Class Of Tyrosine Kinase Inhibitors Research Articles

Systematic Evaluation of Tyrosine Kinase Inhibitors as OATP1B1 Substrates Using a Competitive Counterflow Screen.

Despite the established exposure-pharmacodynamic relationships for many TKIs, the mechanisms underlying the agents' unpredictable pharmacokinetic profiles remain poorly understood. We report here that the disposition of many TKIs depends on hepatic transport by OATP1B1, a process that has toxicologic ramifications for agents that are associated with hepatotoxicity.

Discovery of new sulfonamide-tethered 2-aryl-4-anilinoquinazolines as the first-in-class dual carbonic anhydrase and EGFR inhibitors

In today's medical field, there is a growing trend of exploiting a single small molecule to target two different molecular targets concurrently. This approach is proving to be highly effective in fighting against cancer. The 4-anilinoquinazoline scaffold, known for its potential in cancer therapy and its effectiveness as a leading class of tyrosine kinase inhibitors, was employed to develop a novel series of anilinoquinazoline-sulfonamides (AQSs) (8a-d, 9a-f, and 10a-d) as dual inhibitors of the tumor-associated carbonic anhydrases (CA) IX/XII and EGFR. 2-(3-Methoxyphenyl)quinazoline bearing p-sulfanilamide 10b elicited superior hCA IX and XII inhibition in the low nanomolar range (KIs = 38.4 and 8.9 nM, respectively). Also, 10b shined as a potent and selective EGFR inhibitor, boasting an impressive IC50 value of 51.2 ± 0.97 nM, surpassing the reference EGFR inhibitor Erlotinib (IC50 = 80 ± 2.0 nM). Compound 10b exhibited broadest-spectrum antiproliferative activity against the NCI-tumor panel with a mean GI% value of 68 %. Of special interest, 10b demonstrated potent growth inhibition (GI% ≥ 80–97 %) toward cell lines reported to express high levels of EGFR belonging to renal, colon, breast, and lung cancers. Compound 10b's molecular docking in the CA IX/XII and EGFR active sites revealed binding modes that justify its potent enzyme inhibitory effects. Additionally, molecular dynamic simulations demonstrated strong and stable interactions of 10b with the binding sites of these targets.

Varying concentrations of tyrosine kinase inhibitors in chronic myeloid leukemia patients following bariatric surgery: a case series.

Bariatric surgery is increasingly performed to treat severe obesity. As a result of anatomical and physiological changes in the gastrointestinal tract, the pharmacokinetics (PK) of oral drugs can be altered, affecting their efficacy and safety. This includes the class of tyrosine kinase inhibitors (TKIs) which are used to treat chronic myeloid leukemia (CML). This case series describes the clinical course of four CML cases with a history of bariatric surgery. The patients used various TKIs (nilotinib, dasatinib, bosutinib, ponatinib, and imatinib) for which 15 drug levels were measured. The measured TKI concentrations were in part subtherapeutic, and highly variable when compared to mean levels measured in the general population. Multiple drug levels were measured in these patients, as the clinicians were aware of the possible impact of bariatric surgery. The drug levels were used as additional input for clinical decision-making. All four patients required TKI switches and/or dose modifications to achieve an effective and tolerable treatment. Eventually, adequate clinical and molecular remissions were achieved in all cases. In summary, TKI concentrations of patients undergoing bariatric surgery may be subtherapeutic. Moreover, there is substantial interindividual and intraindividual variation, which may be explained by the complex interference of bariatric surgery and associated weight loss. For clinical practice, therapeutic drug monitoring is advised in patients with a history of bariatric surgery in case of suboptimal response or loss of response.

Abstract 1078: A Cross-species Platform And Phosphoproteomics Analysis To Mitigate Vegfri-induced Hypertension And Endothelial Dysfunction

