Subject(s)
Anticonvulsants , Lamotrigine , Topiramate , Valproic Acid , Humans , Lamotrigine/therapeutic use , Lamotrigine/adverse effects , Topiramate/therapeutic use , Topiramate/adverse effects , Valproic Acid/therapeutic use , Valproic Acid/adverse effects , Anticonvulsants/therapeutic use , Anticonvulsants/adverse effects , Female , Autistic Disorder/drug therapy , Male , Child , Fructose/analogs & derivatives , Fructose/adverse effects , Fructose/therapeutic use , Triazines/therapeutic use , Triazines/adverse effects , Child, PreschoolABSTRACT
Baloxavir marboxil (baloxavir), approved as an anti-influenza drug in Japan in March 2018, can induce reduced therapeutic effectiveness due to PA protein substitutions. We assessed PA substitutions in clinical samples from influenza-infected children and adults pre- and post-baloxavir treatment, examining their impact on fever and symptom duration. During the 2022-2023 influenza season, the predominant circulating influenza subtype detected by cycling-probe RT-PCR was A(H3N2) (n = 234), with a minor circulation of A(H1N1)pdm09 (n = 10). Of the 234 influenza A(H3N2) viruses collected prior to baloxavir treatment, 2 (0.8%) viruses carry PA/I38T substitution. One virus was collected from a toddler and one from an adult, indicating the presence of viruses with reduced susceptibility to baloxavir, without prior exposure to the drug. Of the 54 paired influenza A(H3N2) viruses collected following baloxavir treatment, 8 (14.8%) viruses carried E23 K/G, or I38 M/T substitutions in PA. Variant calling through next-generation sequencing (NGS) showed varying proportions (6-100 %), a polymorphism and a mixture of PA/E23 K/G, and I38 M/T substitutions in the clinical samples. These eight viruses were obtained from children aged 7-14 years, with a median fever duration of 16.7 h and a median symptom duration of 93.7 h, which were similar to those of the wild type. However, the delayed viral clearance associated with the emergence of PA substitutions was observed. No substitutions conferring resistance to neuraminidase inhibitors were detected in 37 paired samples collected before and following oseltamivir treatment. These findings underscore the need for ongoing antiviral surveillance, informing public health strategies and clinical antiviral recommendations for seasonal influenza.
Subject(s)
Amino Acid Substitution , Antiviral Agents , Dibenzothiepins , Drug Resistance, Viral , Influenza A Virus, H3N2 Subtype , Influenza, Human , Morpholines , Pyridones , Triazines , Viral Proteins , Humans , Dibenzothiepins/therapeutic use , Dibenzothiepins/pharmacology , Influenza, Human/drug therapy , Influenza, Human/virology , Influenza A Virus, H3N2 Subtype/genetics , Influenza A Virus, H3N2 Subtype/drug effects , Influenza A Virus, H3N2 Subtype/enzymology , Triazines/therapeutic use , Triazines/pharmacology , Japan , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Morpholines/therapeutic use , Drug Resistance, Viral/genetics , Child , Adult , Child, Preschool , Adolescent , Viral Proteins/genetics , RNA-Dependent RNA Polymerase/genetics , Female , Male , Thiepins/therapeutic use , Thiepins/pharmacology , Infant , Middle Aged , Seasons , Pyridines/therapeutic use , Pyridines/pharmacology , Young Adult , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/drug effects , AgedABSTRACT
PURPOSE: This phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: In phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200-400 mg bid plus nazartinib 50-150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1-3 prior lines; EGFRL858R/ex19del; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0-2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFRL858R/ex19del; T790M-; any MET); group 4 (with food; 0-2 prior lines; EGFRL858R/ex19del; any T790M/MET). Primary endpoints in phase 2 were investigator-assessed overall response rate (ORR) per RECIST v1.1 (groups 1-3), safety, and tolerability of the combination with food (group 4). Efficacy was assessed by T790M and MET status for a subgroup of patients. RESULTS: The RP2D was capmatinib 400 mg bid plus nazartinib 100 mg qd. In phase 2 (n = 144), the ORR was 28.8 %, 33.3 %, 61.7 %, and 42.9 % in groups 1 (n = 52), 2 (n = 3), 3 (n = 47), and 4 (n = 42), respectively. In group 1 +phase 1b RP2D, the ORR was 45.8 %, 26.2 %, 37.9 %, and 32.4 % in MET+ (n = 24), MET- (n = 42), T790M+ (n = 29), and T790M- (n = 34) patients. Most common any-grade treatment-related adverse events (≥25 %; n = 144) were peripheral edema (54.9 %), nausea (41.7 %), diarrhea (34.0 %), and maculopapular rash (25.0 %). CONCLUSION: Capmatinib plus nazartinib showed antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC. The overall safety profile was acceptable. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02335944.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Lung Neoplasms , Mutation , Triazines , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Male , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Female , ErbB Receptors/genetics , ErbB Receptors/antagonists & inhibitors , Middle Aged , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Triazines/administration & dosage , Triazines/therapeutic use , Triazines/adverse effects , Adult , Benzamides/administration & dosage , Benzamides/adverse effects , Benzamides/therapeutic use , Aged, 80 and over , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/therapeutic use , ImidazolesABSTRACT
