Heart Lung Circ. 2023 Dec 30:S1443-9506(23)04414-1. doi: 10.1016/j.hlc.2023.11.005. Online ahead of print.

ABSTRACT

Cardiac tumours can occur in association with genetic syndromes. Rhabdomyomas have been reported in association with tuberous sclerosis, myxomas with Carney's complex, cardiac fibromas with Gorlin syndrome, and paragangliomas with multiple endocrine neoplasm syndrome. The presentation and prognosis of cardiac tumours associated with genetic syndromes differ compared with sporadic cases. Knowledge about the associated syndromes' genetic features and extracardiac manifestations is essential for the diagnosis, prognosis, and management of cardiac neoplasms. Moreover, identifying genetic mutations in benign and malignant cardiac tumours is needed to personalise management and improve treatment outcomes. Thus, this review discusses the genetic abnormalities associated with cardiac tumours, the current genetic screening recommendations, and the effect of those genetic mutations on the outcomes.

PMID:38161083 | DOI:10.1016/j.hlc.2023.11.005

Pac Symp Biocomput. 2024;29:341-358.

ABSTRACT

Gene imputation and TWAS have become a staple in the genomics medicine discovery space; helping to identify genes whose regulation effects may contribute to disease susceptibility. However, the cohorts on which these methods are built are overwhelmingly of European Ancestry. This means that the unique regulatory variation that exist in non-European populations, specifically African Ancestry populations, may not be included in the current models. Moreover, African Americans are an admixed population, with a mix of European and African segments within their genome. No gene imputation model thus far has incorporated the effect of local ancestry (LA) on gene expression imputation. As such, we created LA-GEM which was trained and tested on a cohort of 60 African American hepatocyte primary cultures. Uniquely, LA-GEM include local ancestry inference in its prediction of gene expression. We compared the performance of LA-GEM to PrediXcan trained the same dataset (with no inclusion of local ancestry) We were able to reliably predict the expression of 2559 genes (1326 in LA-GEM and 1236 in PrediXcan). Of these, 546 genes were unique to LA-GEM, including the CYP3A5 gene which is critical to drug metabolism. We conducted TWAS analysis on two African American clinical cohorts with pharmacogenomics phenotypic information to identity novel gene associations. In our IWPC warfarin cohort, we identified 17 transcriptome-wide significant hits. No gene reached are prespecified significance level in the clopidogrel cohort. We did see suggestive association with RAS3A to P2RY12 Reactivity Units (PRU), a clinical measure of response to anti-platelet therapy. This method demonstrated the need for the incorporation of LA into study in admixed populations.

PMID:38160291

J Adv Res. 2023 Dec 28:S2090-1232(23)00405-8. doi: 10.1016/j.jare.2023.12.018. Online ahead of print.

ABSTRACT

INTRODUCTION: The population of Taiwan has a long history of ethno-cultural evolution. The Taiwanese population was isolated from other large populations such as the European, Han Chinese, and Japanese population. The Taiwan Biobank (TWB) project has built a nationwide database, particularly for personal whole-genome sequence (WGS) to facilitate basic and clinical collaboration nationally and internationally, making it one of the most valuable public datasets of the East Asian population.

OBJECTIVES: This study provides comprehensive medical genomic findings from TWB WGS data, for better characterization of disease susceptibility and the choice of ideal treatment regimens in Taiwanese population.

METHODS: We reanalyzed 1,496 WGS using a PrecisionFDA Truth challenge winner method Sentieon DNAscope. Single nucleotide variants (SNV) and small insertions/deletions (INDEL) were benchmarked. We also analyzed pharmacogenomic (PGx) drug-associated alleles, and copy number variants (CNV). Multiple practicing clinicians reviewed and curated the clinically significant variants. Variant annotations can be browsed at TaiwanGenomes (https://genomes.tw).