Introduction: Vascular endothelial growth factor receptor inhibitors (VEGFRis) are a class of tyrosine kinase inhibitors (TKIs) used to treat human and canine cancers, but these drugs also cause hypertension (HTN) and endothelial cell (EC) dysfunction. Purpose: We combined phosphoproteomic analysis in ECs with a cross-species in-vitro and in-vivo approach to identify mitigating therapies for VEGFRi-induced EC dysfunction and HTN. Methods and Results: We developed a sorafenib-induced HTN mouse model showing increased blood pressure, mesenteric resistance vessel EC dysfunction (decreased phosphorylation of Ser1177 on endothelial nitric oxide synthase [p-eNOS], increased endothelin-1 [ET-1]), and renal glomerular endotheliosis. Human umbilical vein ECs were treated with VEGFR TKIs, non-VEGFR TKIs, and cardiovascular drugs. Phosphoproteomic mass spectrometry and a marker selection algorithm identified a 14-phosphopeptide signature differentiating VEGFR TKIs from non-VEGFR TKIs. The signature peptide RBM17 pS222 increased with VEGFRi treatment in human, canine, and mouse aortic ECs, correlating with reduced p-eNOS. By screening for cardiovascular drugs that reverse the VEGFRi phosphoproteomic signature, we found alpha-adrenergic antagonists, particularly doxazosin, had the most anti-correlated signatures. Doxazosin prevented VEGFRi-induced EC dysfunction in primary aortic ECs across species. In mice, doxazosin reversed sorafenib-induced EC dysfunction in resistance vessels without affecting blood pressure or renal glomerular endotheliosis. Conversely, lisinopril reduced HTN and glomerular endotheliosis but not EC dysfunction. Preliminary results from our clinical trial in canine cancer patients confirmed that toceranib induced HTN and showed that both doxazosin and lisinopril significantly lowered blood pressure in dogs with cancer and VEGFRi-induced HTN. Conclusion: Our study demonstrates the utility of phosphoproteomics and cross-species analysis in identifying EC-protective effects of doxazosin in VEGFRi-induced HTN. Our mouse data suggest distinct mechanisms for VEGFRi-induced EC dysfunction and HTN, potentially involving renal glomerular damage.

The Status Quo of Pharmacogenomics of Tyrosine Kinase Inhibitors in Precision Oncology: A Bibliometric Analysis of the Literature.

Precision oncology and pharmacogenomics (PGx) intersect in their overarching goal to institute the right treatment for the right patient. However, the translation of these innovations into clinical practice is still lagging behind. Therefore, this study aimed to analyze the current state of research and to predict the future directions of applied PGx in the field of precision oncology as represented by the targeted therapy class of tyrosine kinase inhibitors (TKIs). Advanced bibliometric and scientometric analyses of the literature were performed. The Scopus database was used for the search, and articles published between 2001 and 2023 were extracted. Information about productivity, citations, cluster analysis, keyword co-occurrence, trend topics, and thematic evolution were generated. A total of 448 research articles were included in this analysis. A burst of scholarly activity in the field was noted by the year 2005, peaking in 2017, followed by a remarkable decline to date. Research in the field was hallmarked by consistent and impactful international collaboration, with the US leading in terms of most prolific country, institutions, and total link strength. Thematic evolution in the field points in the direction of more specialized studies on applied pharmacokinetics of available and novel TKIs, particularly for the treatment of lung and breast cancers. Our results delineate a significant advancement in the field of PGx in precision oncology. Notwithstanding the practical challenges to these applications at the point of care, further research, standardization, infrastructure development, and informed policymaking are urgently needed to ensure widespread adoption of PGx.

Liquid chromatography and mass spectrometric studies of gilteritinib fumarate and characterization of its major degradation products by NMR.

Gilteritinib fumarate (GTB) is an anti-cancer drug belonging to the class of tyrosine kinase inhibitors used for the treatment of acute myeloid leukemia. It has been designated as an orphan drug by the US Food and Drug Administration (US FDA). The present research focused on carrying out the forced degradation studies of GTB and developing a UHPLC-PDA stability indicating method capable of separating GTB and its degradation products. The degradation studies were carried out under hydrolytic (acid, base, and neutral), oxidative, thermal, and light conditions. The drug degraded under hydrolytic and oxidative conditions whereas it was found to be stable under thermal and light exposure. The separation of the components was achieved on an Acquity BEH C18 column (2.1 × 100 mm; 1.7μ) and a mobile phase comprising ammonium acetate and acetonitrile eluting in gradient mode at a flow rate of 0.3 mL min-1. A total of five degradation products were obtained and were structurally characterized with the help of accurate mass and tandem mass experiments performed on LC-QTOF-MS equipment and DP-1 was isolated and characterized using 1D and 2D NMR experiments. The UHPLC-PDA method was validated as per the ICH Q2 (R1) guidelines for its accuracy, precision, linearity, and specificity. The method was found to be appropriate for its intended purpose and can be effectively used in the determination of GTB and its degradation products and/or impurities in bulk drugs as well as formulations.

Simultaneous Quantitation of Anlotinib and Osimertinib by Isotope-Labeled UHPLC-MS/MS in Human Plasma: Application in NSCLC Patients.

Anlotinib and osimertinib are a class of tyrosine kinase inhibitors for the treatment of malignant tumor. The combination of anlotinib and osimertinib is currently used for treating non-small cell lung cancer (NSCLC) patients. This study aimed to develop a simple and rapid isotope-labeled UHPLC-MS/MS method for the simultaneous determination of anlotinib and osimertinib in human plasma. The analytes were extracted by protein precipitation with acetonitrile and were then separated on a Shim-pack GIST C18 column. The detection was performed on Shimadzu 8050 triple quadruple mass spectrometer in the positive electrospray ionization mode with multiple reaction monitoring. The precursor-to-product ion transitions were m/z 408.10→339.75, 500.25→72.20 and 413.50→344.50 for anlotinib, osimertinib and D5-anlotinib, respectively. Validation is based on US Food and Drug Administration guidelines. The linearity ranges were 0.5-100ng/mL for anlotinib and were 1-500ng/mL for osimertinib with the correlation coefficients (r 2) ≥ 0.99. Accuracy and precision, matrix effect, extraction recovery and stability of anlotinib and osimertinib were acceptable after validation. The UHPLC-MS/MS method was successfully validated and was applied to monitor the concentration of anlotinib and osimertinib in NSCLC patients.

