Kinase Inhibitors FDA Approved 2018–2023: Drug Targets, Metabolic Pathways, and Drug-Induced Toxicities

Drug Metabolism and Disposition, Год журнала: 2024, Номер 52(6), С. 479 - 492

Опубликована: Янв. 29, 2024

Small molecule kinase inhibitors are one of the fastest growing classes drugs, which approved by US Food and Drug Administration (FDA) for cancer non-cancer indications. As September 2023, there were over 70 FDA-approved small on market, 42 in past five years (2018-2023). This minireview discusses recent advances our understanding pharmacology, metabolism, toxicity profiles recently with a central focus tyrosine (TKIs). In this we discuss most common therapeutic indications molecular target(s) 2018-2023. We also describe unique aspects bioactivation, drug-drug interaction (DDI) potential inhibitors; drug concerns related to inhibitors, such as drug-induced liver injury; highlight clinical outcomes challenges relevant TKI therapy. Case examples provided targets, metabolism pathways, DDI potential, risks serious adverse reactions. The concludes discussion perspectives future research optimize therapy maximize efficacy minimize toxicity. Significance Statement highlights important pharmacology toxicology key targets major pathways TKIs discussed. Clinically case that demonstrate risk hepatotoxic interactions involving co-administered drugs.

Язык: Английский

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Therapeutic development targeting host heparan sulfate proteoglycan in SARS-CoV-2 infection

Frontiers in Medicine, Год журнала: 2024, Номер 11

Опубликована: Март 27, 2024

The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an urgent need for effective therapeutic options. SARS-CoV-2 is a novel responsible COVID-19 that resulted in significant morbidity and mortality worldwide. virus known enter host cells binding angiotensin-converting enzyme (ACE2) receptor, emerging evidence suggests heparan sulfate proteoglycans (HSPGs) play crucial role facilitating this process. HSPGs are abundant cell surface proteoglycan present many tissues, including lung, have been shown interact directly with spike protein of SARS-CoV-2. This review aims summarize current understanding infection potential developing new therapies targeting HSPGs.

Язык: Английский

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Strategies for mitigating adverse events related to selective RET inhibitors in patients with RET-altered cancers

Cell Reports Medicine, Год журнала: 2023, Номер 4(12), С. 101332 - 101332

Опубликована: Дек. 1, 2023

The US Food and Drug Administration (FDA) approval of the selective RET inhibitors selpercatinib pralsetinib has led to a paradigm change in treatment RET-altered lung thyroid cancers through higher response rate more tolerable safety toxicity profile than multi-kinase inhibitors. Recently, received tissue-agnostic FDA for all RET-fusion-positive cancers, shown pan-cancer activity as well. Given anticipated increase use both drugs across multiple tumor types, it is crucial recognize possible side effects approaches their optimal management order maximize clinical benefit treated patients. In this review, we underscore potential toxicities associated with discuss strategies mitigate them.

Язык: Английский

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Oral antivirals for COVID-19 among patients with cancer

Supportive Care in Cancer, Год журнала: 2024, Номер 32(8)

Опубликована: Июль 9, 2024

Язык: Английский

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A Simple and Rapid LC-MS/MS Method for the Quantification of Nirmatrelvir/Ritonavir in Plasma of Patients with COVID-19

International Journal of Analytical Chemistry, Год журнала: 2024, Номер 2024, С. 1 - 9

Опубликована: Март 6, 2024

The combined prescriptions of nirmatrelvir/ritonavir and other drugs are limited due to potential drug-drug interactions, so therapeutic drug monitoring (TDM) becomes particularly important. In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for determination the in plasma patients with COVID-19, providing technical theoretical support TDM. Plasma samples were processed by protein precipitation using acetonitrile, analytes separated on an Agilent Poroshell 120 SB-C18 (2.1 × 75 mm, 2.7 μm) column at 35°C. Acetonitrile 0.1% formic acid water (52 : 48) utilized as mobile phases flow rate 0.3 mL/min. multiple reaction (MRM) mode, nirmatrelvir ritonavir monitored precursor/product ions: m/z 500.2/110.1 721.3/296.1, respectively, selinexor internal standard. linear range both 2.0 ng/mL 5000 good inter- intraday precision accuracy, recovery 92.0%-107% 85.7%-106% ritonavir. Finally, successfully applied monitor exposure levels from hemodialysis patients.

Язык: Английский

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Predictors of nirmatrelvir–ritonavir receipt among COVID-19 patients in a large US health system

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Март 29, 2024

Abstract A clear understanding of real-world uptake nirmatrelvir–ritonavir for treatment SARS-CoV-2 can inform allocation strategies and improve interpretation effectiveness studies. We used data from a large US healthcare system to describe dispenses among all positive patients aged ≥ 12 years meeting recommended National Institutes Health eligibility criteria the study period between 1 January 31 December, 2022. Overall, 10.9% (N = 34,791/319,900) eligible with infections received over period. Although increased time, by end 2022, less than quarter had nirmatrelvir–ritonavir. Across patient demographics, was generally consistent tiered guidelines, concentrated 65 (14,706/63,921; 23.0%), multiple comorbidities (10,989/54,431; 20.1%). However, neighborhoods lower socioeconomic status (upper third neighborhood deprivation index [NDI]) 12% (95% CI: 7–18%) 28% (25–32%) odds dispense time periods studied compared NDI distribution, even after accounting demographic clinical characteristics. limited chart review 40) confirmed that in some cases decision not treat appropriate aligned national guidelines use judgement on case-by-case basis. There is need enhance provider awareness availability benefits COVID-19 illness.