BACKGROUND: KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions. METHODS: Cell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model. RESULTS: Our research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression. CONCLUSIONS: We posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Mutation , Omeprazole , Proto-Oncogene Proteins c-met , Proto-Oncogene Proteins p21(ras) , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/metabolism , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Proto-Oncogene Proteins p21(ras)/genetics , Cell Line, Tumor , Animals , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/metabolism , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Omeprazole/pharmacology , Omeprazole/therapeutic use , Mice , Pyridines/pharmacology , Pyridines/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Xenograft Model Antitumor Assays , Mice, Nude , Pyrimidinones/pharmacology , Pyrimidinones/therapeutic use , Female , Triazines/pharmacology , Triazines/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Piperazines , Piperidines , Pyridazines , PyridonesABSTRACT
BACKGROUND: This study provides comparative evidence of the selective MET inhibitor capmatinib versus standard of care (SOC) in first-line (1 L) and second-line (2 L) non-small cell lung cancer (NSCLC) patients with METex14 mutations in German routine care. METHODS: SOC data were collected from German routine care via retrospective chart review. Analyses were conducted as naive and propensity score adjusted (PSA) comparisons to capmatinib-treated patients within the GEOMETRY mono-1 trial. Effectiveness endpoints included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), time to CNS progression (CNSprog), and exploratory safety endpoints. RESULTS: The SOC arm included 119 patients in 1 L and 46 in 2 L versus 60 patients in 1 L and 81 in 2 L treated with capmatinib, with balanced baseline characteristics after PSA. In 1 L, the naive comparison showed a significant benefit of capmatinib versus SOC for OS (median: 25.49 vs 14.59 months; HR 0.58; 95 % CI 0.39-0.87; P = 0.011), PFS (median: 12.45 vs 5.03 months; HR: 0.44; 95 % CI: 0.31-0.63; P < 0.001), and ORR (event rate: 68.3 vs 26.9 %; RR 2.54; 95 % CI 1.80-3.58; P < 0.001). In 2 L, OS, PFS, and ORR showed positive trends favoring capmatinib over SOC. Capmatinib treatment in the 1 L and 2 L led to significant benefit in CNSprog. PSA analyses showed consistent results to naive analysis. Exploratory safety endpoints indicated a manageable safety profile for capmatinib. CONCLUSIONS: The present study demonstrates the important role of capmatinib in providing robust clinically meaningful benefit to patients with NSCLC harboring METex14 mutations and its significant role in preventing the development of brain metastases.
Subject(s)
Benzamides , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Mutation , Proto-Oncogene Proteins c-met , Triazines , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Male , Female , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Middle Aged , Aged , Benzamides/therapeutic use , Germany , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Triazines/therapeutic use , Triazines/adverse effects , Retrospective Studies , Adult , Aged, 80 and over , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , ImidazolesABSTRACT
We compared the duration of fever in children infected with A(H1N1)pdm09, A(H3N2), or influenza B viruses following treatment with baloxavir marboxil (baloxavir) or neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, or laninamivir). This observational study was conducted at 10 outpatient clinics across 9 prefectures in Japan during the 2012-2013 and 2019-2020 influenza seasons. Patients with influenza rapid antigen test positive were treated with one of four anti-influenza drugs. The type/subtype of influenza viruses were identified from MDCK or MDCK SIAT1 cell-grown samples using two-step real-time PCR. Daily self-reported body temperature after treatment were used to evaluate the duration of fever by treatment group and various underlying factors. Among 1742 patients <19 years old analyzed, 452 (26.0%) were A(H1N1)pdm09, 827 (48.0%) A(H3N2), and 463 (26.0%) influenza B virus infections. Among fours treatment groups, baloxavir showed a shorter median duration of fever compared to oseltamivir in univariate analysis for A(H1N1)pdm09 virus infections (baloxavir, 22.0 h versus oseltamivir, 26.7 h, P < 0.05; laninamivir, 25.5 h, and zanamivir, 25.0 h). However, this difference was not significant in multivariable analyses. For A(H3N2) virus infections, there were no statistically significant differences observed (20.3, 21.0, 22.0, and 19.0 h) uni- and multivariable analyses. For influenza B, baloxavir shortened the fever duration by approximately 15 h than NAIs (20.3, 35.0, 34.3, and 34.1 h), as supported by uni- and multivariable analyses. Baloxavir seems to have comparable clinical effectiveness with NAIs on influenza A but can be more effective for treating pediatric influenza B virus infections than NAIs.