Simultaneous Determination of Two Tyrosine Kinase Inhibitors in Tablets by HPLC-MS analysis.

The class of tyrosine kinase inhibitors (TKIs) is represented by a group of compounds which are currently used in the treatment of different types of cancer. These oral medicines present a narrow therapeutic index and a large inter-and intra-individual variability. Within this work, a simple, accurate and rapid reversed phase ultra-high-performance liquid chromatographic (RP-UHPLC) method with mass spectrometric (MS) detection for simultaneous analysis of two TKIs, ibrutinib and ruxolitinib, using pentoxifylline as internal standard (IS) in tablet dosage forms is presented. The separation was carried out on a Waters (Milford, Massachusetts, USA) Arc System coupled with a Waters QDa mass detector. The column used was a Waters CORTECS C18 (4.6×50mm, 2.7μm); a gradient elution was carried out using a mixture of ammonium formate 10 mM aqueous solution and acetonitrile. The flow rate of the mobile phase was set to 0.5mL/min. The column temperature was equilibrated to 40°C. The injected volume was 5μL. All samples were kept at 20°C during the entire analysis. Mass spectra were recorded in positive ionization mode in the range of m/z 100-400 for ruxolitinib and m/z 100-500 for ibrutinib. Quantification was established in single ion recording (SIR) mode for each compound, using pentoxifylline as internal standard. The method was validated according to International Guidelines in terms of stability, limit of detection, limit of quantitation, linearity, precision and accuracy. The validated method can be successfully applied for simultaneous determination of TKIs in tablet dosage forms.

Resolution of choroidal metastasis in lung adenocarcinoma with gefitinib

The choroid is the structure with the highest occurrence of ocular metastasis. The sites that most commonly metastasize to the choroid are the lung and breast, with lung carcinoma responsible for about 30% of choroidal metastases. We report a case of a female patient with choroidal metastasis in the left eye due to pulmonary adenocarcinoma. The patient presented low visual acuity with the presence of a mass in the upper temporal region, endophytic, irregular and non-pigmented, associated with a detachment of sensorineural retina. It was conducted with the immunomodulator Gefitinib, a drug class of tyrosine kinase inhibitors. After 03 months using the medication, the patient showed improvement in visual symptoms, and marked regression of the lesion in the left eye. The result shows the benefit of this medication in a patient with this specific type of tumor.

A RARE CAUSE OF INTERSTITIAL LUNG DISEASE

TOPIC: Diffuse Lung Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Clinicians should be aware of the potential adverse effects and complications that can occur with molecularly targeted agents for them to be able to diagnose and treat the condition. CASE PRESENTATION: 65-year-old female with stage IV epidermal growth factor receptor (EGFR) lung adenocarcinoma with metastases to the brain, spine, liver, and kidneys undergoing treatment with osimertinib for two months presented with a subjective fever of 102 °F. On admission the patient was tachycardic with an elevated lactate warranting investigation and treatment of sepsis secondary to a UTI. Despite using broad spectrum antibiotics and proper fluid resuscitation, her hospital course was complicated with the development of a new onset dyspnea with exertion and insidious hypoxic respiratory failure. Computed tomography angiography (CTA) of the chest revealed an incidental sub segmental pulmonary embolism which was not treated with anticoagulation due to underlying hemorrhagic brain metastasis. More importantly, the CTA showed new ground glass opacities demonstrated on the upper lung fields concerning for interstitial lung disease (ILD). Osimertinib was discontinued and high-dose IV methylprednisolone was administered resulting in immediate relief of dyspnea and cessation of relapsing fever. There was also a significant improvement to the hypoxia within a 24-hour period. Patient was transitioned to oral prednisone and discharged home the following day. DISCUSSION: Anti-epidermal growth factor receptor agents, a class of small molecule kinase inhibitors, are primarily used for the treatment of advanced non-small cell lung cancer. Common side effects for this particular class of tyrosine kinase inhibitors (TKIs) include fatigue, rashes, and lymphopenia. The risk of ILD for patient's taking EGFR-TKIs is a rare incidence, occurring at a rate of 1-3%, within the first 2-3 months of initiating therapy. The exact mechanism of TKI induced lung injury remains unknown, the proposing theory is an interruption to the alveolar repair mechanism which potentiates lung injury to other causes, such as sepsis, medications, and prior radiation therapy. Discontinuation of EGFR-TKIs therapy is the primary modality to prevent worsening of ILD. Utilization of high-dose glucocorticoids is an additional measure that can be employed for the treatment of drug-induced ILD. CONCLUSIONS: Physicians must be vigilant, with a high degree of clinical suspicion, to discontinue the offending agent in the event that a patient on EGFR-TKIs therapy presents with fever, acute dyspnea with or without cough, tachycardia, and hypoxia. If symptoms of the adverse reaction are not recognized early enough, they may progress to other conditions, such as pulmonary fibrosis. In addition, there is an increased mortality ratewith the continuation of these agents once ILD develops. REFERENCE #1: Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib.Ann Oncol. 2019;30(5):839. DISCLOSURES: No relevant relationships by Ankita Aggarwal, source=Web Response No relevant relationships by Yashar Eshman, source=Web Response no disclosure on file for Mohammad Fityan; No relevant relationships by Victoria Gonzalez, source=Web Response No relevant relationships by Zain Kulairi, source=Web Response

