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Artificial Organs Jun 2024Gastrointestinal bleeding (GIB) in patients with continuous flow left ventricular assist devices (CF-LVADs) is often related to GI angiodysplasia (GIAD). We previously...
BACKGROUND
Gastrointestinal bleeding (GIB) in patients with continuous flow left ventricular assist devices (CF-LVADs) is often related to GI angiodysplasia (GIAD). We previously reported data on VEGF inhibition with IV bevacizumab in the treatment of LVAD-associated GIAD bleeding, and now present follow-up data on patients treated with IV bevacizumab and/or low-dose oral pazopanib.
METHODS
All consecutive adult patients with LVAD-associated GIB from GIAD treated with bevacizumab or pazopanib, from July 20, 2017 to June 22, 2022, were included in the analysis. Data on hospitalizations, GI endoscopic procedures, and blood transfusions were obtained from first admission for GIB up to a median of 35.7 months following treatment initiation (range 1.3-59.8 months).
RESULTS
Eleven patients (91% male, mean 69.5 ± 8.9 years) were included. Eight patients (73%) received IV bevacizumab, two patients (18%) received oral pazopanib, and one patient (9%) received bevacizumab followed by pazopanib therapy. We observed a significantly decreased number of annualized hospitalizations for GIB (median difference - 2.87, p = 0.002), blood transfusions (median difference - 20.9, p = 0.01), and endoscopies (median difference - 6.95, p = 0.007) in patients pre- and post-anti-angiogenic therapy (bevacizumab and/or pazopanib). Similarly, a significant improvement in these clinical outcomes was noted in the bevacizumab group with decreased annualized hospitalizations (median difference - 2.75, p = 0.014), blood transfusions (median difference - 24.5, p = 0.047), and number of endoscopies (median differences -6.88, p = 0.006).
CONCLUSION
Anti-angiogenic therapy with IV bevacizumab and/or low-dose oral pazopanib appears to provide benefits in patients with LVAD-associated GIB with reduced hospitalizations, blood transfusions, and need for GI endoscopic procedures.
Topics: Humans; Male; Heart-Assist Devices; Female; Gastrointestinal Hemorrhage; Angiogenesis Inhibitors; Aged; Pyrimidines; Bevacizumab; Middle Aged; Sulfonamides; Indazoles; Retrospective Studies; Treatment Outcome; Angiogenesis
PubMed: 38131635
DOI: 10.1111/aor.14694 -
Journal of Oncology Pharmacy Practice :... Jan 2024Molecular multitargeted small tyrosine kinase inhibitory (TKI) agents such as axitinib, sunitinib and pazopanib are commonly used in several types of solid tumors....
INTRODUCTION
Molecular multitargeted small tyrosine kinase inhibitory (TKI) agents such as axitinib, sunitinib and pazopanib are commonly used in several types of solid tumors. Anemia is not a rare effect of these drugs which may occur at all grades. However, drug-induced immune hemolytic anemia (IHA), a very rare condition is distinctive from other types of anemia with its specific mechanism and management strategy.
CASE REPORTS
We reported three different TKI-induced IHA cases that occurred due to axitinib, sunitinib, and pazopanib, respectively. The first two cases were diagnosed with renal cell carcinoma and the last one was diagnosed with soft tissue sarcoma. They all presented with the characteristic symptoms of anemia and hemolysis. All the cases were detected positive for the complement C3d direct antiglobulin (direct coombs) test.
MANAGEMENT AND OUTCOMES
Discontinuation of the causative drug and 1 mg/kg/day dose of corticosteroid treatment were able to control IHA in all three cases. Excluding the other factors of IHA and an evident laboratory and clinical benefit after withholding the TKI led to the diagnosis of TKI-related IHA in each case.
DISCUSSION
TKIs are relatively new in clinical practice and are being used for more indications and in more patients. To our knowledge#these three cases are unique in terms of axitinib#sunitinib#and pazopanib-related IHA.
Topics: Humans; Anemia, Hemolytic; Axitinib; Carcinoma, Renal Cell; Indazoles; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Sunitinib; Tyrosine Kinase Inhibitors
PubMed: 37724017
DOI: 10.1177/10781552231202530 -
Bioactive Materials Jan 2024Atypical teratoid/rhabdoid tumor (ATRT) is a rare childhood malignancy that originates in the central nervous system. Over ninety-five percent of ATRT patients have...