Язык: Английский

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Remarkable response to low dose of selpercatinib in a patient with RET-rearranged non-small cell lung cancer.

Respiratory Medicine Case Reports, Год журнала: 2025, Номер 53, С. 102176 - 102176

Опубликована: Янв. 1, 2025

Chromosomal rearrangements of the RET (rearranged during transfection) gene are detected in approximately 1-2% non-small cell lung cancers (NSCLC) and have function as oncogenic driver genes. Selpercatinib is a highly effective inhibitor for RET-rearranged patients with NSCLC shows mostly tolerable adverse events. However, hypertension, aspartate aminotransferase increase, alanine increase most common events, dose modification or discontinuation required occasionally. Here, we describe case who has response to 40 mg selpercatinib every other day because had be adjusted owing events such liver dysfunction. Dose selpercatinib, according event incidences, may considered, some cases even at very low concentrations.

Язык: Английский

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Non-enzymatic protein targeting agents as a promising strategy for cancer treatment

Frontiers in Drug Discovery, Год журнала: 2025, Номер 5

Опубликована: Янв. 29, 2025

Increased research attention has been brought to non-enzymatic protein targeting agents as a new and effective strategy for advancing cancer treatment. To discover this class of anticancer drugs, two molecular approaches the activities proteins have shown promising experimental, preclinical, clinical results. In first approach, selective known PROteolysis-TArgeting Chimeras (PROTACs) employ innate endogenous degradation machinery in cells proteolyze targeted protein. The combination highly PROTACs exploitation cellular pathways provides opportunity treat diseases that were previously deemed incurable due lack enzymatic proteins. second approach targets protein-protein interactions (PPIs) an alternative route alters functional complexes thus significantly influence cell fitness survival. efficiently identify potential chemical leads these approaches, high-throughput screening (HTS) extremely valuable its ability quickly screen large libraries compounds. review paper, we will provide overview developing anti-cancer impact inhibitors.

Язык: Английский

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Efficacy and safety of azvudine versus nirmatrelvir/ritonavir in cancer patients with COVID-19

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Март 31, 2025

Cancer significantly contributes to the unfavorable prognosis of coronavirus disease 2019 (COVID-19) patients. The efficacy and safety azvudine nirmatrelvir/ritonavir (Paxlovid) in cancer patients with COVID-19 remain uncertain. Therefore, we designed a comprehensive retrospective study encompassing clinical data 32,864 hospitalized patients, 691 whom were treated 200 Paxlovid. After 2:1 propensity score matching, 397 group 199 Paxlovid enrolled. Cox regression analysis revealed risk all-cause death (HR: 1.84, 95% CI: 1.059–3.182, P = 0.030) composite progression 1.70, 1.043–2.757, 0.033) greater than group. Two sensitivity analyses confirmed robustness our findings. adverse events no statistically significant differences between two groups. In conclusion, carried out first compare demonstrated that reduced among compared

Язык: Английский

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Development and application of a UHPLC-MS/MS method for the simultaneous determination of firmonertinib and its main metabolite AST-5902 in rat plasma: a study on the in vivo drug interaction between firmonertinib and paxlovid

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Май 12, 2025

Due to the potential occurrence of drug interactions, combined application firmonertinib and paxlovid carries a relatively high risk. Nevertheless, as now, there has been no comprehensive research on interaction between paxlovid. Our aim was establish validate an accurate, stable, rapid simple UPLC-MS/MS method for simultaneous determination its metabolite AST-5902 in rat plasma, which applied study vivo Gefitinib selected internal standard. After protein precipitation plasma samples with acetonitrile, separation carried out Shimadzu LC-20AT UHPLC. The chromatographic column Shim-pack Volex PFPP (50 mm × 2.1 mm, 1.8 μm), mobile phase composed 0.1% formic acid - water methanol. Mass spectrometry detection performed using 8,040 mass spectrometer ESI+ MRM mode. precision, accuracy, recovery matrix effect this were detected. linearity stability assessed. Subsequently, parent ions typical fragment firmonertinib, IS are respectively m/z 569.25 → 72.15, 555.50 498.10 447.25→ 128.20. selectivity, specificity, linearity, recovery, effect, accuracy precision all adequately verified. results showed that when paxlovid, AUC Cmax significantly increased, while AUC, Tmax, decreased. established UHPLC-MS/MS is simple. Paxlovid exhibit significant inhibitory metabolism rats.

Язык: Английский

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