FP09.01 Mobocertinib in Platinum-Pretreated EGFR Exon 20 Insertion+ Metastatic NSCLC Patients With/Without Prior Anti-PD(L)-1 Therapy

No approved, targeted therapies are available to specifically treat EGFR exon 20 insertion+ (ex20ins+) non–small cell lung cancer (NSCLC). Anti-programmed-death (ligand)-1 (anti-PD(L)-1) therapies are recommended for NSCLC patients without activating mutations as preferred therapy; however, their efficacy in EGFR ex20ins+ NSCLC is limited, with median progression-free survival (PFS) typically of 2–3 months. Mobocertinib (TAK-788) is an oral EGFR tyrosine kinase inhibitor (TKI) targeting EGFR ex20ins; it holds Breakthrough Therapy Designation for patients with EGFR ex20ins+ NSCLC who previously progressed on platinum-based chemotherapy (in the United States) or who had prior chemotherapy (in China), based on preliminary phase 1/2 results. Here we present data for platinum-pretreated patients (PPP; n=114) with/without prior anti-PD(L)-1 therapy from this study. The 3-part, open-label, phase 1/2, multicenter study (NCT02716116), consisting of dose-escalation/-expansion and extension cohorts, evaluated mobocertinib in patients with EGFR ex20ins+ metastatic NSCLC. PPP (from all 3 parts) had ECOG performance status 0–1, and ≥1 prior line of therapy for locally advanced/metastatic disease; patients received mobocertinib 160 mg QD. Primary endpoint was confirmed overall objective response rate (ORR) per RECIST v1.1 assessed by independent review committee (IRC). Efficacy endpoints included confirmed ORR per investigator; disease control rate (DCR), duration of response (DoR), and PFS per IRC and investigator; and overall survival (OS). Among PPP (n=114), 43% had received prior immunotherapy. Among patients with prior anti-PD(L)-1 therapy (n=48), 32 (67%) had received ≥2 prior systemic anticancer lines; 28 (58%) received immunotherapy as part of most recent anticancer therapy. Confirmed ORR per IRC in PPP was 28% [95% CI: 20–37]; DCR was 78% [95% CI: 69–85]. Confirmed ORR per IRC was 25% in PPP with prior anti-PD(L)-1 therapy and 30% in PPP without prior anti-PD(L)-1 therapy; other efficacy endpoints are shown in the Table. Treatment-related adverse events (TRAEs) observed ≥10% more frequently in patients with prior anti-PD(L)-1 were nausea, fatigue, and maculopapular rash. No significant difference was observed in treatment-related diarrhea or pneumonitis/interstitial lung disease. AEs led to treatment discontinuation in 10 (21%) and 9 (14%) patients with and without prior anti-PD(L)-1 therapy, respectively.Tabled 1EfficacyPPP With PriorAnti-PD(L)-1 Therapy (n=48)PPP Without PriorAnti-PD(L)-1 Therapy (n=66)Confirmed ORR per IRC, n (%) [95% CI]12 (25) [14–40]20 (30) [20–43]Confirmed ORR per investigator, n (%) [95% CI]18 (38) [24–53]22 (33) [22–46]Confirmed DCR per IRC, n (%) [95% CI]37 (77) [63–88]52 (79) [67–88]≥6-month DoR per IRC*, n (%)7 (58)12 (60)Median PFS per IRC, mo [95% CI]7.4 [5.5–21.1]7.3 [5.4–10.2]Median OS, mo [95% CI]21.0 [13.1–not estimable]24.0 [13.1–not estimable]Safety OverviewAny TRAE48 (100)66 (100)Grade ≥3 TRAEs28 (58)26 (39)Serious AEs26 (54)30 (45)Dose modification due to AEs37 (77)36 (55)Discontinuation due to AEs10 (21)9 (14)*Per descriptive data. Open table in a new tab *Per descriptive data. Efficacy of mobocertinib was similar in patients with and without prior anti-PD(L)-1 therapies. Safety was consistent with EGFR TKI class and manageable in both populations.