RESULTS: We found that each participant had an average of 6,870.7 globally novel variants and 75.3% (831/1103) of the participants harbored at least one PharmGKB-selected high evidence level human leukocyte antigen (HLA) risk allele. 54 PharmGKB-reported high-level instances of evidence of Cytochrome P450 variant-drug pairs, with a population frequency of over 13.2%. We also identified 23 variants in the ACMG secondary finding V3 gene list from 25 participants, suggesting that 1.67% (25/1496) of the population is harboring at least one medical actionable variant. Our carrier status analyses suggest that one in 25 couples (3.94%) would risk having offspring with at least one pathogenic variant, which is in line with rates found in Japan and Singapore. For pathogenic CNV, we detected 6.88% and 2.02% carrier rates for alpha thalassemia and spinal muscular atrophy, respectively.

CONCLUSION: Our study highlights the overall medical insights of a complete Taiwanese genomic profile.

PMID:38159844 | DOI:10.1016/j.jare.2023.12.018

Arch Pharm Res. 2023 Dec 30. doi: 10.1007/s12272-023-01476-9. Online ahead of print.

ABSTRACT

Pitavastatin, a potent 3-hydroxymethylglutaryl coenzyme A reductase inhibitor, is indicated for the treatment of hypercholesterolemia and mixed dyslipidemia. Hepatic uptake of pitavastatin is predominantly occupied by the organic anion transporting polypeptide 1B1 (OATP1B1) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene, which is a polymorphic gene that encodes OATP1B1. SLCO1B1 genetic polymorphism significantly alters the pharmacokinetics of pitavastatin. This study aimed to establish the physiologically based pharmacokinetic (PBPK) model to predict pitavastatin pharmacokinetics according to SLCO1B1 genetic polymorphism. PK-Sim® version 10.0 was used to establish the whole-body PBPK model of pitavastatin. Our pharmacogenomic data and a total of 27 clinical pharmacokinetic data with different dose administration and demographic properties were used to develop and validate the model, respectively. Physicochemical properties and disposition characteristics of pitavastatin were acquired from previously reported data or optimized to capture the plasma concentration-time profiles in different SLCO1B1 diplotypes. Model evaluation was performed by comparing the predicted pharmacokinetic parameters and profiles to the observed data. Predicted plasma concentration-time profiles were visually similar to the observed profiles in the non-genotyped populations and different SLCO1B1 diplotypes. All fold error values for AUC and Cmax were included in the two fold range of observed values. Thus, the PBPK model of pitavastatin in different SLCO1B1 diplotypes was properly established. The present study can be useful to individualize the dose administration strategy of pitavastatin in individuals with various ages, races, and SLCO1B1 diplotypes.

PMID:38159179 | DOI:10.1007/s12272-023-01476-9

Hum Genet. 2023 Dec 30. doi: 10.1007/s00439-023-02628-z. Online ahead of print.

ABSTRACT

Pharmacogenomics (PGx) is a promising field of precision medicine where efficacy of drugs is maximized while side effects are minimized for individual patients. Knowledge of the frequency of PGx-relevant variants (pharmacovariants) in the local population is a pre-requisite to informed policy making. Unfortunately, such knowledge is largely lacking from the Middle East. Here, we describe the use of a large clinical exome database (n = 13,473) and HLA haplotypes (n = 64,737) from Saudi Arabia, one of the largest countries in the Middle East, along with previously published data from the local population to ascertain allele frequencies of known pharmacovariants. In addition, we queried another exome database (n = 816) of well-phenotyped research subjects from Saudi Arabia to discover novel candidate variants in known PGx genes (pharmacogenes). Although our results show that only 26% (63/242) of class 1A/1B PharmGKB variants were identified, we estimate that 99.57% of the local population have at least one such variant. This translates to a minimum estimated impact of 9% of medications dispensed by our medical center annually. We also highlight the contribution of rare variants where 71% of the pharmacogenes devoid of common pharmacovariants had at least one potentially deleterious rare variant. Thus, we show that approaches that go beyond the use of commercial PGx kits that have been optimized for other populations should be implemented to ensure universal and equitable access of all members of the local population to personalized prescription practices.