Subject(s)
Antiviral Agents , Dibenzothiepins , Fever , Guanidines , Influenza A Virus, H1N1 Subtype , Influenza A Virus, H3N2 Subtype , Influenza B virus , Influenza, Human , Morpholines , Oseltamivir , Pyrans , Pyridones , Sialic Acids , Triazines , Zanamivir , Humans , Influenza, Human/drug therapy , Influenza, Human/virology , Antiviral Agents/therapeutic use , Antiviral Agents/pharmacology , Influenza B virus/drug effects , Influenza B virus/genetics , Child , Zanamivir/therapeutic use , Zanamivir/analogs & derivatives , Zanamivir/pharmacology , Triazines/therapeutic use , Triazines/pharmacology , Guanidines/therapeutic use , Influenza A Virus, H3N2 Subtype/drug effects , Influenza A Virus, H3N2 Subtype/genetics , Influenza A Virus, H1N1 Subtype/drug effects , Pyridones/therapeutic use , Dibenzothiepins/therapeutic use , Japan , Female , Male , Child, Preschool , Oseltamivir/therapeutic use , Fever/drug therapy , Fever/virology , Adolescent , Morpholines/therapeutic use , Infant , Seasons , Thiepins/therapeutic use , Thiepins/pharmacology , Oxazines/therapeutic use , Time Factors , Benzoxazines/therapeutic useABSTRACT
BACKGROUND: The transmission of influenza virus in households, especially by children, is a major route of infection. Prior studies suggest that timely antiviral treatment of ill cases may reduce infection in household contacts. The aim of the study was to compare the effects of oseltamivir (OTV) and baloxavir marboxil (BXM) treatment of index cases on the secondary attack rate (SAR) of influenza within household. METHODS: A post hoc analysis was done in BLOCKSTONE trial-a placebo-controlled, double-blinded post-exposure prophylaxis of BXM. Data were derived from the laboratory-confirmed index cases' household contacts who received placebo in the trial and also from household members who did not participate in the trial but completed illness questionnaires. To assess the SAR of household members, multivariate analyses adjusted for factors including age, vaccination status, and household size were performed and compared between contacts of index cases treated with BXM or OTV. RESULTS: In total, 185 index cases (116 treated with BXM and 69 treated with OTV) and 410 household contacts (201 from trial, 209 by questionnaire) were included. The Poisson regression modeling showed that the SAR in household contacts of index cases treated with BXM and OTV was 10.8% and 18.5%, respectively; the adjusted relative reduction in SAR was 41.8% (95% confidence interval: 1.0%-65.7%, p = 0.0456) greater with BXM than OTV. Similar reductions were found in contacts from the trial and those included by questionnaire. CONCLUSION: BXM treatment of index cases appeared to result in a greater reduction in secondary household transmission than OTV treatment.
Subject(s)
Antiviral Agents , Dibenzothiepins , Family Characteristics , Influenza, Human , Morpholines , Oseltamivir , Post-Exposure Prophylaxis , Pyridones , Triazines , Humans , Influenza, Human/drug therapy , Influenza, Human/prevention & control , Influenza, Human/transmission , Pyridones/therapeutic use , Antiviral Agents/therapeutic use , Triazines/therapeutic use , Dibenzothiepins/therapeutic use , Female , Male , Oseltamivir/therapeutic use , Adult , Adolescent , Child , Middle Aged , Young Adult , Post-Exposure Prophylaxis/methods , Child, Preschool , Morpholines/therapeutic use , Thiepins/therapeutic use , Double-Blind Method , Infant , Pyridines/therapeutic use , Aged , Oxazines/therapeutic useABSTRACT
INTRODUCTION: ZSP1601 is a novel pan-phosphodiesterase inhibitor developed in China specifically for the treatment of nonalcoholic fatty liver disease (NAFLD). AIM: The aim is to develop a population pharmacokinetic (pop PK) model for ZSP1601 by integrating data from two clinical studies. This undertaking aims to deepen our understanding of the clinical factors that influence ZSP1601 exposure while simultaneously investigating exposure-response (ER) relationships related to efficacy and safety. The goal is to guide formulating optimal dosage strategies in the subsequent phases of clinical trials. METHODS: Analysis of pooled concentration-time data from 95 subjects, with 2647 observations from two clinical trials involving healthy volunteers and NAFLD patients, employed a nonlinear mixed-effects modeling approach to characterize ZSP1601 pharmacokinetics. Covariate impact on ZSP1601 pharmacokinetics was investigated, and relationships between ZSP1601 exposure, efficacy and safety endpoints were explored. RESULTS: A two-compartment model featuring sequential zero-order then first-order absorption and first-order elimination effectively described ZSP1601's pharmacokinetic profile. Covariate analyses identified body weight as a statistically significant factor affecting drug central volume, while FED (food consumption) influenced absorption rate constant and duration. The Sigmoid Emax model aptly captured exposure-response relationships for ALT (alanine aminotransferase), AST (aspartate aminotransferase), and LFC (liver fat content) percentage changes relative to baseline and ZSP1601 exposure levels (AUCss) on the 29th day. ZSP1601 exposure levels (Cmax1) exhibited a significant exposure-response relationship with headaches (p < 0.001). CONCLUSION: The PopPK model and ER analysis, based on available data, comprehensively characterizes ZSP1601's pharmacokinetic, safety and efficacy profile, aiding informed decisions regarding dosage selection for the drug's complete developmental trajectory. The exposure-response (ER) analysis yields quantitative insights into the optimal balance of efficacy and safety within different dosage regimens for patient administration. In light of these findings, the dose regimen of 100 mg administered twice daily is proposed for subsequent clinical investigations.
