Kidney Int. 2023 Oct;104(4):652-654. doi: 10.1016/j.kint.2023.06.036.

ABSTRACT

Lloberas et al. provide further evidence for the benefits of an individualized tacrolimus dosing algorithm based on population pharmacokinetics and pharmacogenetics. Better tacrolimus dosing could prevent underexposure and overexposure and potentially save costs. Most important, this could be the start of precision medicine in kidney transplantation, incorporating improved immunologic and donor quality assessments, advanced biopsy readouts, innovative pharmacogenomics for drug safety, and novel diagnostic and outcome algorithms to guide a truly personalized therapy.

PMID:37739615 | DOI:10.1016/j.kint.2023.06.036

Cancer Lett. 2023 Sep 20:216396. doi: 10.1016/j.canlet.2023.216396. Online ahead of print.

ABSTRACT

Recent discoveries in cancer metabolism have revealed promising metabolic targets to modulate cancer progression, drug response, and anti-cancer immunity. Combination therapy, consisting of metabolic inhibitors and chemotherapeutic or immunotherapeutic agents, offers new opportunities for improved cancer therapy. However, it also presents challenges due to the complexity of cancer metabolic pathways and the metabolic interactions between tumor cells and immune cells. Many studies have been published demonstrating potential synergy between novel inhibitors of metabolism and chemo/immunotherapy, yet our understanding of the underlying mechanisms remains limited. Here, we review the current strategies of altering the metabolic pathways of cancer to improve the anti-cancer effects of chemo/immunotherapy. We also note the need to differentiate the effect of metabolic inhibition on cancer cells and immune cells and highlight nanotechnology as an emerging solution. Improving our understanding of the complexity of the metabolic pathways in different cell populations and the anti-cancer effects of chemo/immunotherapy will aid in the discovery of novel strategies that effectively restrict cancer growth and augment the anti-cancer effects of chemo/immunotherapy.

PMID:37739209 | DOI:10.1016/j.canlet.2023.216396

Sci Rep. 2023 Sep 22;13(1):15792. doi: 10.1038/s41598-023-43141-7.

ABSTRACT

Telomere dysfunction is a notable event observed in many cancers contributing to their genomic instability. A major factor controlling telomere stability is the human telomerase reverse transcriptase catalytic subunit (hTERT). Telomere shortening has been observed in multiple myeloma (MM), a plasma cell malignancy with a complex and heterogeneous genetic background. In the present study, we aimed to analyse telomere length and hTERT genetic variants as potential markers of risk and survival in 251 MM patients. We found that telomere length was significantly shorter in MM patients than in healthy individuals, and patients with more advanced disease (stage III according to the International Staging System) had shorter telomeres than patients with less advanced disease. MM patients with hTERT allele rs2736100 T were characterized with significantly shorter progression-free survival (PFS). Moreover, allele rs2736100 T was also found to be less common in patients with disease progression in response to treatment. hTERT rs2853690 T was associated with higher haemoglobin blood levels and lower C-reactive protein. In conclusion, our results suggest that telomere length and hTERT genetic variability may affect MM development and can be potential prognostic markers in this disease.

PMID:37737335 | DOI:10.1038/s41598-023-43141-7

Pharmacy (Basel). 2023 Sep 14;11(5):146. doi: 10.3390/pharmacy11050146.

ABSTRACT

As healthcare continues to embrace the concept of person- and patient-centered care, pharmacogenomics, patient experience, and medication experience will continue to play an increasingly important role in care delivery. This review highlights the intersection between these concepts and provides considerations for patient-centered medication and pharmacogenomic experiences. Elements at the patient, provider, and system level can be considered in the discussion, supporting the use of pharmacogenomics, with components of the patient and medication experience contributing to the mitigation of barriers surrounding patient use and the valuation of pharmacogenomic testing.

PMID:37736918 | DOI:10.3390/pharmacy11050146

Pharmacy (Basel). 2023 Sep 10;11(5):144. doi: 10.3390/pharmacy11050144.