Tyrosine Kinase Inhibitors Reduce Glucose Uptake by Binding to an Exofacial Site on hGLUT-1: Influence on 18 F-FDG PET Uptake.

Positron emission tomography (PET) using 2‐deoxy‐2‐[18F]fluoro‐d‐glucose ([18F]FDG), a marker of energy metabolism and cell proliferation, is routinely used in the clinic to assess patient response to chemotherapy and to monitor tumor growth. Treatment with some tyrosine kinase inhibitors (TKIs) causes changes in blood glucose levels in both nondiabetic and diabetic patients. We evaluated the interaction of several classes of TKIs with human glucose transporter‐1 (hGLUT‐1) in FaDu and GIST‐1 cells by measuring [3H]2‐deoxy‐d‐glucose ([3H]2‐DG) and [3H]FDG uptake. Uptake of both was inhibited to varying extents by the TKIs, and representative TKIs from each class showed competitive inhibition of [3H]2‐DG uptake. In GIST‐1 cells, [3H]FDG uptake inhibition by temsirolimus and nilotinib was irreversible, whereas inhibition by imatinib, gefitinib, and pazopanib was reversible. Molecular modeling studies showed that TKIs form multiple hydrogen bonds with polar residues of the sugar binding site (i.e., Q161, Q282, Q283, N288, N317, and W388), and van der Waals interactions with the H‐pocket site. Our results showed interaction of TKIs with amino acid residues at the glucose binding site to inhibit glucose uptake by hGLUT‐1. We hypothesize that inhibition of hGLUT‐1 by TKIs could alter glucose levels in patients treated with TKIs, leading to hypoglycemia and fatigue, although further studies are required to evaluate roles of other SLC2 and SLC5 members. In addition, TKIs could affect tumor [18F]FDG uptake, increasingly used as a marker of tumor response. The hGLUT‐1 inhibition by TKIs may have implications for routine [18F]FDG‐PET monitoring of tumor response in patients.

Tyrosine Kinase Inhibitors against Cancer: Their Safety in 216 Moroccan Patients

Tyrosine kinase inhibitors (TKIs) have become a prominent option in the therapeutic arsenal of several cancers. The safety of these drugs has shown various toxicities with varying frequency and severity between different agents. The aim of this study is to describe the safety profile of different classes of TKI used in various solid tumors. It is a retrospectively descriptive study conducted in the Department of Medical Oncology at Hassan II University Hospital of Fez, Morocco, over a period of 6 years from April 2013 until April 2019. It included 216 patients who received one or more TKI for different indications in solid tumors. The average age in our series was 61.4 years with a sex ratio F/M of 1.07. Among the most used TKIs in our department according to their availability: Imatinib (32%) and sunitinib (32%). All patients received one or more tyrosine kinase inhibitors according to the indication. Kidney cancer was the most common malignancy (36%), followed by gastrointestinal stromal tumors (33%). The median duration of treatment was 15 months with extremes of 1 month and 102 months. The main side effects were: Cutaneous in 43% of patients. Digestive toxicity occurred in 36% of cases. Hematotoxicity was reported in 33% of cases. The safety profile of TKIs used in our study was comparable to their global tolerance reported in literature. More studies are needed to investigate the relationship between their toxicity and their efficacy in Moroccan population.

