JAMA Netw Open. 2022 Nov 1;5(11):e2242370. doi: 10.1001/jamanetworkopen.2022.42370.

ABSTRACT

IMPORTANCE: The recent successes of poly-ADP ribose polymerase (PARP) inhibitors and belzutifan support germline genetic data as an exciting, accessible source for biomarkers in cancer treatment. This study hypothesizes, however, that most oncology clinical trials using germline data largely prioritize BRCA1/2 as biomarkers and PARP inhibitors as therapy.

OBJECTIVE: To characterize past and ongoing oncology trials that use germline data.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cross-sectional study of oncology trials used the Informa Trialtrove database to evaluate trial attributes. Trials using germline information (including the terms germline, hereditary, or inherited in the title, treatment plan, interventions, end points, objectives, results, or notes) and conducted globally between December 1, 1990, and April 4, 2022 (data freeze date), were included.

MAIN OUTCOMES AND MEASURES: Trials by cancer type, phase, participants, sponsor type, end points, outcomes, and locations were described. Associated biomarkers and mechanisms of action for studied therapeutic interventions were counted. How germline data in trial inclusion and exclusion criteria are associated with end points, outcomes, and enrollment were also examined.

RESULTS: A total of 887 of 84 297 (1.1%) oncology clinical trials in the Trialtrove database that use germline data were identified. Most trials were conducted in cancer types where PARP inhibitors are already approved. A total of 74.8% (672) of trials were performed in the phase 2 setting or above. Trials were primarily sponsored by industry (523 trials [59.0%]), academia (382 trials [43.1%]), and the government (274 trials [30.9%]), where trials may have multiple sponsor types. Among 343 trials using germline data with outcomes in Trialtrove, 180 (52.5%) reported meeting primary end points. Although BRCA1/2 are the most frequent biomarkers seen (BRCA1, 224 trials [25.3%]; BRCA2, 228 trials [25.7%]), trials also examine pharmacogenomic variants and germline mediators of somatic biomarkers. PARP inhibitors or immunotherapy were tested in 69.9% of trials; PARP inhibition was the most frequently studied mechanism (367 trials [41.4%]). An overwhelming number of trials using germline data were conducted in the US, Canada, and Europe vs other countries, mirroring disparities in cancer genetics data. Germline data in inclusion and exclusion criteria are associated with altered end point, outcomes, and enrollment compared with oncology trials with no germline data use. Examples of inclusion and exclusion criteria regarding germline data that may unintentionally exclude patients were identified.

CONCLUSIONS AND RELEVANCE: These findings suggest that for germline biomarkers to gain clinical relevance, trials must expand biomarkers, therapies, and populations under study.

PMID:36383380 | DOI:10.1001/jamanetworkopen.2022.42370

Bioinformatics. 2022 Nov 16:btac728. doi: 10.1093/bioinformatics/btac728. Online ahead of print.

ABSTRACT

MOTIVATION: Association testing on genome-wide association studies (GWAS) data is commonly performed under a single (mostly additive) genetic model framework. However, the underlying true genetic mechanisms are often unknown in practice for most complex traits. When the employed inheritance model deviates from the underlying model, statistical power may be reduced. To overcome this challenge, an integrative association test that directly infers the underlying genetic model from GWAS data has previously been proposed for single-SNP analysis.

RESULTS: In this article, we propose a Cauchy combination Genetic Model-based association test (CauchyGM) under a generalized linear model framework for SNP-set level analysis. CauchyGM does not require prior knowledge on the underlying inheritance patterns of each SNP. It performs a score test which first estimates an individual p-value of each SNP in a SNP-set with both minor allele frequency (MAF) > 1% and three genotypes and further aggregates the rest SNPs using SKAT. CauchyGM then combines the correlated p-values across multiple SNPs and different genetic models within the set using Cauchy Combination Test. To further accommodate both sparse and dense signal patterns, we also propose an omnibus association test (CauchyGM-O) by combining CauchyGM with SKAT and burden test. Our extensive simulations show that both CauchyGM and CauchyGM-O maintain type I error well at the genome-wide significance level and provide substantial power improvement compared to existing methods. We apply our methods to a pharmacogenomic GWAS data from a large cardiovascular randomized clinical trial. Both CauchyGM and CauchyGM-O identify several novel genome-wide significant genes.