Atypical teratoid/rhabdoid tumor (ATRT) is a rare childhood malignancy that originates in the central nervous system. Over ninety-five percent of ATRT patients have biallelic inactivation of the tumor suppressor gene . ATRT has no standard treatment, and a major limiting factor in therapeutic development is the lack of reliable ATRT models. We employed CRISPR/Cas9 gene-editing technology to knock out and genes in human episomal induced pluripotent stem cells (Epi-iPSCs), followed by brief neural induction, to generate an ATRT-like model. The dual knockout Epi-iPSCs retained their stemness with the capacity to differentiate into three germ layers. High expression of and in neurally induced knockout spheroids was comparable to that in two ATRT cell lines. Beta-catenin protein expression was higher in SMARCB1-deficient cells and spheroids than in normal Epi-iPSC-derived spheroids. Nucleophosmin, Osteopontin, and Ki-67 proteins were also expressed by the SMARCB1-deficient spheroids. In summary, the tumor model resembled embryonal features of ATRT and expressed ATRT biomarkers at mRNA and protein levels. Ribociclib, PTC-209, and the combination of clofilium tosylate and pazopanib decreased the viability of the ATRT-like cells. This disease modeling scheme may enable the establishment of individualized tumor models with patient-specific mutations and facilitate high-throughput drug testing.
PubMed: 37637078
DOI: 10.1016/j.bioactmat.2023.08.009 -
Journal of the Chinese Medical... Jan 2024Vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) are a common cancer treatment. However, the pharmacologic characteristics of VEGF-TKIs may... (Meta-Analysis)
Meta-Analysis
Major adverse cardiovascular events of vascular endothelial growth factor tyrosine kinase inhibitors among patients with different malignancy: A systemic review and network meta-analysis.
BACKGROUND
Vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) are a common cancer treatment. However, the pharmacologic characteristics of VEGF-TKIs may influence cardiovascular risks. The relative risks of major adverse cardiovascular events (MACEs) associated with VEGF-TKIs are poorly understood.
METHODS
We searched PubMed, Embase, and ClinicalTrials.gov from inception until August 31, 2021, for phase II/III randomized controlled trials of 11 VEGF-TKIs (axitinib, cabozantinib, lenvatinib, pazopanib, ponatinib, ripretinib, regorafenib, sorafenib, sunitinib, tivozanib, and vandetanib). The endpoints were heart failure, thromboembolism, and cardiovascular death. The Mantel-Haenszel method was used to calculate the risk of VEGF-TKI among users by comparing it to nonusers. Pairwise meta-analyses with a random-effects model were used to estimate the risks of the various VEGF-TKIs. We estimated ranked probability with a P-score and assessed credibility using the Confidence in Network Meta-Analysis framework.
RESULTS
We identified 69 trials involving 30 180 patients with cancer. The highest risk of MACEs was associated with high-potency tivazonib (odds ratio [OR]: 3.34), lenvatinib (OR: 3.26), and axitinib (OR: 2.04), followed by low-potency pazopanib (OR: 1.79), sorafenib (OR: 1.77), and sunitinib (OR: 1.66). The risk of heart failure significantly increased in association with less-selective sorafenib (OR: 3.53), pazopanib (OR: 3.10), and sunitinib (OR: 2.65). The risk of thromboembolism significantly increased in association with nonselective lenvatinib (OR: 3.12), sorafenib (OR: 1.54), and sunitinib (OR: 1.53). Higher potency (tivozanib, axitinib) and lower selectivity (sorafenib, vandetanib, pazopanib, sunitinib) were associated with a higher probability of heart failure. Low selectivity (lenvatinib, cabozantinib, sorafenib, sunitinib) was associated with a higher probability of thromboembolism.
CONCLUSION
Higher-potency and lower-selectivity VEGF-TKIs may influence the risks of MACEs, heart failure, and thromboembolism. These findings may facilitate evidence-based decision-making in clinical practice.
Topics: Humans; Sunitinib; Antineoplastic Agents; Vascular Endothelial Growth Factor A; Sorafenib; Tyrosine Kinase Inhibitors; Axitinib; Network Meta-Analysis; Protein Kinase Inhibitors; Neoplasms; Heart Failure; Thromboembolism
PubMed: 37991373
DOI: 10.1097/JCMA.0000000000001026 -
Nature Communications Jan 2024We aimed to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in metastatic...
We aimed to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in metastatic and/or recurrent soft tissue sarcoma (STS). In this single-arm phase 2 trial (NCT03798106), treatment consisted of pazopanib 800 mg orally once a day and durvalumab 1500 mg once every 3 weeks. Primary outcome was overall response rate (ORR) and secondary outcomes included progression-free survival (PFS), overall survival, disease control rate, immune-related response criteria, and safety. The ORR was 30.4% and the trial met the pre-specified endpoint. The median PFS was 7.7 months (95% confidence interval: 5.7-10.4). The common treatment-related adverse events of grades 3-4 included neutropenia (9 [19.1%]), elevated aspartate aminotransferase (7 [14.9%]), alanine aminotransferase (5 [10.6%]), and thrombocytopenia (4 [8.5%]). In a prespecified transcriptomic analysis, the B lineage signature was a significant key determinant of overall response (P = 0.014). In situ analysis also showed that tumours with high CD20 B cell infiltration and vessel density had a longer PFS (P = 6.5 × 10) than those with low B cell infiltration and vessel density, as well as better response (50% vs 12%, P = 0.019). CD20 B cell infiltration was identified as the only independent predictor of PFS via multivariate analysis. Durvalumab combined with pazopanib demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile.