Ripretinib for the treatment of advanced gastrointestinal stromal tumor

Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal (GI) tract yet represent the most common GI sarcomas. Most GISTs are driven by activating mutations of the KIT and/or PDGFRA genes. Prior to the development of tyrosine kinase inhibitors (TKIs), GISTs were associated with a poor prognosis because conventional cytotoxic chemotherapy was relatively ineffective. However, TKIs that inhibit the most common driver mutations in KIT or PDGFRA have revolutionized the treatment of GISTs over the past two decades. Notwithstanding, ongoing management challenges relate to the development of secondary mutations in these genes, resulting in tumor progression. Due to both the intra- and inter-patient heterogeneity of these secondary mutations in GISTs, optimal treatment requires an agent that blocks as many mutant genes as possible. Ripretinib – a novel switch-control TKI – inhibits many of the most common primary and secondary activating KIT and PDGFRA mutants involved in GIST progression through a dual mechanism of action. In the pivotal INVICTUS phase III trial, patients with advanced GIST that had progressed on at least imatinib, sunitinib, and regorafenib and who received ripretinib experienced significantly longer progression-free survival (primary endpoint) as well as prolongation of overall survival, compared with those receiving placebo. Treatment with ripretinib was associated with durable improvements in quality-of-life indices and a manageable toxicity profile. The most frequent side effects were common to the class of TKIs used in the management of GIST. These results led to the approval of ripretinib for treatment of advanced GIST in adults who have received three or more TKIs, including imatinib. Ripretinib is also under investigation in the second-line treatment of advanced GIST in a phase III trial (INTRIGUE) comparing ripretinib with sunitinib in patients with advanced GIST after treatment with imatinib.Plain language summary Use of ripretinib for the treatment of gastrointestinal stromal tumors (GISTs) Gastrointestinal stromal tumors (GISTs) are a rare type of tumor most commonly located in the stomach and small intestine but can develop anywhere throughout the gastrointestinal tract. The symptoms of GISTs vary in extent depending on location of the primary tumor and include a feeling of fullness, abdominal pain, intestinal bleeding, and fatigue. Since these symptoms are nonspecific, making a diagnosis can be challenging. Most GISTs carry initial mutations in genes that control specific enzymes called tyrosine kinases. Historically, treatment of GISTs was limited because traditional chemotherapy is ineffective against these tumors. However, with the introduction of drugs that inhibit tyrosine kinases [i.e., tyrosine kinase inhibitors (TKIs)], survival has been extended substantially. However, many GISTs go on to develop secondary mutations that render them resistant to a given TKI. Prior to the approval of ripretinib, four TKIs were available for the treatment of GIST: imatinib; sunitinib; regorafenib; and, recently, avapritinib. Each drug is used until resistance develops or patients are unable to tolerate the side effects of treatment, after which the next drug is started. Ripretinib was recently approved by the FDA as the fourth drug in the usual treatment sequence recommended for patients with advanced GIST who have progressed (or are treatment intolerant) after receiving three or more TKIs, including imatinib. Approval of ripretinib was based on the results of the INVICTUS trial, which demonstrated that the drug significantly improves the time patients have without progression of the disease or death compared with placebo. The most common side effects related to ripretinib were hair loss, muscle pain, nausea, fatigue, hand-foot syndrome, and diarrhea, although most events were not very severe. Ripretinib is being further studied as the second TKI used in patients with GIST who have progressed on or could not tolerate first-line treatment with imatinib.

Changes in blood pressure during treatment with the tyrosine kinase inhibitor lenvatinib.

BackgroundWithin the class of tyrosine kinase inhibitors (TKIs), which are used for the treatment of numerous advanced cancers, lenvatinib is associated with a higher prevalence of hypertension (HT) compared with other TKIs. In this study, we investigated the effect of lenvatinib on blood pressure (BP) and associated factors.MethodsThis single-centre, retrospective observational study included 25 consecutive patients treated with lenvatinib for unresectable hepatocellular carcinoma from April 2018 to December 2018 at the study institution. We assessed changes in BP using ambulatory BP monitoring, urinary sodium excretion, kidney function, use of antihypertensive agents and diuretics, and fluid retention following treatment initiation with lenvatinib.ResultsAt 1 week after treatment initiation, the mean BP and the percentage of patients with riser pattern significantly increased compared with those at the baseline. Although there were no significant changes at 1 week, urinary sodium excretion (153.4 ± 51.7 and 112.5 ± 65.0 mEq/day at 1 and 3 weeks, respectively, P < 0.05) and estimated glomerular filtration rate significantly decreased and the number of patients with fluid retention increased at 3 weeks. Furthermore, patients with fluid retention had significantly higher BP or required more intensive BP treatment compared with those without fluid retention.ConclusionsLenvatinib might lead to HT without fluid retention soon after the initiation of treatment, subsequently leading to a reduction in urinary sodium excretion, thereby contributing to a rise in BP by fluid retention.

Role of Oatp2b1 in Drug Absorption and Drug-Drug Interactions.

The organic anion transporting polypeptide (OATP)2B1 is localized on the basolateral membrane of hepatocytes and is expressed in enterocytes. Based on its distribution pattern and functional similarity to OATP1B-type transporters, OATP2B1 might have a role in the absorption and disposition of a range of xenobiotics. Although several prescription drugs, including hydroxymethylglutaryl-coenzyme A-CoA reductase inhibitors (statins) such as fluvastatin, are OATP2B1 substrates in vitro, evidence supporting the in vivo relevance of this transporter remains limited, and most has relied on substrate-inhibitor interactions resulting in altered pharmacokinetic properties of the victim drugs. To address this knowledge deficit, we developed and characterized an Oatp2b1-deficient mouse model and evaluated the impact of this transporter on the absorption and disposition of fluvastatin. Consistent with the intestinal localization of Oatp2b1, we found that the genetic deletion or pharmacological inhibition of Oatp2b1 was associated with decreased absorption of fluvastatin by 2- to 3-fold. The availability of a viable Oatp2b1-deficient mouse model provides an opportunity to unequivocally determine the contribution of this transporter to the absorption and drug-drug interaction potential of drugs. SIGNIFICANCE STATEMENT: The current investigation suggests that mice deficient in Oatp2b1 provide a valuable tool to study the in vivo importance of this transporter. In addition, our studies have identified novel potent inhibitors of OATP2B1 among the class of tyrosine kinase inhibitors, a rapidly expanding class of drugs used in various therapeutic areas that may cause drug-drug interactions with OATP2B1 substrates.