PMID:38159139 | DOI:10.1007/s00439-023-02628-z

Ter Arkh. 2023 Dec 28;95(12):1056-1063. doi: 10.26442/00403660.2023.12.202501.

ABSTRACT

Autoimmunity and autoinflammation, co-potentiating pathological processes, are considered within the "immune-inflammatory" continuum (continuity with a variety of elements), reflecting the close relationship between the innate and acquired immune responses. Autoimmunity is the leading pathogenetic mechanism for a specific type of human chronic inflammatory disorders - autoimmune diseases, affecting more than 10% of people in the general population. Advances in molecular biology, pharmacogenetics, and bioinformatics provided the background for individualizing therapy for systemic autoimmune rheumatic diseases within personalized medicine. Studying the immunopathogenesis mechanisms, improving diagnostics, interpreting the molecular taxonomy, and developing approaches to the prevention and personalized therapy of systemic autoimmune rheumatic diseases are the priority issues of modern medicine.

PMID:38158939 | DOI:10.26442/00403660.2023.12.202501

Neurochem Int. 2023 Dec 27:105672. doi: 10.1016/j.neuint.2023.105672. Online ahead of print.

ABSTRACT

Neuropsychiatric disorders are considered to be the most common cause of disability worldwide. Serotonin and its transporter is a prominent paradigm in mood disorders. Response to selective serotonin reuptake inhibitors (SSRI) is altered due to heterogeneity in the serotonin transporter gene, SLC6A4 (solute carrier family 6 member 4). The reported polymorphisms are found to be in different regions of the transporter gene: promoter region (5-HTTLPR and various single nucleotide polymorphisms within it), intron (STin2), and exon 9 (I425V). The long and short alleles of the 5-HTTLPR gene, which are prevalent among variations, may mediate differential effects. In long allelic variant carriers, an increased response to SSRI and timely recovery is due to increased availability of SERT. Whereas, SERT availability is significantly decreased in short allelic carriers, necessitating a reduction in SSRI dosage due to the increased risk of adverse drug reactions. Thus, pharmacogenetic investigations are required to understand the impact of functional variations on the efficacy and tolerability of SSRI. Identifying the carrier variants may aid in clear-decision making of the treatment regimen, aiding the approach of personalized medication.

PMID:38157886 | DOI:10.1016/j.neuint.2023.105672

Urologiia. 2023 Dec;(6):5-13.

ABSTRACT

INTRODUCTION: Tamsulosin is a member of the group of selective 1-adrenoblockers. Tamsulosin monotherapy is the most common first-line option in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and can be used regardless on severity of LUTS. The CYP2D6, CYP3A4, and CYP3A5 enzymes are involved in the metabolism of tamsulosin. Carriage of different allelic variants of CYP2D6, CYP3A4 and CYP3A5, involved in its metabolism, may potentially affect the variability of efficacy and safety of the drug.

AIM: To evaluate the effect of carriage of allelic variants of cytochrome P450 superfamily enzyme genes (CYP2D6*3, CYP2D6*4, CYP2D6*9, CYP2D6*10, CYP2D6*41, CYP3A4*3, CYP3A4*22 and CYP3A5*3) on the efficiency and safety of tamsulosin in patients with LUTS associated with BPH.

MATERIALS AND METHODS: All phases of the study were completed by 106 patients with LUTS/BPH (N40 according to ICD 10). All patients received monotherapy with tamsulosin 0.4 mg/day for a minimum of 8 weeks. Based on the severity of symptoms, they were divided into two groups using the International Prostate Symptom Score (IPSS). In Group 1, there were patients with moderate symptoms (IPSS score of 8-19) (n=57), while Group 2 consisted of those with severe symptoms (IPSS score >20) (n=49). Treatment outcomes were assessed using the IPSS score with determination of quality of life (QoL), transrectal ultrasound with evaluation of prostate volume and residual urine, and uroflowmetry. Follow-up visits were at 2, 4, and 8 weeks after the start of therapy. Genotyping of all patients was performed using polymerase chain reaction to determine the CYP2D6 (*3, *4, *9, *10, and *41), CYP3A4 (*3, *22), and CYP3A5*3 markers.