AVAILABILITY AND IMPLEMENTATION: The R package CauchyGM is publicly available on github: https://github.com/ykim03517/CauchyGM.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:36383169 | DOI:10.1093/bioinformatics/btac728

Ann Hum Biol. 2022 Nov 16:1-31. doi: 10.1080/03014460.2022.2140826. Online ahead of print.

ABSTRACT

BACKGROUND: Organic anion transporting polypeptide 1B1 (OATP1B1) and the ATP-binding cassette subfamily G member 2, ABCG2, are important transporters involved in the transport of endogenous substrates and xenobiotics, including drugs. Genetic polymorphisms of these transporters have effect on transporter activity. There is significant interethnic variability in the frequency of allele variants.

AIM: To determined allele and genotype frequencies of ABCG2 and SLCO1B1 genes in Croatian populations of European descent.

SUBJECTS AND METHODS: A total of 905 subjects (482 women) were included. Genotyping for ABCG2 c.421C > A (rs2231142) and for SLCO1B1 c.521T > C (rs4149056), was performed by real-time polymerase chain reaction (PCR) using TaqMan® DME Genotyping Assays.

RESULTS: For ABCG2 c.421C > A, the frequency of CC, CA and AA genotypes was 81.4%, 17.8% and 0.8% respectively. The frequency of variant ABCG2 421A allele was 9.7%. For SLCO1B1 c.521T > C, the frequency of TT, TC and CC genotypes was 61.7%, 34.8% and 3.5% respectively. The frequency of variant SLCO1B1 521C allele was 20.9%.

CONCLUSION: The frequency of the ABCG2 and SLCO1B1 allelic variants and genotypes in the Croatian population is in accordance with other European populations. Pharmacogenetic analysis can serve to individualise drug therapy and minimise the risk of developing adverse drug reactions.

PMID:36382878 | DOI:10.1080/03014460.2022.2140826

Pharmacogenomics. 2022 Nov 16. doi: 10.2217/pgs-2022-0124. Online ahead of print.

ABSTRACT

Capecitabine is a widely-used antineoplastic drug, a prodrug to 5-fluorouracil which commonly induces gastrointestinal toxicity. Enterocolitis, as a rarely recognized gastrointestinal adverse effect (AE) of capecitabine, is potentially severe and usually results in antitumor treatment withdrawal. For the better management of severe AEs, pharmacogenetics is one promising field. Herein, we describe a case of capecitabine-induced enterocolitis presenting with severe diarrhea in order to improve recognition by clinicians. Moreover, we conduct a pharmacogenetic profile of the patient and review the current studies of gene polymorphisms of 5-fluorouracil-related diarrhea, hoping to offer a reference for further clinical pharmacogenetic practice in predicting capecitabine AEs showing diarrhea as the main symptom.

PMID:36382550 | DOI:10.2217/pgs-2022-0124

J Clin Pharm Ther. 2022 Nov 15. doi: 10.1111/jcpt.13804. Online ahead of print.

ABSTRACT

BACKGROUND: Tacrolimus is a widely prescribed immunosuppressant agent for kidney transplantation. However, optimal dosing is challenging due to its narrow therapeutic index, potentially serious adverse effects, and wide inter-individual variability in pharmacokinetics. Cytochrome P450 3A (CPY3A) enzymes metabolize tacrolimus, so allelic variants such as CYP3A4*22 and CYP3A5*3 may contribute to individual differences in pharmacokinetics and therapeutic efficacy of tacrolimus. This study assessed the frequency and influences of CYP3A4*22 and CYP3A5*3 genotypes, alone and combined, on tacrolimus pharmacokinetics and dose requirements in Egyptian kidney transplant patients.