Subject(s)
Dose-Response Relationship, Drug , Models, Biological , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/drug therapy , Male , Adult , Middle Aged , Female , Triazines/pharmacokinetics , Triazines/administration & dosage , Triazines/therapeutic use , Young Adult , Phosphodiesterase Inhibitors/pharmacokinetics , Phosphodiesterase Inhibitors/administration & dosageABSTRACT
With the increasing prevalence of type 2 diabetes mellitus (T2DM), it has become critical to identify effective treatment strategies. In recent years, the novel oral hypoglycaemic drug Imeglimin has attracted much attention in the field of diabetes treatment. The mechanisms of its therapeutic action are complex and are not yet fully understood by current research. Current evidence suggests that pancreatic ß-cells, liver, and skeletal muscle are the main organs in which Imeglimin lowers blood glucose levels and that it acts mainly by targeting mitochondrial function, thereby inhibiting hepatic gluconeogenesis, enhancing insulin sensitivity, promoting pancreatic ß-cell function, and regulating energy metabolism. There is growing evidence that the drug also has a potentially volatile role in the treatment of diabetic complications, including metabolic cardiomyopathy, diabetic vasculopathy, and diabetic neuroinflammation. According to available clinical studies, its efficacy and safety profile are more evident than other hypoglycaemic agents, and it has synergistic effects when combined with other antidiabetic drugs, and also has potential in the treatment of T2DM-related complications. This review aims to shed light on the latest research progress in the treatment of T2DM with Imeglimin, thereby providing clinicians and researchers with the latest insights into Imeglimin as a viable option for the treatment of T2DM.
Subject(s)
Diabetes Mellitus, Type 2 , Hypoglycemic Agents , Mitochondria , Humans , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Animals , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/pharmacology , Mitochondria/drug effects , Mitochondria/metabolism , Blood Glucose/drug effects , Blood Glucose/metabolism , Triazines/therapeutic use , Triazines/pharmacologyABSTRACT
It is imperative to optimize chemotherapy for heightened anti-tumor therapeutic efficacy. Unrestrained tumor cell proliferation and sustained angiogenesis are pivotal for cancer progression. Plinabulin, a vascular disrupting agent, selectively destroys tumor blood vessels. Tirapazamine (TPZ), a hypoxia-activated prodrug, intensifies cytotoxicity in diminishing oxygen levels within tumor cells. Despite completing Phase III clinical trials, both agents exhibited modest treatment efficiency due to dose-limiting toxicity. In this study, we employed methoxy poly(ethylene glycol)-b-poly(D,L-lactide) (mPEG-b-PDLLA) to co-deliver Plinabulin and TPZ to the tumor site, concurrently disrupting blood vessels and eliminating tumor cells, addressing both symptoms and the root cause of tumor progression. Plinabulin was converted into a prodrug with esterase response (PSM), and TPZ was synthesized into a hexyl chain-containing derivative (TPZHex) for effective co-delivery. PSM and TPZHex were co-encapsulated with mPEG-b-PDLLA, forming nanodrugs (PT-NPs). At the tumor site, PT-NPs responded to esterase overexpression, releasing Plinabulin, disrupting blood vessels, and causing nutritional and oxygen deficiency. TPZHex was activated in response to increased hypoxia, killing tumor cells. In treating 4T1 tumors, PT-NPs demonstrated enhanced therapeutic efficacy, achieving a 92.9 % tumor suppression rate and a 20 % cure rate. This research presented an innovative strategy to enhance synergistic efficacy and reduce toxicity in combination chemotherapy.