RESULTS: In the group of patients with moderate symptoms, carriers of the CYP2D6*10 and CYP2D6*41 polymorphisms showed a significantly greater reduction in symptoms according to the overall IPSS score at 8 weeks (p=0.046) and in the micturition symptom subscale starting from 4 weeks of treatment (p<0.05). Carriers of the CYP2D6*10 polymorphism in both groups were associated with a decrease in residual urine volume at 8 weeks (p<0.05). The presence of the CYP3A5*3 variant in those with severe symptoms significantly improved quality of life during therapy. Allelic variants of the CYP2D6 and CYP3A genes did not affect the frequency of adverse events.

CONCLUSION: The results obtained by calculating the prognostic significance of individual polymorphic markers pointed to the contribution of CYP2D6*10 and CYP2D6*41. Tamsulosin therapy is more effective in patients with LUTS who are carriers of these allele variants. The safety parameters of tamsulosin were not influenced by the studied polymorphic variants. It was found that CYP3A5*3 was associated with an increase in the subjective assessment of the patient's quality of life, but it is too early to draw final conclusions. The issue of the contribution of genetic factors to the efficiency and safety of treatment of LUTS in BPH requires further study with a larger sample size and analyzed parameters.

PMID:38156677

Gen Psychiatr. 2023 Dec 26;36(6):e101050. doi: 10.1136/gpsych-2023-101050. eCollection 2023.

ABSTRACT

BACKGROUND: Pharmacogenomics (PGx) is a promising tool to realise tailored drug therapy for depression.

AIMS: To investigate the treatment efficacy of PGx for treatment-resistant depression (TRD) compared with treatment as usual.

METHODS: A systematic search was conducted in PubMed, Embase, the Cochrane Library, Web of Science and PsycINFO to identify relevant studies published from inception to 15 April 2023. Two-arm randomised controlled trials (RCTs) exploring the efficacy of PGx-guided versus unguided treatment for TRD were included. The risk of bias in the included studies was evaluated using the Cochrane risk of bias assessment tool. The overall quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

RESULTS: Seven RCTs (n=3003) comparing PGx-guided (n=1492) and unguided (n=1511) groups were identified and analysed. PGx-guided treatment was superior to treatment as usual in response (relative risk (RR)=1.31; 95% confidence interval (95% CI): 1.15 to 1.49; p<0.001) and remission (RR=1.40; 95% CI: 1.09 to 1.80; p=0.009) improvements. Effect sizes for acceptability (RR=0.90; 95% CI: 0.80 to 1.02; p=0.100) and side effect burden (RR=0.58; 95% CI: 0.29 to 1.15; p=0.120) between the two groups were not statistically different. The overall quality of evidence was rated from 'very low' (25%) to 'low' (75%) based on the GRADE criteria.

CONCLUSIONS: PGx-guided treatment has shown a small overall effect in improving the response and remission rates for patients with TRD. However, these results should be interpreted cautiously because of the few included studies and the low quality of evidence. Further high-quality clinical trials are warranted to confirm the findings.

PROSPERO REGISTRATION NUMBER: CRD42022340182.

PMID:38155841 | PMC:PMC10753713 | DOI:10.1136/gpsych-2023-101050

Nat Genet. 2023 Dec 28. doi: 10.1038/s41588-023-01584-8. Online ahead of print.

ABSTRACT

Although over 90 independent risk variants have been identified for Parkinson's disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson's disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations.

PMID:38155330 | DOI:10.1038/s41588-023-01584-8

J Antimicrob Chemother. 2023 Dec 28:dkad399. doi: 10.1093/jac/dkad399. Online ahead of print.

NO ABSTRACT

PMID:38153247 | DOI:10.1093/jac/dkad399

Genet Med. 2023 Dec 25:101056. doi: 10.1016/j.gim.2023.101056. Online ahead of print.