ABSTRACT

Since the rebirth of pharmacogenomics (PGx) in the 1990s and 2000s, with new discoveries of genetic variation underlying adverse drug response and new analytical technologies such as sequencing and microarrays, there has been much interest in the clinical application of PGx testing. The early involvement of pharmacists in clinical studies and the establishment of organizations to support the dissemination of information about PGx variants have naturally resulted in leaders in clinical implementation. This paper presents an overview of the evolving role of pharmacists, and discusses potential challenges and future paths, primarily focused in the U.S. Pharmacists have positioned themselves as leaders in clinical PGx testing, and will prepare the next generation to utilize PGx testing in their scope of practice.

PMID:37736916 | DOI:10.3390/pharmacy11050144

Geriatrics (Basel). 2023 Aug 24;8(5):84. doi: 10.3390/geriatrics8050084.

ABSTRACT

BACKGROUND: Pharmacogenomic factors affect the susceptibility to drug-drug interactions (DDI). We identified drug interaction perpetrators among the drugs prescribed to a cohort of 290 older adults and analysed the prevalence of gene polymorphisms that can increase their interacting potential. We also pinpointed clinical decision support systems (CDSSs) that incorporate pharmacogenomic factors in DDI risk evaluation.

METHODS: Perpetrator drugs were identified using the Drug Interactions Flockhart Table, the DRUGBANK website, and the Mayo Clinic Pharmacogenomics Association Table. Allelic variants affecting their activity were identified with the PharmVar, PharmGKB, dbSNP, ensembl and 1000 genome databases.

RESULTS: Amiodarone, amlodipine, atorvastatin, digoxin, esomperazole, omeprazole, pantoprazole, simvastatin and rosuvastatin were perpetrator drugs prescribed to >5% of our patients. Few allelic variants affecting their perpetrator activity showed a prevalence >2% in the European population: CYP3A4/5*22, *1G, *3, CYP2C9*2 and *3, CYP2C19*17 and *2, CYP2D6*4, *41, *5, *10 and *9 and SLC1B1*15 and *5. Few commercial CDSS include pharmacogenomic factors in DDI-risk evaluation and none of them was designed for use in older adults.

CONCLUSIONS: We provided a list of the allelic variants influencing the activity of drug perpetrators in older adults which should be included in pharmacogenomics-oriented CDSSs to be used in geriatric medicine.

PMID:37736884 | DOI:10.3390/geriatrics8050084

Per Med. 2023 Sep 22. doi: 10.2217/pme-2022-0074. Online ahead of print.

NO ABSTRACT

PMID:37736874 | DOI:10.2217/pme-2022-0074

Microbes Infect. 2023 Sep 19:105228. doi: 10.1016/j.micinf.2023.105228. Online ahead of print.

ABSTRACT

It has recently been found that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) m6A modifications can affect viral replication and function. However, no studies to date have shown a correlation between SARS-CoV-2 m6A modifications and viral pathogenicity. In this study, we analyzed m6A modification in 2,190,667 SARS-CoV-2 genomic RNAs. m6A modifications of SARS-CoV-2 from different lineages, causing mild or severe COVID-19 and showing breakthrough for different vaccines were analyzed to explore correlations with viral pathogenicity. The results suggested that the presence of more m6A modifications in the SARS-CoV-2 N region (positive strand) correlates with weaker pathogenicity. In addition, we identified three m6A modification sites correlating with weak pathogenicity (924 in ORF1ab, 15659 in ORF1ab, 28288 in N, 28633 in N and 29385 in N, 29707 in 3'UTR) and one with strong pathogenicity (74 in 5'UTR). These results provide new information for understanding the prevalence of SARS-CoV-2 and controlling the virus.

PMID:37734532 | DOI:10.1016/j.micinf.2023.105228

Biomed Pharmacother. 2023 Sep 19;167:115479. doi: 10.1016/j.biopha.2023.115479. Online ahead of print.