Topics: Humans; Neoplasm Recurrence, Local; Sarcoma; Soft Tissue Neoplasms; Antibodies, Monoclonal; Indazoles; Pyrimidines; Sulfonamides
PubMed: 38263321
DOI: 10.1038/s41467-024-44875-2 -
Cancer Chemotherapy and Pharmacology Feb 2024Data on the effects of obesity on drug exposure of oral targeted oncolytics is scarce. Therefore, the aim of this study was to investigate the influence of body weight...
PURPOSE
Data on the effects of obesity on drug exposure of oral targeted oncolytics is scarce. Therefore, the aim of this study was to investigate the influence of body weight and body mass index (BMI) on trough levels of oral oncolytics with an exposure-response relationship. The oral oncolytics of interest were abiraterone, alectinib, cabozantinib, crizotinib, imatinib, pazopanib, sunitinib and trametinib.
METHODS
This retrospective cohort study included patients treated with the selected oral oncolytics at the standard dose, with a measured trough level at steady state and with available body weight. The Spearman's correlation test was used to determine the correlation between body weight and trough levels. The Fisher's exact text was used to compare the frequency of inadequate trough levels between BMI categories.
RESULTS
1265 patients were included across the different oral oncolytics. A negative correlation coefficient was observed between weight and trough levels for crizotinib (n = 75), imatinib (n = 201) and trametinib (n = 310), respectively, ρ = - 0.41, ρ = - 0.24 and ρ = - 0.23, all with a p-value < 0.001. For crizotinib, a higher percentage of patients with a body weight > 100 kg had inadequate trough levels. No statistically significant differences were observed in the frequency of inadequate trough levels between BMI categories.
CONCLUSION
Higher body weight was only correlated with lower plasma trough levels for crizotinib, imatinib, and trametinib. Therefore, patients with a high body weight may require dose escalation to obtain adequate target levels when treated with these oral oncolytics.
Topics: Humans; Imatinib Mesylate; Crizotinib; Retrospective Studies; Sunitinib; Obesity
PubMed: 37906253
DOI: 10.1007/s00280-023-04601-z -
European Heart Journal. Cardiovascular... Jul 2023
Topics: Humans; Myocarditis; Myocardium; Indazoles; Fibrosis
PubMed: 37200612
DOI: 10.1093/ehjci/jead101 -
Clinical Genitourinary Cancer Jun 2024Inter-individual variability in drug response pose significant challenges to treatment with tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell... (Review)
Review
Inter-individual variability in drug response pose significant challenges to treatment with tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC). TKIs meet traditional criteria for using therapeutic drug monitoring (TDM), but research is still limited. Understanding the role of TDM in individualizing treatment strategies could help optimize treatment. Here we review the state of knowledge of TDM for TKIs in mRCC treatment. A comprehensive literature review of original research studies focusing on TDM of TKIs in mRCC treatment, clinical in vivo studies reporting on pharmacokinetics-pharmacodynamics, therapeutic ranges, drug concentrations, dose adjustments, clinical outcomes, or other relevant aspects related to TDM. We reviewed studies involving human subjects published in peer-reviewed journals. A narrative synthesis approach was employed to summarize the findings. Key themes and trends related to TDM of TKIs in mRCC treatment were identified and synthesized to provide a comprehensive overview of the current state of knowledge. Our search yielded 25 articles. Most were observational. The most consistently reported association between plasma concentration and effect was pazopanib Ctrough >20 µg/mL, but this concentration was not significant across all studies. We found inconsistent evidence for sunitinib and cabozantinib. For axitinib, we found a clear exposure-response relationship, but research was too diverse to conclude on a therapeutic window to use for TDM. We found much heterogeneity between recommended time of measurement (minimum plasma concentration [C], maximal plasma concentration [C], area under the curve [AUC]) and large variation in plasma concentration associated with clinical outcomes, which makes it difficult to recommend specific concentration intervals based on 1 or more of these measurements. Results were more consistent with TKIs continuously administered. Further research is needed to elucidate the long-term impact of TDM to possibly establish standardized therapeutic intervals. Prospective studies are suggested. The application of TDM in TKI-combination therapy is warranted in future research.