ABSTRACT

PURPOSE: Combinatorial pharmacogenetic (PGx) panels intended to aid psychiatric prescribing are available to clinicians. Here we evaluated the documentation of PGx panel results and subsequent prescribing patterns within a tertiary healthcare system.

METHODS: We performed a query of psychiatry service note text in our electronic health record (EHR) using 71 predefined PGx terms. Patients who underwent combinatorial PGx testing were identified, and documentation of test results was analyzed. Prescription data following testing were examined for the frequency of prescriptions influenced by genes on the panel along with the medical specialties involved.

RESULTS: A total of 341 patients received combinatorial PGx testing, and documentation of results was found to be absent or incomplete for 198 patients (58%). The predominant method of documentation was through PDFs uploaded to the EHR's "Media" section. Among patients with at least one year of follow-up, a large majority (194/228, 85%) received orders for medications affected by the tested genes, including 132/228 (58%) patients receiving at least one non-psychiatric medication influenced by the test results.

CONCLUSION: Results from combinatorial PGx testing were poorly documented. Medications affected by these results were often prescribed after testing, highlighting the need for discrete results and clinical decision support.

PMID:38153010 | DOI:10.1016/j.gim.2023.101056

Brief Bioinform. 2023 Nov 22;25(1):bbad470. doi: 10.1093/bib/bbad470.

ABSTRACT

Polygenic risk scores (PRSs) have emerged as promising tools for the prediction of human diseases and complex traits in disease genome-wide association studies (GWAS). Applying PRSs to pharmacogenomics (PGx) studies has begun to show great potential for improving patient stratification and drug response prediction. However, there are unique challenges that arise when applying PRSs to PGx GWAS beyond those typically encountered in disease GWAS (e.g. Eurocentric or trans-ethnic bias). These challenges include: (i) the lack of knowledge about whether PGx or disease GWAS/variants should be used in the base cohort (BC); (ii) the small sample sizes in PGx GWAS with corresponding low power and (iii) the more complex PRS statistical modeling required for handling both prognostic and predictive effects simultaneously. To gain insights in this landscape about the general trends, challenges and possible solutions, we first conduct a systematic review of both PRS applications and PRS method development in PGx GWAS. To further address the challenges, we propose (i) a novel PRS application strategy by leveraging both PGx and disease GWAS summary statistics in the BC for PRS construction and (ii) a new Bayesian method (PRS-PGx-Bayesx) to reduce Eurocentric or cross-population PRS prediction bias. Extensive simulations are conducted to demonstrate their advantages over existing PRS methods applied in PGx GWAS. Our systematic review and methodology research work not only highlights current gaps and key considerations while applying PRS methods to PGx GWAS, but also provides possible solutions for better PGx PRS applications and future research.

PMID:38152980 | DOI:10.1093/bib/bbad470

Food Chem. 2023 Dec 13;440:138214. doi: 10.1016/j.foodchem.2023.138214. Online ahead of print.

ABSTRACT

Pesticide residue poses a significant global public health concern, necessitating improved detection methods. Here, a novel platform was introduced based on surface-enhanced Raman spectroscopy (SERS) to detect ten distinct types of pesticides. Notably, the sensitivity of this approach is exemplified by detecting trace amounts of 50 pM (10 ppt) thiabendazole. The correlation between the characteristic peak intensity of coexisting pesticides and their concentrations displays an exceptional linear relationship (R2 = 0.9999), underscoring its utility for quantitative mixed pesticide detection. Additionally, qualitative analysis of five mixed pesticides was conducted leveraging distinctive peak labeling. Harnessing machine learning techniques, a model for classifying and predicting pesticides on pericarps was developed. Remarkably, the convolutional neural network achieved classification accuracy of 100 % and prediction accuracy of 99.62 %. This innovative approach accurately identifies and quantifies diverse pesticides, thus offering a feasible scheme for in-situ detection of pesticide residues. Ultimately, this strategy contributes to ensuring food safety and public health.