ABSTRACT

A wide interindividual variability in therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) palbociclib, ribociclib and abemaciclib, among patients with HR+/HER2- metastatic breast cancer has been reported. This study explored the impact of genetic polymorphisms in ADME genes (responsible for drug absorption, distribution, metabolism, and elimination) on CDKis safety profiles in 230 patients. Selected endpoints include grade 3/4 neutropenia at day 14 of the first treatment cycle, early dose-limiting toxicities (DLTs), and dose reductions within the initial three cycles. Our analysis revealed associations between these endpoints and polymorphisms in CYP3A4, CYP3A5, ABCB1, and ABCG2 genes. Their impact on CDKis plasma concentrations (Ctrough) was also examined. Specifically, ABCB1 c.1236C>T and c.2677C>T polymorphisms correlated significantly with grade 3/4 neutropenia at day 14 (OR 3.94, 95% CI 1.32-11.75; p = 0.014 and OR 3.32, 95% CI 1.12-9.85; p = 0.030). Additionally, ABCB1 c.3435C>T was associated with an elevated risk of early DLTs and dose reductions (OR 3.28, 95% CI 1.22-8.84, p = 0.019; OR 2.60, 95% CI 1.20-5.60, p = 0.015). Carriers of the CYP3A4*22 allele also demonstrated in univariate a higher risk of early DLTs (OR 3.10, 95% CI 1.01-9.56, p = 0.049). Furthermore, individuals with the ABCB1 1236T-3435T-2677T(A) variant haplotype exhibited significant associations with grade 3/4 neutropenia at day 14 (OR 3.36, 95% CI 1.20-9.41; p = 0.021) and early DLTs in univariate (OR 3.08, 95% CI 1.19-7.95; p = 0.020). Homozygous carriers of the ABCB1 T-T-T(A) haplotype tended to have a higher mean ribociclib Ctrough (934.0 ng/mL vs. 752.0 ng/mL and 668.0 ng/mL). Regardless preliminary, these findings offer promising insights into the role of pharmacogenetic markers in CDKis safety profiles, potentially contributing to address the interindividual variability in CDKis responses.

PMID:37734262 | DOI:10.1016/j.biopha.2023.115479

Nat Genet. 2023 Sep 21. doi: 10.1038/s41588-023-01506-8. Online ahead of print.

ABSTRACT

Candidate cis-regulatory elements (cCREs) in microglia demonstrate the most substantial enrichment for Alzheimer's disease (AD) heritability compared to other brain cell types. However, whether and how these genome-wide association studies (GWAS) variants contribute to AD remain elusive. Here we prioritize 308 previously unreported AD risk variants at 181 cCREs by integrating genetic information with microglia-specific 3D epigenome annotation. We further establish the link between functional variants and target genes by single-cell CRISPRi screening in microglia. In addition, we show that AD variants exhibit allelic imbalance on target gene expression. In particular, rs7922621 is the effective variant in controlling TSPAN14 expression among other nominated variants in the same cCRE and exerts multiple physiological effects including reduced cell surface ADAM10 and altered soluble TREM2 (sTREM2) shedding. Our work represents a systematic approach to prioritize and characterize AD-associated variants and provides a roadmap for advancing genetic association to experimentally validated cell-type-specific phenotypes and mechanisms.

PMID:37735198 | DOI:10.1038/s41588-023-01506-8

Cas Lek Cesk. 2023 Summer;162(4):148-151.

ABSTRACT

In medicine, there are two main methods of improving the healthcare provided: perfecting (optimizing) the existing ones and seeking new treatment procedures. Despite of tremendous development in the central nervous system research, current treatment of severe mental illnesses, such as schizophrenia and depressive disorder, is suboptimal. Nowadays, optimization of treatment in psychiatry includes therapeutic drug monitoring (TDM) and pharmacogenomic testing, which examines genetic variation involved in medication metabolism and drug action. The TDM enables to determine drug concentrations in blood and adjust the dose accordingly if clinical effects correlate better with drug blood levels than drug doses. The first international guidelines for TDM in neuropsychopharmacology were published in 2004 and regularly updated. The recent update provides therapeutic reference ranges for a majority of commonly prescribed psychiatric medications and gives example of patients regularly treated in clinical practice profiting from TDM (using antipsychotics and changing their smoking habits). TDM in psychiatry is an underused tool, given its ability to optimize treatment, as well as to improve treatment effectiveness.

PMID:37734940

Pharmacol Res Perspect. 2023 Oct;11(5):e01137. doi: 10.1002/prp2.1137.