Subject(s)
Polyethylene Glycols , Tirapazamine , Tirapazamine/pharmacology , Animals , Cell Line, Tumor , Humans , Polyethylene Glycols/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Female , Mice , Mice, Inbred BALB C , Neovascularization, Pathologic/drug therapy , Triazines/pharmacology , Triazines/chemistry , Triazines/therapeutic use , DiketopiperazinesABSTRACT
MET exon14 skipping mutations (METex14s) are rarely reported as a potential resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs). The efficacy of targeted therapy against METex14s emerging after osimertinib resistance is uncertain. Herein, we report a case of EGFR-mutated metastatic lung adenocarcinoma in which METex14 was detected in a re-biopsy upon first-line osimertinib resistance. The patient received capmatinib monotherapy as third-line therapy, which was ineffective, followed by an exceptional response to salvage therapy with afatinib. This report highlights the heterogeneity of EGFR-TKI resistance and that targeting rare resistance mechanisms remains challenging.
Subject(s)
Acrylamides , Adenocarcinoma of Lung , Aniline Compounds , Drug Resistance, Neoplasm , ErbB Receptors , Lung Neoplasms , Proto-Oncogene Proteins c-met , Humans , Male , Acrylamides/therapeutic use , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/genetics , Afatinib/therapeutic use , Afatinib/administration & dosage , Aniline Compounds/therapeutic use , Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Drug Resistance, Neoplasm/genetics , ErbB Receptors/genetics , Exons/genetics , Imidazoles , Indoles , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-met/genetics , Pyrimidines , Salvage Therapy , Triazines/therapeutic use , Triazines/administration & dosageABSTRACT
The aberrant activation of the PI3K/mTOR signaling pathway is implicated in various human cancers. Thus, the development of inhibitors targeting mTOR has attracted considerable attention. In this study, we used a structure-based drug design strategy to discover a highly potent and kinase-selective mTOR inhibitor 24 (PT-88), which demonstrated an mTOR inhibitory IC50 value of 1.2 nM without obvious inhibition against another 195 kinases from the kinase profiling screening. PT-88 displayed selective inhibition against MCF-7 cells (IC50: 0.74 µM) with high biosafety against normal cells, in which autophagy induced by mTOR inhibition was implicated. After successful encapsulation in a lipodisc formulation, PT-88 demonstrated favorable pharmacokinetic and biosafety profiles and exerted a large antitumor effect in an MCF-7 subcutaneous bearing nude mice model. Our study shows the discovery of a highly selective mTOR inhibitor using a structure-based drug discovery strategy and provides a promising antitumor candidate for future study and development.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Drug Design , MTOR Inhibitors , Mice, Nude , TOR Serine-Threonine Kinases , Triazines , Humans , Animals , Triazines/chemical synthesis , Triazines/pharmacology , Triazines/chemistry , Triazines/pharmacokinetics , Triazines/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Female , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Mice , MTOR Inhibitors/pharmacology , MTOR Inhibitors/chemical synthesis , MTOR Inhibitors/therapeutic use , MTOR Inhibitors/chemistry , Structure-Activity Relationship , MCF-7 Cells , Cell Proliferation/drug effects , Xenograft Model Antitumor Assays , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacokinetics , Mice, Inbred BALB C , Autophagy/drug effectsABSTRACT
Limited treatment options are available for patients with relapsed/refractory acute myeloid leukemia (R/R AML). We recently reported results from the phase 3 IDHENTIFY trial (NCT02577406) showing improved response rates and event-free survival with enasidenib monotherapy compared with conventional care regimens (CCR) in heavily pretreated, older patients with late-stage R/R AML bearing IDH2 mutations. Here we investigated the prognostic impact of mutational burden and different co-mutation patterns at study entry within the predominant IDH2 variant subclasses, IDH2-R140 and IDH2-R172. The prognostic relevance of these variants is well documented in newly diagnosed AML, but data are lacking in R/R AML. In this large R/R AML patient cohort, targeted next-generation sequencing at baseline (screening) revealed distinct co-mutation patterns and mutational burden between subgroups bearing different IDH2 variants: variant IDH2-R140 was associated with greater mutational burden and was enriched predominantly with poor-risk mutations, including FLT3, RUNX1, and NRAS, while variant IDH2-R172 was associated with lower mutational burden and was preferentially co-mutated with DNMT3A. In multivariable analyses, RAS and RTK pathway mutations were significantly associated with decreased overall survival, after adjusting for treatment arm, IDH2 variant, and mutational burden. Importantly, enasidenib-mediated survival benefit was more pronounced in patients with IDH2-R172 variants.