PMID:38150903 | DOI:10.1016/j.foodchem.2023.138214

J Integr Bioinform. 2023 Dec 28. doi: 10.1515/jib-2023-0026. Online ahead of print.

ABSTRACT

The first approaches in recent years for the integration of pharmacogenomic plausibility checks into clinical practice show both a promising improvement in the drug therapy safety, but also difficulties in application. One of the difficulties is the meaningful interpretation of the text-based results by the medical practitioner. We propose here as an appropriate and sensible solution to avoid misunderstandings and to include evidence-based, pharmacogenomic recommendations in prescriptions, which should be the graph-based visualization of the reports. This allows for a plausible interpretation and relate complex, even contradictory guidelines. The improved overview over the pharmacogenomics (PGx) guidelines using the graphical visualization makes the medical practitioner's choice of dose and medication more patient-specific, improves the treatment outcome and thus, increases the drug therapy safety.

PMID:38150373 | DOI:10.1515/jib-2023-0026

Arch Pharm Res. 2023 Dec 27. doi: 10.1007/s12272-023-01478-7. Online ahead of print.

ABSTRACT

Pantoprazole is used to treat gastroesophageal reflux disease (GERD), maintain healing of erosive esophagitis (EE), and control symptoms related to Zollinger-Ellison syndrome (ZES). Pantoprazole is mainly metabolized by cytochrome P450 (CYP) 2C19, converting to 4'-demethyl pantoprazole. CYP2C19 is a genetically polymorphic enzyme, and the genetic polymorphism affects the pharmacokinetics and/or pharmacodynamics of pantoprazole. In this study, we aimed to establish the physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of pantoprazole in populations with various CYP2C19 metabolic activities. A comprehensive investigation of previous reports and drug databases was conducted to collect the clinical pharmacogenomic data, physicochemical data, and disposition properties of pantoprazole, and the collected data were used for model establishment. The model was evaluated by comparing the predicted plasma concentration-time profiles and/or pharmacokinetic parameters (AUC and Cmax) with the clinical observation results. The predicted plasma concentration-time profiles in different CYP2C19 phenotypes properly captured the observed profiles. All fold error values for AUC and Cmax were included in the two-fold range. Consequently, the minimal PBPK model for pantoprazole related to CYP2C19 genetic polymorphism was properly established and it can predict the pharmacokinetics of pantoprazole in different CYP2C19 phenotypes. The present model can broaden the insight into the individualized pharmacotherapy for pantoprazole.

PMID:38150171 | DOI:10.1007/s12272-023-01478-7

Gut Microbes. 2024 Jan-Dec;16(1):2296603. doi: 10.1080/19490976.2023.2296603. Epub 2023 Dec 27.

ABSTRACT

The human gut microbiota constitutes a vast and complex community of microorganisms. The myriad of microorganisms present in the intestinal tract exhibits highly intricate interactions, which play a crucial role in maintaining the stability and balance of the gut microbial ecosystem. These interactions, in turn, influence the overall health of the host. The mammalian gut microbes have evolved a wide range of mechanisms to suppress or even eliminate their competitors for nutrients and space. Simultaneously, extensive cooperative interactions exist among different microbes to optimize resource utilization and enhance their own fitness. This review will focus on the competitive mechanisms among members of the gut microorganisms and discuss key modes of actions, including bacterial secretion systems, bacteriocins, membrane vesicles (MVs) etc. Additionally, we will summarize the current knowledge of the often-overlooked positive interactions within the gut microbiota, and showcase representative machineries. This information will serve as a reference for better understanding the complex interactions occurring within the mammalian gut environment. Understanding the interaction dynamics of competition and cooperation within the gut microbiota is crucial to unraveling the ecology of the mammalian gut microbial communities. Targeted interventions aimed at modulating these interactions may offer potential therapeutic strategies for disease conditions.