Drug-Drug Interactions of 257 Antineoplastic and Supportive Care Agents With 7 Anticoagulants: A Comprehensive Review of Interactions and Mechanisms.

Data on drug–drug interactions (DDI) of antineoplastic drugs with anticoagulants is scarce. We aim to evaluate factors associated with DDI of antineoplastic and supportive care drugs with anticoagulants resulting in modification of pharmacokinetics of these last mentioned. A literature review on DDI databases and summaries of products characteristics (SmPC) was done. Drug–drug interactions of 257 antineoplastic and supportive care drugs with direct oral anticoagulants (DOACs), warfarin, enoxaparin, or fondaparinux were categorized as no clinically significant expected DDI, potentially weak DDI, potentially clinically significant DDI, and recommendation against coadministration. Logistic regression models were performed to analyze the association between the dependent variable potentially clinically significant interaction/recommendation against coadministration and the mechanisms of DDI. Of the 1799 associations, 84.4% were absence of DDI, 3.6% potentially weak DDI, 10.2% potentially clinically relevant DDI, and 2.0% recommendation against coadministration. Warfarin has higher DDI potential than other anticoagulants. Enoxaparin and fondaparinux have fewer DDI than others. There was no difference between DOACs. Drug–drug interactions with apixaban and rivaroxaban was independently associated with the absence of CYP3A4 competition, P-glycoprotein inhibition, CYP3A4 induction, and drug class of tyrosine kinase inhibitors. Drug–drug interactions with dabigatran and edoxaban was associated with inhibition of P-glycoprotein and tyrosine kinase inhibitors. Warfarin, induction of CYP3A4, and inhibition of CYP2C9. Enoxaparin and fondaparinux, only tyrosine kinase inhibitors. Direct oral anticoagulants did not differ regarding DDI with antineoplastic agents. Warfarin presented more DDI than other anticoagulants. P-glycoprotein inhibition and CYP3A4 induction were independently associated with DDI of antineoplastic agents with DOACs.

Role of OATP2B1 in Drug Absorption and Drug‐Drug Interactions

BackgroundThe human organic anion‐transporting polypeptide 2B1 (OATP2B1; SLC21A9) is localized to the basolateral membrane of hepatocytes and the brush‐border membrane of small‐intestinal enterocytes. Based on its distribution pattern and functional similarity to OATP1B‐type transporters, it has been hypothesized that OATP2B1 might influence the absorption and disposition properties of a wide range of xenobiotic agents. Although several prescription drugs, including statins such as fluvastatin, have been identified as OATP2B1 substrates in vitro, the lack of a useful in vivo model system has limited our understanding of the pharmacological role of this transporter.Experimental designOATP2B1‐overexpressing cells were generated by transfecting HEK293 cells with an empty vector (VC) or a construct containing human OATP2B1 or mouse OATP2B1 cDNA. Transporter function was evaluated in vitro by measuring the comparative cellular uptake of [3H]estrone‐3‐sulfate (ES) in VC cells and OATP2B1‐overexpressing cells. Candidate substrates and inhibitors were identified based on the difference in intracellular accumulation of radioactivity. OATP2B1‐knockout (KO) mice were obtained from the Slco2b1tm1a(KOMP)Wtsi clone, and derived chimera and subsequent progeny were mated to C57BL/6N for germline production and colony expansion. Mouse genotypes were confirmed by PCR, and OATP2B1 gene deletion was verified by qPCR on major organs. The pharmacokinetic profiles of fluvastatin, a known OATP2B1 substrate, and sorafenib, a known OATP2B1 inhibitor, were determined through serial blood collection and subsequent LC‐MS/MS analysis. Noncompartmental pharmacokinetic parameters were calculated using WinNolin 6.2 software (Pharsight).ResultsAn approximately four‐fold increase in intracellular accumulation of radiolabeled ES (2.5 μM) was observed in the OATP2B1 overexpressing cells compared to VC cells (34.8 ± 2.45 pmol/mg vs 8.38 ± 0.341 pmol/mg, respectively). Subsequently, we identified several drugs as candidate OATP2B1 substrates, including multiple tyrosine kinase inhibitors (TKIs). Knockout of OATP2B1 in organs from KO mice was confirmed at the gene level (P&lt;0.01), and consistent with the intestinal localization of OATP2B1, we found that the absorption of fluvastatin was affected by OATP2B1 deficiency (Tmax: 1 h vs 0.5 h; Cmax: 1.05 μg/mL vs 2.19 μg/mL). No gender differences in mRNA expression levels were detected. Among 24 different agents tested, sorafenib was identified as one of the most potent OATP2B1 inhibitors in the class of TKIs. However, the pharmacokinetic properties of sorafenib and its main metabolites were not significantly affected by OATP2B1 deficiency.ConclusionOur studies have identified novel potent inhibitors of OATP2B1 among TKIs, a rapidly expanding class of drugs used in various therapeutic areas. The availability of a viable, well‐characterized OATP2B1‐deficient mouse model provides a previously unavailable opportunity to unequivocally determine the contribution of this transporter to the absorption and drug‐drug interaction potential of drugs.Support or Funding InformationEli Lilly Fellowship in PharmaceuticsThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Micelle-solubilized axitinib for ocular administration in anti-neovascularization