Subject(s)
Isocitrate Dehydrogenase , Leukemia, Myeloid, Acute , Mutation , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Aminopyridines/therapeutic use , Drug Resistance, Neoplasm/genetics , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Prognosis , Triazines/therapeutic useABSTRACT
As a selective and potent inhibitor targeting the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib obtained approval from the US Food and Drug Administration (FDA) in 2017 for adult patients with acute myeloid leukemia (AML) with an IDH2 mutation. In vitro investigations demonstrated that enasidenib affects various drug metabolic enzymes and transporters. This current investigation aimed to assess enasidenib on the pharmacokinetics (PKs) of CYP substrates, including dextromethorphan (CYP2D6 probe drug), flurbiprofen (CYP2C9 probe drug), midazolam (CYP3A4 probe drug), omeprazole (CYP2C19 probe drug), and pioglitazone (CYP2C8 probe drug), in patients with AML or myelodysplastic syndrome. Results showed that following the co-administration of enasidenib (100 mg, once daily) for 28 days, the PK parameters AUC(0-∞) and Cmax of dextromethorphan increased by 1.37 (90% confidence interval (CI): 0.96, 1.96) and 1.24 (90% CI: 0.94, 1.65)-fold, respectively, compared to dextromethorphan alone. For flurbiprofen, these parameters increased by 1.14 (90%CI: 1.01, 1.29) and 0.97 (90% CI 0.86, 1.08)-fold, respectively, when compared to flurbiprofen alone. Conversely, midazolam exhibited decreases to 0.57 (90% CI 0.34, 0.97) and 0.77 (90% CI 0.39, 1.53)-fold, respectively, in comparison to midazolam alone. The parameters for omeprazole increased by 1.86 (90% CI: 1.33, 2.60) and 1.47 (0.93, 2.31)-fold, respectively, compared to omeprazole alone, while those for pioglitazone decreased to 0.80 (90% CI: 0.62, 1.03) and 0.87 (90% CI: 0.65, 1.16)-fold, respectively, in comparison to pioglitazone alone. These findings provide valuable insights into dose recommendations concerning drugs acting as substrates of CYP2D6, CYP2C9, CYP3A4, CYP2C19, and CYP2C8 when administered concurrently with enasidenib.
Subject(s)
Dextromethorphan , Drug Interactions , Leukemia, Myeloid, Acute , Midazolam , Myelodysplastic Syndromes , Pioglitazone , Pyridines , Humans , Male , Middle Aged , Leukemia, Myeloid, Acute/drug therapy , Female , Aged , Myelodysplastic Syndromes/drug therapy , Midazolam/pharmacokinetics , Pioglitazone/pharmacokinetics , Pioglitazone/pharmacology , Dextromethorphan/pharmacokinetics , Dextromethorphan/administration & dosage , Pyridines/pharmacokinetics , Pyridines/administration & dosage , Flurbiprofen/pharmacokinetics , Flurbiprofen/administration & dosage , Flurbiprofen/analogs & derivatives , Triazines/pharmacokinetics , Triazines/therapeutic use , Triazines/administration & dosage , Adult , Omeprazole/pharmacokinetics , Omeprazole/administration & dosage , Cytochrome P-450 Enzyme System/metabolism , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/administration & dosage , Recurrence , Aged, 80 and over , AminopyridinesABSTRACT
Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic bunyavirus with a fatality rate of up to 40%. Currently, there are no licensed antiviral drugs for the treatment of CCHF; thus, the World Health Organization (WHO) listed the disease as a priority. A unique viral transcription initiation mechanism called "cap-snatching" is shared by influenza viruses and bunyaviruses. Thus, we tested whether baloxavir (an FDA-approved anti-influenza drug that targets the "cap-snatching" mechanism) could inhibit CCHFV infection. In cell culture, baloxavir acid effectively inhibited CCHFV infection and targeted CCHFV RNA transcription/replication. However, it has weak oral bioavailability. Baloxavir marboxil (the oral prodrug of baloxavir) failed to protect mice against a lethal dose challenge of CCHFV. To solve this problem, baloxavir sodium was synthesized owing to its enhanced aqueous solubility and pharmacokinetic properties. It consistently and significantly improved survival rates and decreased tissue viral loads. This study identified baloxavir sodium as a novel scaffold structure and mechanism of anti-CCHF compound, providing a promising new strategy for clinical treatment of CCHF after further optimization.