PMID:38149632 | DOI:10.1080/19490976.2023.2296603

Pediatr Transplant. 2023 Dec 27:e14677. doi: 10.1111/petr.14677. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic kidney disease (CKD) is reported in 20%-30% of children after liver transplantation (LT). One of the proposed underlying causes is the long-term exposure to tacrolimus, a calcineurin inhibitor (CNI), which is the main immunosuppressive drug used after LT. Variation in tacrolimus absolute exposure and relative dose requirements are believed to be important risk factors for developing CNI-associated nephrotoxicity.

AIM: To describe the long-term renal outcome of pediatric LT recipients and determine the effects of tacrolimus exposure on renal outcome parameters.

METHODS: Retrospective single center study of renal function (GFR, proteinuria) and pharmacokinetic parameters (C0 , AUC0-12h ) obtained during annual follow-up in children after liver transplantation, between 1998 and 2019. Relevant pharmacogenetic variants for tacrolimus disposition (CYP3A5 and ABCB1) were determined in recipients and donors. The evolution of individual renal function and tacrolimus exposure was evaluated using linear mixed models for repeated measurements.

RESULTS: Twenty-six children were included (mean follow-up: 10.4 years (range 2-18.9)). Mean estimated GFR was 109.3 (SE: 7.4), vs. measured: 91.3 mL/min/1.73 m2 (SE: 6.3), which remained stable during follow-up. CKD stage ≥2 was observed in 32.8% of the visits based on eGFR versus 50.0% on mGFR. CKD stage ≥3 was uncommon (4.1% and 6.2% resp.). Mean tacrolimus C0 was 5.3 ng/mL (SE: 2.5) with a AUC0-12h of 72.7 ng*h/mL (SE: 30.3), which demonstrated a small decrease during follow-up. There was a negative correlation between C0 and mGFR (rS = -0.3; p < .001). We found no correlation between GFR and tacrolimus dose requirements ((ng/mL)/(mg/kg)) or pharmacogenetic background.

CONCLUSION: Renal function during long-term follow-up after pediatric LT remained stable for the majority of our cohort. However, mild CKD was relatively common, warranting follow-up into adulthood. Although absolute tacrolimus exposure has a small depressing effect on concurrent GFR, there is no progressive deterioration of GFR due to long-term exposure, dose requirements or genetic background under the current target levels. These findings should be confirmed in a larger sample set, ideally including data from multiple centers.

PMID:38149466 | DOI:10.1111/petr.14677

Clin Trials. 2023 Dec 27:17407745231213882. doi: 10.1177/17407745231213882. Online ahead of print.

ABSTRACT

Since the middle of the 20th century, oncology's dose-finding paradigm has been oriented toward identifying a drug's maximum tolerated dose, which is then carried forward into phase 2 and 3 trials and clinical practice. For most modern precision medicines, however, maximum tolerated dose is far greater than the minimum dose needed to achieve maximal benefit, leading to unnecessary side effects. Regulatory change may decrease maximum tolerated dose's predominance by enforcing dose optimization of new drugs. Dozens of already approved cancer drugs require re-evaluation, however, introducing a new methodologic and ethical challenge in cancer clinical trials. In this article, we assess the history and current landscape of cancer drug dose finding. We provide a set of strategic priorities for postapproval dose optimization trials of the future. We discuss ethical considerations for postapproval dose optimization trial design and review three major design strategies for these unique trials that would both adhere to ethical standards and benefit patients and funders. We close with a discussion of financial and reporting considerations in the realm of dose optimization. Taken together, we provide a comprehensive, bird's eye view of the postapproval dose optimization trial landscape and offer our thoughts on the next steps required of methodologies and regulatory and funding regimes.

PMID:38148731 | DOI:10.1177/17407745231213882

Med Clin (Barc). 2023 Dec 22:S0025-7753(23)00686-3. doi: 10.1016/j.medcli.2023.11.008. Online ahead of print.

NO ABSTRACT

PMID:38142210 | DOI:10.1016/j.medcli.2023.11.008