METHODS: This is a prospective multicenter observational cohort study. Patients were genotyped for the CYP3A4*22 (rs35599367), and CYP3A5*3 (rs776746). Tacrolimus dose (mg), through blood level (ng/ml), and dose-adjusted trough concentration (C0/D) (ng/ml per mg/kg) were recorded during the first and third months post-transplantation and compared among genotype groups.

RESULTS: The CYP3A4*22 allele was rare (3.2% of subjects) while the CYP3A5*3 allele was widespread (90.38%) in this cohort. At the third month post-transplantation, median C0/D was significantly higher among CYP3A4*22 carriers than CYP3A4*1/*1 (146.25 [100-380] versus 85.57 [27-370] ng/ml per mg/kg, p = 0.028). Patients harbouring the one copy of the CYP3A4*22 allele and the CYP3A5*3/*3 genotype (n = 5) were classified as poor tacrolimus metabolizers, the CYP3A5*3/*3 plus CYP3A4*1/*1 genotype as intermediate metabolizers (n = 60), and the CYP3A4*1/*1 plus CYP3A5*1/*1 genotype as normal metabolizers (n = 13). During the first month post-transplantation, C0/D was significantly greater in poor metabolizers (113.07 ng/ml per mg/kg) than intermediate and normal metabolizers (90.380 and 49.09 ng/ml per mg/kg) (p < 0.0005). This rank order was also observed during the third month. Acute rejection rate and renal function at discharge did not differ among genotypes.

CONCLUSION: Pharmacogenetics testing for CYP3A4*22 and CYP3A5*3 before renal transplantation may help in the adjustment of tacrolimus starting dose and identify patients at risk of tacrolimus overexposure or underexposure.

PMID:36379901 | DOI:10.1111/jcpt.13804

Drug Metab Dispos. 2022 Nov 15:DMD-AR-2022-001048. doi: 10.1124/dmd.122.001048. Online ahead of print.

ABSTRACT

Warfarin, a commonly prescribed oral anticoagulant medication, is highly effective in treating deep vein thrombosis and pulmonary embolism. However, the clinical dosing of warfarin is complicated by high inter-individual variability in drug exposure and response and its narrow therapeutic index. CYP2C9 genetic polymorphism and drug-drug interactions (DDIs) are substantial contributors to this high variability of warfarin pharmacokinetics (PK), among numerous factors. Building a physiological-based pharmacokinetic (PBPK) model for warfarin is not only critical for a mechanistic characterization of warfarin PK, but also useful for investigating the complicated dose-exposure relationship of warfarin. Thus, the objective of this study was to develop a PBPK model for warfarin which integrates information regarding CYP2C9 genetic polymorphisms and their impact on DDIs. Generic PBPK models for both S- and R-warfarin, the two enantiomers of warfarin, were constructed in R with the mrgsolve package. As expected, a generic PBPK model structure did not adequately characterize the warfarin PK profile collected up to 15 days following the administration of single oral dose of warfarin, especially for S-warfarin. However, following the integration of an empirical target-mediated drug disposition (TMDD) component, the PBPK-TMDD model well characterized the PK profiles collected for both S- and R-warfarin in subjects with different CYP2C9 genotypes. Following the integration of enzyme inhibition and induction effects, the PBPK-TMDD model also characterized the PK profiles of both S- and R-warfarin in various DDI settings. The developed mathematic framework may be useful in building algorithms to better inform the clinical dosing of warfarin. Significance Statement The present study found a traditional physiology-based pharmacokinetic (PBPK) model cannot sufficiently characterize the pharmacokinetic profiles of warfarin enantiomers when warfarin is administered as a single dose, but a PBPK model with a target-mediated drug disposition mechanism can. After incorporating CYP2C9 genotypes and drug-drug interaction information, the developed model is anticipated to facilitate the understanding of warfarin disposition in subjects with different CYP2C9 genotypes in the absence and presence of both cytochrome P450 inhibitors and cytochrome P450 inducers.

PMID:36379708 | DOI:10.1124/dmd.122.001048

Drug Metab Pharmacokinet. 2022 Oct 18;47:100480. doi: 10.1016/j.dmpk.2022.100480. Online ahead of print.