Topics: Humans; Carcinoma, Renal Cell; Drug Monitoring; Protein Kinase Inhibitors; Kidney Neoplasms; Indazoles; Sulfonamides; Pyrimidines; Antineoplastic Agents; Axitinib; Sunitinib; Treatment Outcome; Tyrosine Kinase Inhibitors
PubMed: 38555681
DOI: 10.1016/j.clgc.2024.102064 -
AAPS PharmSciTech May 2024Pancreatic ductal adenocarcinoma (PDAC) is one of the highly fatal types of cancer with high mortality/incidence. Considering the crucial role of vascular endothelial...
Pancreatic ductal adenocarcinoma (PDAC) is one of the highly fatal types of cancer with high mortality/incidence. Considering the crucial role of vascular endothelial growth factor (VEGF) in PDAC progression, its inhibition can be a viable strategy for the treatment. Pazopanib, a second-generation VEGF inhibitor, is approved for the treatment of various oncological conditions. However, due to associated limitations like low oral bioavailability (14-39%), high inter/intra-subject variability, stability issues, etc., high doses (800 mg) are required, which further lead to non-specific toxicities and also contribute toward cancer resistance. Thus, to overcome these challenges, pazopanib-loaded PEGylated nanoliposomes were developed and evaluated against pancreatic cancer cell lines. The nanoliposomes were prepared by thin-film hydration method, followed by characterization and stability studies. This QbD-enabled process design successfully led to the development of a suitable pazopanib liposomal formulation with desirable properties. The % entrapment of PZP-loaded non-PEGylated and PEGylated nanoliposomes was found to be 75.2% and 84.9%, respectively, whereas their particle size was found to be 129.7 nm and 182.0 nm, respectively. The developed liposomal formulations exhibited a prolonged release and showed desirable physicochemical properties. Furthermore, these liposomal formulations were also assessed for in vitro cell lines, such as cell cytotoxicity assay and cell uptake. These studies confirm the effectiveness of developed liposomal formulations against pancreatic cancer cell lines. The outcomes of this work provide encouraging results and a way forward to thoroughly investigate its potential for PDAC treatment.
Topics: Indazoles; Liposomes; Humans; Sulfonamides; Pyrimidines; Cell Line, Tumor; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Particle Size; Nanoparticles; Polyethylene Glycols; Antineoplastic Agents; Cell Survival; Drug Liberation; Chemistry, Pharmaceutical
PubMed: 38710894
DOI: 10.1208/s12249-024-02806-w -
Journal of Cancer Research and Clinical... Aug 2023We constructed a zebrafish xenograft tumor model to compare and quantify the antiangiogenic efficacy and safety of nine vascular endothelial growth factor...
PURPOSE
We constructed a zebrafish xenograft tumor model to compare and quantify the antiangiogenic efficacy and safety of nine vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), axitinib, lenvatinib, pazopanib, apatinib, cabozantinib, sunitinib, semaxanib, sorafenib, and regorafenib, in parallel.
METHODS
CT26 and GL261 tumor cells were implanted into the perivitelline space of Tg (flk1: eGFP) zebrafish to construct a xenograft tumor model. VEGFR-TKIs' antiangiogenic efficacy was quantified using AngioTool software, and the median effective dose (ED50) was calculated. The toxicity was evaluated by calculating the median lethal dose (LD50) and gross morphological changes. Cardiac toxicity was further assessed by heart rate, heart rhythm, the distance between the sinus venosus (SV) and bulbus arteriosus (BA), and pericardial edema.
RESULTS
Using the zebrafish xenograft tumor model, we found that all nine VEGFR-TKIs exhibited antiangiogenic abilities, but the effectiveness of semaxanib was worse than that of other VEGFR-TKIs. Meanwhile, the zebrafish toxicity assay showed that all tested VEGFR-TKIs were associated with cardiac-related toxicity, especially apatinib and axitinib, which caused serious pericardial edema in zebrafish at relatively low concentrations. A narrow therapeutic window was found for most VEGFR-TKIs, and the simultaneous occurrence of toxic effects of semaxanib was recognized.
CONCLUSION
Our findings showed the potential of using a zebrafish xenograft tumor model to accelerate VEGFR-TKI screening and further the development of more efficient and less toxic VEGFR-TKIs.
Topics: Animals; Humans; Zebrafish; Protein-Tyrosine Kinases; Axitinib; Heterografts; Vascular Endothelial Growth Factor A; Protein Kinase Inhibitors; Neoplasms; Disease Models, Animal; Edema; Receptors, Vascular Endothelial Growth Factor
PubMed: 36609710
DOI: 10.1007/s00432-022-04560-7