Subject(s)
Antiviral Agents , Dibenzothiepins , Morpholines , Pyridines , Pyridones , Triazines , Virus Replication , Animals , Morpholines/pharmacology , Morpholines/pharmacokinetics , Morpholines/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/pharmacokinetics , Antiviral Agents/chemistry , Dibenzothiepins/pharmacology , Dibenzothiepins/pharmacokinetics , Mice , Pyridines/pharmacology , Pyridines/pharmacokinetics , Pyridines/chemistry , Virus Replication/drug effects , Triazines/pharmacology , Triazines/pharmacokinetics , Triazines/chemistry , Triazines/therapeutic use , Pyridones/pharmacology , Pyridones/pharmacokinetics , Pyridones/chemistry , Thiepins/pharmacology , Thiepins/therapeutic use , Thiepins/pharmacokinetics , Thiepins/chemistry , Viral Load/drug effects , Chlorocebus aethiops , Vero Cells , Female , Oxazines/pharmacology , Oxazines/pharmacokinetics , Oxazines/therapeutic use , Mice, Inbred BALB C , Humans , Thiazoles/pharmacology , Thiazoles/pharmacokinetics , Thiazoles/chemistryABSTRACT
BACKGROUND: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has lasted for three years. Coinfection with seasonal influenza may occur resulting in more severe diseases. The interaction between these two viruses for infection and the effect of antiviral treatment remains unclear. METHODS: A SARS-CoV-2 and influenza H1N1 coinfection model on Calu-3 cell line was established, upon which the simultaneous and sequential coinfection was evaluated by comparing the viral load. The efficacy of molnupiravir and baloxavir against individual virus and coinfection were also studied. RESULTS: The replication of SARS-CoV-2 was significantly interfered when the influenza virus was infected simultaneously or in advance (p < 0.05). On the contrary, the replication of the influenza virus was not affected by the SARS-CoV-2. Molnupiravir monotherapy had significant inhibitory effect on SARS-CoV-2 when the concentration reached to 6.25 µM but did not show any significant anti-influenza activity. Baloxavir was effective against influenza within the dosage range and showed significant effect of anti-SARS-CoV-2 at 16 µM. In the treatment of coinfection, molnupiravir had significant effect for SARS-CoV-2 from 6.25 µM to 100 µM and inhibited H1N1 at 100 µM (p < 0.05). The tested dosage range of baloxavir can inhibit H1N1 significantly (p < 0.05), while at the highest concentration of baloxavir did not further inhibit SARS-CoV-2, and the replication of SARS-CoV-2 significantly increased in lower concentrations. Combination treatment can effectively inhibit influenza H1N1 and SARS-CoV-2 replication during coinfection. Compared with molnupiravir or baloxavir monotherapy, combination therapy was more effective in less dosage to inhibit the replication of both viruses. CONCLUSIONS: In coinfection, the replication of SARS-CoV-2 would be interfered by influenza H1N1. Compared with molnupiravir or baloxavir monotherapy, treatment with a combination of molnupiravir and baloxavir should be considered for early treatment in patients with SARS-CoV-2 and influenza coinfection.
Subject(s)
Antiviral Agents , COVID-19 , Coinfection , Dibenzothiepins , Influenza A Virus, H1N1 Subtype , Influenza, Human , SARS-CoV-2 , Viral Load , Virus Replication , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Humans , SARS-CoV-2/drug effects , Influenza, Human/drug therapy , Influenza, Human/virology , Coinfection/drug therapy , Coinfection/virology , Virus Replication/drug effects , Dibenzothiepins/therapeutic use , Influenza A Virus, H1N1 Subtype/drug effects , COVID-19/virology , Viral Load/drug effects , Pyridones/pharmacology , Pyridones/therapeutic use , Cell Line , Morpholines/pharmacology , Morpholines/therapeutic use , Triazines/pharmacology , Triazines/therapeutic use , COVID-19 Drug Treatment , Hydroxylamines/pharmacology , Hydroxylamines/therapeutic use , Thiazoles/pharmacology , Thiazoles/therapeutic use , Cytidine/analogs & derivativesABSTRACT
INTRODUCTION: Selective tyrosine kinase inhibitors are proven effective in patients with non-small lung cancer (NSCLC) with a MET exon 14 skipping mutation. CASE PRESENTATION: The patient developed a metastatic lung adenocarcinoma with a MET exon 14 skipping mutation. She was treated with a first 1b MET inhibitor, Capmatinib, but had to stop the drug because of major hepatotoxicity. A few months later, she started Tepotinib, another 1b MET inhibitor with this time, no sign of hepatotoxicity. DISCUSSION: Adverse events are frequent with 1b MET inhibitors. However, there is a wide interpatient variability. Absence of cross-toxicity between Capmatinib and Tepotinib is misunderstood but can be explained by slight differences in phamarcodynamics and pharmacokinetics. Practitionners have to be warned about severe adverse events to stop or change the drug if necessary. CONCLUSION: This is the first case showing the absence of cross-toxicity between 1b MET inhibitors.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Exons , Lung Neoplasms , Mutation , Protein Kinase Inhibitors , Proto-Oncogene Proteins c-met , Humans , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Female , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Benzamides/therapeutic use , Benzamides/adverse effects , Pyrimidines/adverse effects , Pyrimidines/therapeutic use , Acrylamides/adverse effects , Acrylamides/therapeutic use , Triazines/adverse effects , Triazines/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Middle Aged , Pyridazines/adverse effects , Pyridazines/therapeutic use , Imidazoles , PiperidinesABSTRACT