ABSTRACT

Co-trimoxazole is mainly used as a first-line drug for treatment and prophylaxis against Pneumocystis jiroveci pneumonia. This drug, however, has been reported as the most common causative drug for severe cutaneous adverse reactions (SCARs). This study aimed to extensively elucidate the associations between genetic polymorphisms of HLA class I and genes involved in bioactivation and detoxification of co-trimoxazole on co-trimoxazole-induced SCARS in a large sample size and well-defined Thai SCARs patients. A total of 67 patients with co-trimoxazole-induced SCARs, consisting of 51 SJS/TEN patients and 16 DRESS patients, and 91 co-trimoxazole tolerant controls were enrolled in the study. The results clearly demonstrated that the HLA-B∗13:01 allele was significantly associated with co-trimoxazole-induced SCARs, especially with DRESS (OR = 8.44, 95% CI = 2.66-26.77, P = 2.94 × 10-4, Pc = 0.0126). Moreover, the HLA-C∗08:01 allele was significantly associated with co-trimoxazole-induced SJS/TEN in the HIV/AIDS patients with an OR of 8.51 (95% CI = 2.18-33.14, P = 8.60 × 10-4, Pc = 0.0241). None of the genes involved in the bioactivation and detoxification of co-trimoxazole investigated in this study play any major role in the development of all phenotypes of SCARs.

PMID:36379177 | DOI:10.1016/j.dmpk.2022.100480

Eur Heart J. 2022 Nov 15:ehac644. doi: 10.1093/eurheartj/ehac644. Online ahead of print.

NO ABSTRACT

PMID:36378517 | DOI:10.1093/eurheartj/ehac644

Cancer Cell Int. 2022 Nov 15;22(1):354. doi: 10.1186/s12935-022-02777-7.

ABSTRACT

Recent technological advances in nanoscience and material designing have led to the development of point-of-care devices for biomolecule sensing and cancer diagnosis. In situ and portable sensing devices for bedside, diagnosis can effectively improve the patient's clinical outcomes and reduce the mortality rate. Detection of exosomal RNAs by immuno-biochip with increased sensitivity and specificity to diagnose cancer has raised the understanding of the tumor microenvironment and many other technology-based biosensing devices hold great promise for clinical innovations to conquer the unbeatable fort of cancer metastasis. Electrochemical biosensors are the most sensitive category of biomolecule detection sensors with significantly low concentrations down to the atomic level. In this sense, this review addresses the recent advances in cancer detection and diagnosis by developing significant biological sensing devices that are believed to have better sensing potential than existing facilities.

PMID:36376956 | DOI:10.1186/s12935-022-02777-7

Tuberculosis (Edinb). 2022 Dec;137:102271. doi: 10.1016/j.tube.2022.102271. Epub 2022 Oct 20.

ABSTRACT

OBJECTIVE AND METHODS: Our objective was to investigate the role of patient pharmacogenetic variability in determining site of action target attainment during tuberculous meningitis (TBM) treatment. Rifampin and isoniazid PBPK model that included SLCO1B1 and NAT2 effects on exposures respectively were obtained from literature, modified, and validated using available cerebrospinal-fluid (CSF) concentrations. Population simulations of isoniazid and rifampin concentrations in brain interstitial fluid and probability of target attainment according to genotypes and M. tuberculosis MIC levels, under standard and intensified dosing, were conducted.

RESULTS: The rifampin and isoniazid model predicted steady-state drug concentration within brain interstitial fluid matched with the observed CSF concentrations. At MIC level of 0.25 mg/L, 57% and 23% of the patients with wild type and heterozygous SLCO1B1 genotype respectively attained the target in CNS with rifampin standard dosing, improving to 98% and 91% respectively with 35 mg/kg dosing. At MIC level of 0.25 mg/L, 33% of fast acetylators attained the target in CNS with isoniazid standard dosing, improving to 90% with 7.5 mg/kg dosing.