ABSTRACT

Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have β-adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross-sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self-described "White" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p = .0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p = .0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions.

PMID:37732835 | DOI:10.1002/prp2.1137

Pharmacogenomics. 2023 Sep 21. doi: 10.2217/pgs-2023-0138. Online ahead of print.

ABSTRACT

The early detection of acute rejection in the allograft is important as it provides an opportunity for timely therapeutic intervention in order to preserve graft function and achieve longer graft survival. Donor-derived cell-free DNA (dd-cfDNA) has emerged as a new biomarker in the field of kidney transplantation. In this review, we used data from various studies to examine the role of dd-cfDNA in comparison to creatinine and donor-specific antibodies in the early detection of transplant rejection. We also reviewed the use of dd-cfDNA in other organ transplants as well as the challenges and potential future direction for dd-cfDNA as a diagnostic tool.

PMID:37732393 | DOI:10.2217/pgs-2023-0138

medRxiv. 2023 Sep 10:2023.09.08.23295248. doi: 10.1101/2023.09.08.23295248. Preprint.

ABSTRACT

RATIONALE: Standardized dosing of anti-tubercular (TB) drugs leads to variable plasma drug levels, which are associated with adverse drug reactions, delayed treatment response, and relapse. Mutations in genes affecting drug metabolism explain considerable interindividual pharmacokinetic variability; however, pharmacogenomic (PGx) assays that predict metabolism of anti-TB drugs have been lacking.

OBJECTIVES: To develop a Nanopore sequencing panel and validate its performance in active TB patients to personalize treatment dosing.

MEASUREMENTS AND MAIN RESULTS: We developed a Nanopore sequencing panel targeting 15 single nucleotide polymorphisms (SNP) in 5 genes affecting the metabolism of isoniazid (INH), rifampin (RIF), linezolid and bedaquiline. For validation, we sequenced DNA samples (n=48) from the 1000 genomes project and compared variant calling accuracy with Illumina genome sequencing. We then sequenced DNA samples from patients with active TB (n=100) from South Africa on a MinION Mk1C and evaluated the relationship between genotypes and pharmacokinetic parameters for INH and RIF.

RESULTS: The PGx panel achieved 100% concordance with Illumina sequencing in variant identification for the samples from the 1000 Genomes Project. In the clinical cohort, coverage was >100x for 1498/1500 (99.8%) amplicons across the 100 samples. One third (33%) of participants were identified as slow, 47% were intermediate and 20% were rapid isoniazid acetylators. Isoniazid clearance was significantly impacted by acetylator status (p<0.0001) with median (IQR) clearances of 11.2 L/h (9.3-13.4), 27.2 L/h (22.0-31.7), and 45.1 L/h (34.1-51.1) in slow, intermediate, and rapid acetylators. Rifampin clearance was 17.3% (2.50-29.9) lower in individuals with homozygous AADAC rs1803155 G>A substitutions (p=0.0015).

CONCLUSION: Targeted sequencing can enable detection of polymorphisms influencing TB drug metabolism on a low-cost, portable instrument to personalize dosing for TB treatment or prevention.

SUMMARY: This manuscript describes the development and validation of Nanopore sequencing panel to detect host pharmacogenomic markers to guide personalized drug dosing for treatment or prevention of tuberculosis. This article has an online data supplement, which is accessible from this issue's table of content online at www.atsjournals.org.

PMID:37732197 | PMC:PMC10508808 | DOI:10.1101/2023.09.08.23295248

MedComm (2020). 2023 Sep 18;4(5):e369. doi: 10.1002/mco2.369. eCollection 2023 Oct.

