of ALK inhibitors (ALKi) in GI cancers are scarce.

MATERIALS AND METHODS: We assembled a clinical and molecular international data set of pretreated patients with metastatic or nonresectable cancers of GI primary tumor origin with documented ALK rearrangement treated with at least one line of ALKi. Measurable disease as per RECIST 1.1 was required for response analysis.

RESULTS: Primary tumor sites were distributed as follows: 5 (38%) pancreas, 3 (23%) right colon, and 1 (8%) for each one of gastric, duodenal, rectal, left colon, and biliary tract sites. Seven patients (54%) were treated with alectinib, 5 (38%) with crizotinib, and 1 (8%) with entrectinib. After disease progression, five patients (38%) received a subsequent ALKi treatment line, and at the time of data cutoff date, treatment was still ongoing in two patients. Five of 12 evaluable patients (41%) achieved a partial response to first-line ALKi, five patients (41%) had stable disease, and 2 (17%) had progressive disease. No complete responses were registered. At a median follow-up of 39.6 months (interquartile range: 19.8-59.5), the median progression-free survival was 5.0 months (95% CI, 3.68 to no response) and the median overall survival was 9.3 months (95% CI, 5.46 to no response).

CONCLUSION: Treatment with ALKi provides remarkable responses and clinical benefit in pretreated patients with ALK fusion-positive GI malignancies. Despite the rarity, ALK rearrangements represent an important therapeutic target in individual pretreated patients with GI solid tumors. Further work providing prospective clinical validation of this target is needed.

PMID:35476549 | DOI:10.1200/PO.22.00015

Interdiscip Sci. 2022 Apr 27. doi: 10.1007/s12539-022-00517-z. Online ahead of print.

ABSTRACT

Human lung cell lines are utilized widely for investigating tumor biology, experimental therapy, anticancer drug screening and biomarkers identification. However, the consistency of drug responses of these established cell lines and non-small cell lung cancer (NSCLC) is uncertain. In this study, we assessed the drug response consistency between lung cell lines and NSCLC tumors in The Cancer Genome Atlas by hierarchical clustering using copy number variations in driver genes, and profiled the molecular patterns and correlations in cell lines. We found that some frequently used cell lines of NSCLC subtypes were not clustered with their matched subtypes of tumor. Mutation profiles in the oxidative stress response and squamous differentiation pathway in lung cell lines were in concordance with lung squamous cell carcinoma. Furthermore, lung cell lines and tumors in the same sub-cluster had very similar responses to certain drugs but some were inconsistent, suggesting that clustering through copy number variation data could capture part of the suitability of lung cell lines. The analysis of these results could aid investigators in evaluating drug response models and eventually enabling personalized treatment recommendations for individual patients with NSCLC.

PMID:35476185 | DOI:10.1007/s12539-022-00517-z