CONCLUSION: In this study, the combined effects of pharmacogenetic and M. tuberculosis MIC variability were potent determinants of target attainment in CNS. The potential for genotype-guided dosing during TBM treatment should be further explored in prospective clinical studies.

PMID:36375279 | DOI:10.1016/j.tube.2022.102271

Nature. 2022 Nov 14. doi: 10.1038/s41586-022-05492-5. Online ahead of print.

NO ABSTRACT

PMID:36376532 | DOI:10.1038/s41586-022-05492-5

Metabolism. 2022 Nov 11:155344. doi: 10.1016/j.metabol.2022.155344. Online ahead of print.

ABSTRACT

Arrhythmogenic cardiomyopathy (ACM) is characterized by life-threatening ventricular arrhythmias and sudden cardiac death and affects hundreds of thousands of patients worldwide. The deletion of Arginine 14 (p.R14del) in the phospholamban (PLN) gene has been implicated in the pathogenesis of ACM. PLN is a key regulator of sarcoplasmic reticulum (SR) Ca2+ cycling and cardiac contractility. Despite global gene and protein expression studies, the molecular mechanisms of PLN-R14del ACM pathogenesis remain unclear. Using a humanized PLN-R14del mouse model and human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs), we investigated the transcriptome-wide mRNA splicing changes associated with the R14del mutation. We identified >200 significant alternative splicing (AS) events and distinct AS profiles were observed in the right (RV) and left (LV) ventricles in PLN-R14del compared to WT mouse hearts. Enrichment analysis of the AS events showed that the most affected biological process was associated with "cardiac cell action potential", specifically in the RV. We found that splicing of 2 key genes, Trpm4 and Camk2d, which encode proteins regulating calcium homeostasis in the heart, were altered in PLN-R14del mouse hearts and human iPSC-CMs. Bioinformatical analysis pointed to the tissue-specific splicing factors Srrm4 and Nova1 as likely upstream regulators of the observed splicing changes in the PLN-R14del cardiomyocytes. Our findings suggest that aberrant splicing may affect Ca2+-homeostasis in the heart, contributing to the increased risk of arrythmogenesis in PLN-R14del ACM.

PMID:36375644 | DOI:10.1016/j.metabol.2022.155344

Metabolism. 2022 Nov 11:155346. doi: 10.1016/j.metabol.2022.155346. Online ahead of print.

ABSTRACT

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and bariatric surgery have proven to be effective treatments for obesity and cardiometabolic conditions. We aimed to explore the early metabolomic changes in response to GLP-1RA (liraglutide) therapy vs. placebo and in comparison to bariatric surgery.

METHODS: Three clinical studies were conducted: a bariatric surgery cohort study of participants with morbid obesity who underwent either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) studied over four and twelve weeks, and two randomized placebo-controlled, crossover double blind studies of liraglutide vs. placebo administration in participants with type 2 diabetes (T2D) and participants with obesity studied for three and five weeks, respectively. Nuclear magnetic resonance spectroscopy-derived metabolomic data were assessed in all eligible participants who completed all the scheduled in-clinic visits. The primary outcome of the study was to explore the changes of the metabolome among participants with obesity with and without T2D receiving the GLP-1RA liraglutide vs. placebo and participants with obesity undergoing bariatric surgery during the three to five-week study period. In addition, we assessed the bariatric surgery effects longitudinally over the twelve weeks of the study and the differences between the bariatric surgery subgroups on the metabolome. The trials are registered with ClinicalTrials.gov, numbers NCT03851874, NCT01562678 and NCT02944500.