ABSTRACT

Soft tissue sarcoma (STS) is an uncommon malignancy that often carries a grim prognosis. Trophinin-associated protein (TROAP) is augmented in a variety of tumors and can affect tumor proliferation. Nevertheless, the prognostic value and specific functions of TROAP in STS are still vague. Herein, we display that TROAP exhibits an augmented trend in STS, and its elevation correlates with a poor prognosis of STS. Furthermore, its reduction is related to increased immune cell infiltration, enhanced stroma, and elevation of immune activation. Meanwhile, the TROAP-derived genomic signature is validated to predict patient prognosis, immunotherapy, and drug response reliably. A nomogram constructed based on age, metastatic status, and a TROAP-derived risk score of an STS individual could be used to quantify the survival probability of STS. In addition, in vitro experiments have demonstrated that TROAP is overexpressed in STS, and the downregulation of TROAP could affect the proliferation, migration, metastasis, and cell cycle of STS cells. In summary, the TROAP expression is elevated in STS tissues and cells, which is related to the poor prognosis and malignant biological behaviors of STS. It could act as a potential prognostic biomarker for diagnosis and treatment of STS.

PMID:37731946 | PMC:PMC10507284 | DOI:10.1002/mco2.369

Expert Opin Drug Metab Toxicol. 2023 Sep 20. doi: 10.1080/17425255.2023.2261366. Online ahead of print.

ABSTRACT

INTRODUCTION: Although significant development has been made in high-throughput screening of oral drug absorption and oral bioavailability, in silico prediction continues to play an important role in prediction of oral bioavailability and assisting in the proper selection of potential drug candidates.

AREAS COVERED: This review describes the improvements and latest modeling methods and algorithms available for the prediction of this important parameter. We performed a PubMed database search with a focus on the literature published in the last 15 years.

EXPERT OPINION: A tremendous efforts have been done in the past several years to develop reliable prediction tools that can provide accurate prediction for oral bioavailability. Several studies demonstrated new methodologies and techniques to develop either web-based in silico predictive tools or integrated PBPK models to predict oral bioavailability for new molecules. Improvements in the databases and the computational power will enhance the in silico prediction accuracy and reliability. Finally, introducing artificial intelligence to the drug development process will help improve the prediction tools.

PMID:37728393 | DOI:10.1080/17425255.2023.2261366

Int J Mol Cell Med. 2022;11(4):306-319. doi: 10.22088/IJMCM.BUMS.11.4.306.

ABSTRACT

Alternative pathways frequently operate as the origins of resistance to drugs that block the vascular endothelial growth factor (VEGF) pathway. To find possible therapeutic targets and indicators, this study explored the VEGF pathway and how miRNAs control it in recurrent glioblastoma multiforme (rGBM). Differentially expressed miRNAs (DEmiRNAs) were identified by using GBM GSE profiles (GSE32466). To find pathways containing DEmiRNAs, VEGF pathway genes, and their related genes, DIANA-miRPath v3.0 and the ToppGene database were utilized. miRNAs linked to VEGF signaling pathway genes, interactional genes, and DEmiRNAs were discovered by extracting common pathways. The ability of these miRNAs to distinguish rGBM patients from those with primary GBM was assessed using ROC analysis. The study revealed that in rGBM, 30 miRNAs were significantly up-regulated and 49 miRNAs were considerably down-regulated. Among them, the VEGF pathway was connected to 22 up-regulated miRNAs and 29 down-regulated miRNAs. The MAPK pathway shared the most genes with the VEGF pathway, accounting for 1,014 of the interacting genes, which were discovered to have interactions with VEGF signaling pathway genes. Furthermore, 14 miRNAs were identified as having a great deal of potential as molecular biomarkers and therapeutic targets for rGBM. The results indicate that the VEGF pathway in rGBM is regulated by a number of interrelated pathways. The discovered miRNAs hold promise as rGBM biomarkers and therapeutic targets, offering possibilities for novel therapy strategies and aiding rGBM diagnosis and prognosis.

PMID:37727644 | PMC:PMC10506677 | DOI:10.22088/IJMCM.BUMS.11.4.306

Ther Drug Monit. 2023 Jul 13. doi: 10.1097/FTD.0000000000001113. Online ahead of print.

ABSTRACT

BACKGROUND: Cisplatin is commonly used to treat solid tumors; however, its use can be complicated by drug-induced hearing loss (ie, ototoxicity). The presence of certain genetic variants has been associated with the development/occurrence of cisplatin-induced ototoxicity, suggesting that genetic factors may be able to predict patients who are more likely to develop ototoxicity. The authors aimed to review genetic associations with cisplatin-induced ototoxicity and discuss their clinical relevance.