ABSTRACT: Treatment with enasidenib, a selective mutant isocitrate dehydrogenase isoform 2 (IDH2) inhibitor, has been associated with the development of differentiation syndrome (DS) in patients with acute myeloid leukemia (AML). Studies on the incidence and clinical features of DS are limited in this setting, and diagnosis is challenging because of nonspecific symptoms. This study assessed the incidence, diagnostic criteria, risk factors, and correlation with clinical response of DS based on the pooled analysis of 4 clinical trials in patients with IDH2-mutated AML treated with enasidenib as monotherapy, or in combination with azacitidine or with chemotherapy. Across the total AML population, 67 of 643 (10.4%) had ≥1 any-grade DS event, with highest incidence in patients who received enasidenib plus azacitidine and lowest incidence in patients who received enasidenib plus chemotherapy (13/74 [17.6%] and 2/93 [2.2%]). The most common symptoms of DS were dyspnea/hypoxia (80.6%) and pulmonary infiltrate (73.1%). Median time to onset of first DS event across all studies was 32 days (range, 4-129). Most patients (88.1%) received systemic steroids for treatment of DS. Evaluation of baseline risk factors for DS identified higher levels of bone marrow blasts and lactate dehydrogenase as independent factors associated with increased grade 3 to 5 DS risk. Overall, these results suggest that DS associated with IDH inhibition is manageable, given the benefits of enasidenib treatment in IDH2-mutated AML. We further characterized enasidenib-related DS in these patients and identified risk factors, which could be used for DS management in clinical practice. These trials were registered at www.ClinicalTrials.gov as # NCT01915498, NCT02577406, NCT02677922, and NCT02632708.
Subject(s)
Aminopyridines , Isocitrate Dehydrogenase , Leukemia, Myeloid, Acute , Triazines , Humans , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Female , Middle Aged , Aminopyridines/therapeutic use , Aminopyridines/adverse effects , Triazines/therapeutic use , Triazines/adverse effects , Male , Aged , Adult , Mutation , Aged, 80 and over , Clinical Trials as Topic , Cell Differentiation/drug effectsABSTRACT
Influenza viruses (IFVs) have caused several pandemics and have claimed numerous lives since their first record in the early 20th century. While the outbreak of COVID-19 seemed to expel influenza from the sight of people for a short period of time, it is not surprising that it will recirculate around the globe after the coronavirus has mutated into a less fatal variant. Baloxavir marboxil (1), the prodrug of baloxavir (2) and a cap-dependent endonuclease (CEN) inhibitor, were approved by the FDA for the first treatment in almost 20 years. Despite their high antiviral potency, drug-resistant variants have been observed in clinical trials. Herein, we report a novel CEN inhibitor 8 with a delicately designed macrocyclic scaffold that exhibits a significantly smaller shift of inhibitory activity toward baloxavir-resistant variants.
Subject(s)
Dibenzothiepins , Influenza, Human , Morpholines , Thiepins , Humans , Influenza, Human/drug therapy , Oxazines/pharmacology , Pyridines/pharmacology , Endonucleases , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Thiepins/pharmacology , Thiepins/therapeutic use , Pyridones/pharmacology , Pyridones/therapeutic use , Triazines/pharmacology , Triazines/therapeutic useABSTRACT
Canine coccidiosis caused by Cystoisospora canis and Cystoisospora ohioensis-complex is common in kennels. While often underestimated, coccidiosis may cause severe clinical signs in puppies and sometimes even lead to death, so preventative measures are important. This study examines Cystoisospora spp. infection at a Labrador retriever breeding facility in Madrid, Spain. To identify environmental factors associated with infection, dams were examined throughout a reproductive cycle (from oestrus to 60 days postpartum) and their puppies during their first 60 days of life. Also assessed was the efficacy of combined treatment with emodepside (0.9 mg/ml) and toltrazuril (18 mg/ml) at a dose of 0.5 ml/kg of weight, equivalent to 0.45 mg/kg and 9 mg/kg, respectively, in puppies on day 35 of life. Oocyst shedding was detected in 4.6-18.6% of 45 dams examined and in 2.2-9.1% of their litters (315 puppies). In both cases, peak opg elimination was recorded on day 30 postpartum/of life. The species of Cystoisospora detected were C. canis (91.3%) and C. ohioensis-complex (8.7%). While in both dams and puppies opg counts were higher in autumn when rainfall was at its highest, correlation between opg and rainfall emerged as significant only in puppies (p = 0.031). The treatment of 35 day-old puppies with toltrazuril was 100% effective in controlling this infection in the kennel. Our findings therefore suggest the need for a strict hygiene regime and the use of toltrazuril as blanket treatment to reduce Cystoisospora transmission in dog breeding facilities.