RESULTS: Bariatric surgery had a more pronounced effect on weight and body mass index reduction (-14.19 ± 5.27 kg and - 5.19 ± 5.27, respectively, p < 0.001 for both) and resulted in more pronounced metabolomic and lipidomic changes compared to liraglutide therapy at four weeks postoperatively. Significant changes were observed in lipoprotein parameters, inflammatory markers, ketone bodies, citrate, and branched-chain amino acids after the first three to five weeks of intervention. After adjusting for the amount of weight loss, a significant difference among the study groups remained only for acetoacetate, β-hydroxybutyrate, and citrate (p < 0.05 after FDR correction). Glucose levels were significantly reduced in all intervention groups but mainly in the T2D group receiving GLP-1RA treatment. After adjusting for weight loss, only glucose levels remained significant (p = 0.001 after FDR correction), mainly due to the glucose change in the T2D group receiving GLP-1RA. Similar results with those observed at four weeks were observed in the surgical group when delta changes at twelve weeks were assessed. Comparing the two types of bariatric surgery, an intervention effect was more pronounced in the RYGB subgroup regarding total triglycerides, triglyceride-rich lipoprotein size, and trimethylamine-N-oxide (p for intervention: 0.031, 0.028, 0.036, respectively). However, after applying FDR correction, these changes deemed to be only suggestive; only time effects remained significant with no significant changes persisting in relation to the types of bariatric surgery.

CONCLUSIONS: The results of this study suggest that the early metabolomic, lipid and lipoprotein changes observed between liraglutide treatment and bariatric surgery are similar and result largely from the changes in patients' body weight. Specific changes observed in the short-term post-surgical period between bariatric vs. nonsurgical treated participants, i.e., acetoacetate, β-hydroxybutyrate, and citrate changes, may reflect changes in patient diets and calorie intake indicating potential calorie and diet-driven metabolomics/lipidomic effects in the short-term postoperatively. Significant differences observed between SG and RYGB need to be confirmed and extended by future studies.

PMID:36375643 | DOI:10.1016/j.metabol.2022.155346

Am J Manag Care. 2022 Nov;28(11):566-571. doi: 10.37765/ajmc.2022.89259.

ABSTRACT

OBJECTIVES: Drug-drug interactions (DDIs) are among the most common causes of adverse drug reactions and are further complicated by genetic variants of drug-metabolizing enzymes. The aim of this study is to quantify and describe potential DDIs, drug-gene interactions (DGIs), and drug-drug-gene interactions (DDGIs) in a community-based population.

STUDY DESIGN: This was an analysis of deidentified retail pharmacy prescription data for 4761 individuals.

METHODS: Data were first assessed for DDIs, and individuals were stratified to a risk category using the logic of a commercially available digital DDGI tool. To calculate the frequency of potential DGIs and DDGIs, genotypes were imputed and randomly allocated to the cohort 100 times via Monte Carlo simulation according to each variant's frequency in the general population.

RESULTS: The probability of a DDI of any impact was 26.0% and increased to 49.6% (95% CI, 48.4%-50.7%) when drug-metabolizing phenotypes were ascribed according to the distribution of variants of 11 genes as found in a Caucasian population. There was a 7.8% probability of major DDIs, which increased to a 10.1% (95% CI, 9.5%-10.8%) probability with the addition of genetic contributions. The probability of DDGIs of any impact was correlated with the number of medications. Antidepressants, antiemetics, blood products and modifiers, analgesics, and antipsychotics had the highest probability of DDGIs.

CONCLUSIONS: The probability of drug interaction risk increased when phenotypes associated with genetic polymorphisms were attributed to the population. These data suggest that pharmacogenomic assessment may be useful in predicting drug interactions and severity when evaluating patient medication profiles.

PMID:36374614 | DOI:10.37765/ajmc.2022.89259

J Urol. 2022 Nov 14:101097JU0000000000003049. doi: 10.1097/JU.0000000000003049. Online ahead of print.

ABSTRACT

PURPOSE: Adrenal 11-oxygenated androgens may support cancer progression in men with prostate cancer (PCa) owing to their abundance and androgenic potential. We hypothesized that preoperative circulating levels of 11-oxygenated androgens influence clinical outcomes in men with newly diagnosed localized PCa.

MATERIAL AND METHODS: We studied 1793 treatment-naïve patients and 155 patients who received preoperative treatment with 5α-reductase inhibitors (5-ARIs) in the prospective PROCURE cohort for which preoperative plasma samples were obtained prior to radical prostatectomy (RP). Adrenal 11-oxygenated precursors, potent 11-oxygenated androgens and their metabolites (n=7) were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Circulating levels were evaluated in relation to prognostic factors, disease-free survival (DFS), and metastasis-free survival (MFS), using multivariable Cox proportional hazards models.