METHODS: An updated systematic review was conducted on behalf of the Canadian Pharmacogenomics Network for Drug Safety, based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 statement. Pharmacogenomic studies that reported associations between genetic variation and cisplatin-induced ototoxicity were included. The evidence on genetic associations was summarized and evaluated, and knowledge gaps that can be used to inform future pharmacogenomic studies identified.

RESULTS: Overall, 40 evaluated reports, considering 47 independent patient populations, captured associations involving 24 genes. Considering GRADE criteria, genetic variants in 2 genes were strongly (ie, odds ratios ≥3) and consistently (ie, replication in ≥3 independent populations) predictive of cisplatin-induced ototoxicity. Specifically, an ACYP2 variant has been associated with ototoxicity in both children and adults, whereas TPMT variants are relevant in children. Encouraging evidence for associations involving several other genes also exists; however, further research is necessary to determine potential clinical relevance.

CONCLUSIONS: Genetic variation in ACYP2 and TPMT may be helpful in predicting patients at the highest risk of developing cisplatin-induced ototoxicity. Further research (including replication studies considering diverse pediatric and adult patient populations) is required to determine whether genetic variation in additional genes may help further identify patients most at risk.

PMID:37726872 | DOI:10.1097/FTD.0000000000001113

Pharmacogenomics J. 2023 Sep 19. doi: 10.1038/s41397-023-00316-9. Online ahead of print.

ABSTRACT

Personalized medicine is a novel frontier in health care that is based on each person's unique genetic makeup. It represents an exciting opportunity to improve the future of individualized health care for all individuals. Pharmacogenomics, as the main part of personalized medicine, aims to optimize and create a more targeted treatment approach based on genetic variations in drug response. It is predicted that future treatments will be algorithm-based instead of evidence-based that will consider a patient's genetic, transcriptomic, proteomic, epigenetic, and lifestyle factors resulting in individualized medication. A generative pretrained transformer (GPT) is an artificial intelligence (AI) tool that generates language resembling human-like writing enabling users to engage in a manner that is practically identical to speaking with a human being. GPT's predictive algorithms can respond to questions that have never been addressed. Chat Generative Pretrained Transformer (ChatGPT) is an AI chatbot's advanced with conversational capabilities. In the present study, questions were asked from ChatGPT about the future of personalized medicine and pharmacogenomics. ChatGPT predicted both to be a promising approach with a bright future that holds great promises in improving patient outcomes and transforming the field of medicine. But it still has several limitations that need to be solved.

PMID:37726551 | DOI:10.1038/s41397-023-00316-9

Pharm Res. 2023 Sep 19. doi: 10.1007/s11095-023-03603-z. Online ahead of print.

ABSTRACT

AIMS: Dasatinib, a second-generation tyrosine kinase inhibitor of BCR-ABL 1, used for first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML), exhibits high pharmacokinetic (PK) variability. However, its PK data in Chinese patients with CML remains rarely reported to date. Thus, we developed a population pharmacokinetic (PPK) model of dasatinib in Chinese patients and identified the covariate that could explain the individual variability of PK for optimal individual administration.

METHODS: PPK modeling for dasatinib was performed based on 754 plasma concentrations obtained from 140 CML patients and analysis of various genetic and physicochemical parameters. Modeling was performed with nonlinear mixed-effects (NLME) using Phoenix NLME. The finally developed model was evaluated using internal and external validation. Monte Carlo simulations were used to predict drug exposures at a steady state for various dosages.

RESULTS: The PK of dasatinib were well described by a two-compartment with a log-additive residual error model. Patients in the current study had a relatively low estimate of CL/F (126 L/h). A significant association was found between the covariate of age and CL/F of dasatinib, which was incorporated into the final model. None of the genetic factors was confirmed as a significant covariate for dasatinib. The results of external validation with 140 samples from 36 patients were acceptable. Simulation results showed significantly higher exposures in elderly patients.

CONCLUSIONS: This study's findings suggested that low-dose dasatinib would be better suited for Chinese patients, and the dosage can be appropriately reduced according to the increase of age, especially for the elderly.

PMID:37726405 | DOI:10.1007/s11095-023-03603-z