The development of new blood vessels is directly related to the occurrence of eye diseases. Anti-angiogenic drugs can theoretically be extended to the treatment of ophthalmic diseases. In this study, axitinib, a class of tyrosine kinase inhibitors, was loaded via the amphiphilic copolymer MPEG-PCL, improving its dispersibility in water. Axitinib-loaded micelles showed low toxicity in concentration gradient assays. Additionally, multiple doses by scratch assay confirmed that axitinib had no significant effect on normal cell migration, and biosafety test results showed good cell compatibility. After we established the corneal neovascularization model after an alkali burn in rats, the anti-angiogenic efficacy was tested, with dexamethasone as a positive control. The results showed that axitinib-loaded micelles had anti-angiogenic effects without obvious tissue toxicity. As a class of targeted tyrosine kinase inhibitors, axitinib can be used in the treatment of ocular neovascular diseases through nanocrystallization.

Realized and Projected Cost Savings from the Introduction of Generic Imatinib, with Minimal Additional Savings to Payers through Formulary Management

INTRODUCTIONThe availability of imatinib, the first generation tyrosine kinase inhibitor (TKI), has dramatically improved survival of patients with Chronic Myelogenous Leukemia (CML). Second generation TKIs have further advanced patient care. Since loss of exclusivity (LOE) and the entry of a generic imatinib in the US in February 2016, US payers have started realizing savings. However, generic prices have taken two years to decline substantially. Previous work had estimated the anticipated impact of the generic imatinib entry for its first two years, and now the actual prices and savings can be calculated. The objective of this research was to quantify the savings from generic substitution of branded imatinib relative to the potential impact of requiring step therapy through generic imatinib before a 2nd generation TKI. METHODSAn Excel-based model representing the TKI pharmacy budget of a hypothetical 1-million member commercial plan and 1-million member Medicare plan was developed from a pharmacy only perspective. Historical market share and wholesale acquisition cost pricing over the period of January 2016 to February 2018 were combined with CML age-adjusted US epidemiology data to calculate the monthly spend on TKIs over the same period. Logarithmic regression models were fitted to historical market share data in order to project future utilization of branded TKIs and generic imatinib up to 5 years after LOE. Future drug pricing was assumed to remain constant over the forecasted period. It was assumed that a health plan would not mandate changes in choice of TKI among patients with ongoing TKI treatment. Savings were calculated by comparing the costs of TKIs with generic imatinib to a scenario where generic imatinib was not available. The potential impact of implementing formulary restriction in the TKI class in the next 3 years was explored by applying a step edit to require a trial of generic imatinib before 2nd generation TKIs for incident patients with CML who are new to TKI therapy. Analyses were repeated for the entire commercially and Medicare-covered population in the US based on National Census data RESULTSIt was estimated that a 1-million member commercial plan saved $0.5M (3%) in the first year and $3.8M (19%) in the second year after LOE. Projected savings significantly increase to $7.8M (37%), $8.2M (39%), and $8.6M (40%) in the 3rd, 4th, and 5th year after LOE, respectively. Initiating a step edit for newly treated CML patients in the commercial plan setting was associated with a very small incremental savings of 1.5% annually over the next 3 years.It was estimated that a 1-million member Medicare plan saved $1.7M (3%) and $14M (19%) in the first and second year, respectively. Projected savings in a Medicare plan were $27.8M (37%), $29.4M (39%), and $30.7M (40%), and a step edit for newly treated CML patients gained an additional 1.2% per year in savings over the next 3 years in a Medicare health plan population.In the first two years, the introduction of generic imatinib saved US payers $1.5B, 7% of the total spend on this drug class. In the next 3 years, the estimated savings are expected to grow to 22% and result in cumulative savings of $8.3B with no management of the class at all. Nearly all of potential savings from the class, 93%, are estimated to come from the generic imatinib conversion from brand with no management required. CONCLUSIONSLow generic imatinib price is estimated to result in substantial cost savings to US payers over the next 3 years independent of any formulary management strategies. Formulary management restricting access to 2nd generation TKIs may result in minimal additional savings that are unlikely to reach a threshold of value worthy of action by the health plan. [Display omitted] DisclosuresBloudek:Xcenda: Employment. Brokars:Bristol-Myers Squibb: Employment. David:Xcenda: Employment. Makenbaeva:Bristol-Myers Squibb: Employment.