RESULTS: At a median follow-up time of 93.8 months after surgery, 583 patients experienced biochemical recurrence, 104 developed metastatic disease and 168 diseased. Higher levels of 11-hydroxytestosterone (11OHT) and 11-ketotestosterone (11KT) were observed in men with prostatic specific antigen (PSA) >20 ng/ml and positive nodal status (P<.05). In multivariable analyses, no significant association between 11-oxygenated androgens and DFS was observed. Adrenal 11β-hydroxyandrostenedione (11OHA4), the predominant androgenic 11KT, and its metabolite 11-ketoandrosterone (11KAST), modeled as quartiles, were associated with MFS (P=.06, .03, and 0.008, respectively). A significant accumulation of 11-oxygenated androgen precursors and bioactive androgens, but reduced metabolite levels, was observed in 5-ARIs patients (P<.001).

CONCLUSIONS: Preoperative circulating 11-oxygenated androgen levels are associated with MFS in men with localized PCa undergoing RP and are affected by 5-ARI treatment.

PMID:36373402 | DOI:10.1097/JU.0000000000003049

Clin Pharmacol Ther. 2022 Nov 13. doi: 10.1002/cpt.2773. Online ahead of print.

ABSTRACT

Pharmacogenetic implementation programs are increasingly feasible due to the availability of clinical guidelines for implementation research. The utilization of these resources has been reported with selected drug-gene pairs; however, little is known about how prescribers respond to pharmacogenetic recommendations for statin therapy. We prospectively assessed prescriber interaction with point-of-care clinical decision support (CDS) to guide simvastatin therapy for a diverse cohort of primary care patients enrolled in a clinical pharmacogenetics program. Of the 1639 preemptively genotyped patients, 298 (18.2%) had an intermediate function (IF) OATP1B1 phenotype and 25 (1.53%) had a poor function (PF) phenotype, predicted by a common single nucleotide variant in the SLCO1B1 gene (c.521T>C; rs4149056). Clinicians were presented with CDS when simvastatin was prescribed for IF or PF patients through the Electronic Health Record. Importantly, 64.2% of the CDS deployed at the point-of-care was accepted by the prescribers and resulted in prescription changes. Statin intensity was found to significantly influence prescriber adoption of the pharmacogenetic-guided CDS, whereas patient gender or race, prescriber type, or pharmacogenetic training status did not significantly influence adoption. This study demonstrates that primary care providers readily adopt pharmacogenetic information to guide statin therapy for the majority of patients with preemptive genotype data.

PMID:36372942 | DOI:10.1002/cpt.2773

Biomed Pharmacother. 2022 Nov 10;157:114003. doi: 10.1016/j.biopha.2022.114003. Online ahead of print.

NO ABSTRACT

PMID:36371855 | DOI:10.1016/j.biopha.2022.114003

Med (N Y). 2022 Nov 11;3(11):740-759. doi: 10.1016/j.medj.2022.08.006.

ABSTRACT

Genome sequencing in the clinic often allows patients to receive a molecular diagnosis. However, variants are most often evaluated for pathogenicity, neglecting potential treatability and thus often yielding limited clinical benefit. Antisense oligonucleotides (ASOs), among others, offer attractive programmable and relatively safe platforms for customized therapy based upon the causative genetic variant. The landscape of ASO-treatable variants is largely uncharted, with new developments emerging for loss-of-function, haploinsufficient, and gain-of-function effects. ASOs can access the transcriptome to target splice-gain variants, poison exons, untranslated/regulatory regions, and naturally occurring antisense transcripts. Here we assess public variant databases and find that approximately half of pathogenic variants have one or more viable avenues for ASO therapy. The future might see medical teams considering "treatability" when interpreting genomic sequencing results to fully realize benefits for patients.

PMID:36370694 | DOI:10.1016/j.medj.2022.08.006

J Am Pharm Assoc (2003). 2022 Sep 28:S1544-3191(22)00320-X. doi: 10.1016/j.japh.2022.09.019. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenetic (PGx) testing is an evidence-based approach to finding effective medication therapies. While community pharmacists are ideally situated to provide PGx testing, the extent of its implementation is limited within community pharmacies.

OBJECTIVE: This study aimed to explore trends in the international peer-reviewed primary literature on community pharmacists' implementation of PGx and map the main findings on the Theoretical Domains Framework (TDF).

METHODS: A literature search and 2-step screening were conducted per PRISMA Extension for Scoping Reviews. Inclusion criteria were English language, community pharmacy setting, full papers, and empirical research. Data were collated in a data extraction form. The main findings were deductively mapped on the TDF with a content analysis approach.

RESULTS: Of 1176 identified documents screened, 39 were included in this scoping review. Four groups of research were identified: pre-implementation surveys, interviews, and focus groups (56%, n=22), PGx implementation: single cohort to assess feasibility (38%, n=15), PGx implementation: controlled study to assess feasibility (n=1, 2.5%), and efficacy of PGx (2.5%, n=1). Most studies throughout the 4 groups sought pharmacists' perceptions (46%, n=18) and used the quantitative paradigm (77%, n=30). TDF mapping documented positive beliefs about the benefits of PGx testing as a part of the pharmacists' role. Barriers to PGx use included pharmacists' awareness of knowledge gaps, low confidence in interpreting and communicating PGx results, concerns about cost, privacy, and integration into pharmacy workflow.

CONCLUSION: Research addressing PGx implementation within the community pharmacy evolved from assessing individuals' perceptions of PGx to determining the feasibility of PGx testing in pharmacies and evaluating the impact of PGx testing on patient outcomes in depression. Mapping the main findings on the TDF facilitates the development of multidimensional interventions, potentially targeting patients, pharmacists, and health policy.

PMID:36371398 | DOI:10.1016/j.japh.2022.09.019

Orphanet J Rare Dis. 2022 Nov 12;17(1):412. doi: 10.1186/s13023-022-02562-9.

ABSTRACT

BACKGROUND: X-linked hypophosphatemia (XLH) is characterized by increased serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphatemia and insufficient endogenous synthesis of calcitriol. Beside rickets, odonto- and osteomalacia, disproportionate short stature is seen in most affected individuals. Vitamin D analogs and phosphate supplements, i.e., conventional therapy, can improve growth especially when started early in life. Recombinant human growth hormone (rhGH) therapy in XLH children with short stature has positive effects, although few reports are available. Newly available treatment (burosumab) targeting increased FGF23 signaling leads to minimal improvement of growth in XLH children. So far, we lack data on the growth of XLH children treated with concomitant rhGH and burosumab therapies.

RESULTS: Thirty-six patients received burosumab for at least 1 year after switching from conventional therapy. Of these, 23 received burosumab alone, while the others continued rhGH therapy after switching to burosumab. Children treated with burosumab alone showed a minimal change in height SDS after 1 year (mean ± SD 0.0 ± 0.3 prepubertal vs. 0.1 ± 0.3 pubertal participants). In contrast, rhGH clearly improved height during the first year of treatment before initiating burosumab (mean ± SD of height gain 1.0 ± 0.4); patients continued to gain height during the year of combined burosumab and rhGH therapies (mean ± SD height gain 0.2 ± 0.1). As expected, phosphate serum levels normalized upon burosumab therapy. No change in serum calcium levels, urinary calcium excretion, or 25-OHD levels was seen, though 1,25-(OH)2D increased dramatically under burosumab therapy.

CONCLUSION: To our knowledge, this is the first study on growth under concomitant rhGH and burosumab treatments. We did not observe any safety issue in this cohort of patients which is one of the largest in Europe. Our data suggest that continuing treatment with rhGH after switching from conventional therapy to burosumab, if the height prognosis is compromised, might be beneficial for the final height.

PMID:36371259 | DOI:10.1186/s13023-022-02562-9