Drugs in Research & Development最新文献

Background: The FLT3/ITD mutation exists in many acute myeloid leukemia (AML) patients and is related to the poor prognosis of patients. In this study, we attempted to evaluate the antitumor activity of simvastatin, a member of the statin class of drugs, in vitro and in vivo models of FLT3/ITD AML and to identify the potential mechanisms.

Methods: Cell Counting Kit-8 (CCK-8) and Annexin V/propidium iodide (PI) staining kits were used to detect cell viability and apoptosis, respectively. Subsequently, Western blot and rescue experiment were applied to explore the potential molecular mechanism. In vivo anti-leukemia activity of simvastatin was evaluated in xenograft mouse models.

Results: In vitro experiments revealed that simvastatin inhibited AML progression in a dose- and time-dependent manner, while in vivo experiments showed that simvastatin significantly reduced tumor burden in FLT3/ITD xenograft mouse models. After simvastatin treatment of FLT3/ITD AML cells, intracellular Rap1 was downregulated and the phosphorylation levels of its downstream targets MEK, ERK and p38 were significantly inhibited. The rescue experiment showed that mevalonate, an intermediate product of the metabolic pathway of mevalonate, and its downstream geranylgeranyl pyrophosphate (GGPP) played a key role in this process. Finally, we demonstrate that simvastatin can induce apoptosis of primary AML cells, while having no effect on peripheral blood mononuclear cells from normal donors.

Conclusions: Simvastatin can selectively and effectively eradicate FLT3/ITD AML cells in vitro and in vivo, and its mechanism may be related to the disruption of the HMG-CoA reductase pathway and the downregulation of the MEK/ERK and p38-MAPK signaling pathways.

Background and objective: Tucatinib is a selective tyrosine kinase inhibitor of the human epidermal growth factor receptor 2 (HER2) approved to treat metastatic HER2-positive breast and colorectal cancers. The International Council for Harmonisation of Technical Requirements for Human Use (ICH) E14 guideline mandates that new drugs are assessed for potential effects on cardiac repolarization through electrocardiogram (ECG) evaluation in a QT/corrected QT (TQT) study.

Methods: We evaluated the effect of tucatinib on cardiac repolarization in healthy volunteers in a phase I, randomized, partially double-blind, placebo-and positive-controlled three-period crossover study. The primary endpoint was the placebo-corrected change from baseline in QT interval values, corrected for heart rate using Fridericia's method (ΔΔQTcF).

Results: After achieving steady-state tucatinib exposures with 300 mg twice daily, the observed ΔΔQTcF ranged from -2.9 msec at 2 hours post-dose to 0 msec at 4 hours post-dose. The upper bound of the 90% confidence interval (CI) was below 5 ms at all post-dose timepoints. Assay sensitivity was confirmed as the lower bound of the 90% CI and was >5 ms following moxifloxacin dosing. As the mean ΔΔQTcF of tucatinib was predicted to be -  1.80 ms (90% CI -  3.90, 0.30) at clinically relevant tucatinib concentrations (511 ng/mL), an effect of tucatinib on QTcF exceeding 10 ms was excluded within observed ranges of tucatinib (up to ~1000 ng/mL). Tucatinib had no clinically relevant effect on heart rate or cardiac conduction. The safety profile of tucatinib was manageable after multiple doses.

Conclusion: Tucatinib had no clinically relevant effects on studied ECG parameters. This study constitutes a clearly negative TQT study per ICH E14 guidance.

Clinical trial registration: This trial (NCT03777761) was registered on 17 December 2018.

Background and objective: Glioblastoma is a cranial malignant tumor with a high recurrence rate after surgery and a poor response to chemoradiotherapy. Bevacizumab has demonstrated efficacy in the treatment of glioblastoma by inhibiting vascular endothelial growth factor, but the efficacy of vascular endothelial growth factor receptor tyrosine kinase inhibitors varies in treating glioblastoma. This single-arm prospective study aimed to explore the efficacy and safety of the vascular endothelial growth factor receptor tyrosine kinase inhibitor apatinib in treating recurrent glioblastoma after chemoradiotherapy.

Methods: A total of 15 patients with recurrent glioblastoma (2016 World Health Organization grade IV) after chemoradiotherapy were enrolled in this study from September 2017 to September 2019 and treated with apatinib 500 mg once daily. Responses were evaluated according to the Response Assessment in Neuro-Oncology criteria, and adverse events were recorded according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.

Results: The overall response rate was 33.3%, and the disease control rate was 66.6%. The median progression-free survival was 2 months, and the median overall survival was 6.5 months. The apatinib dose was adjusted in seven patients because of adverse events (46.6%). The most common adverse events were thrombocytopenia (53.3%), asthenia (40%), and hand-foot syndrome (33.3%).

Conclusions: Apatinib might be effective in treating recurrent glioblastoma after chemoradiotherapy in terms of the overall response rate, but the efficacy is not durable and the clinical benefit is limited. The adverse effects of apatinib were acceptable.

Clinical trial registration: ChiCTR-ONC-17013098, date of registration: 24 October, 2017.

Introduction: BAY1128688 is a selective inhibitor of aldo-keto reductase family 1 member C3 (AKR1C3), an enzyme implicated in the pathology of endometriosis and other disorders. In vivo animal studies suggested a potential therapeutic application of BAY1128688 in treating endometriosis. Early clinical studies in healthy volunteers supported the start of phase IIa.

Objective: This manuscript reports the results of a clinical trial (AKRENDO1) assessing the effects of BAY1128688 in adult premenopausal women with endometriosis-related pain symptoms over a 12-week treatment period.

Methods: Participants in this placebo-controlled, multicenter phase IIa clinical trial (NCT03373422) were randomized into one of five BAY1128688 treatment groups: 3 mg once daily (OD), 10 mg OD, 30 mg OD, 30 mg twice daily (BID), 60 mg BID; or a placebo group. The efficacy, safety, and tolerability of BAY1128688 were investigated.

Results: Dose-/exposure-dependent hepatotoxicity was observed following BAY1128688 treatment, characterized by elevations in serum alanine transferase (ALT) occurring at around 12 weeks of treatment and prompting premature trial termination. The reduced number of valid trial completers precludes conclusions regarding treatment efficacy. The pharmacokinetics and pharmacodynamics of BAY1128688 among participants with endometriosis were comparable with those previously found in healthy volunteers and were not predictive of the subsequent ALT elevations observed.

Conclusions: The hepatotoxicity of BAY1128688 observed in AKRENDO1 was not predicted by animal studies nor by studies in healthy volunteers. However, in vitro interactions of BAY1128688 with bile salt transporters indicated a potential risk factor for hepatotoxicity at higher doses. This highlights the importance of in vitro mechanistic and transporter interaction studies in the assessment of hepatoxicity risk and suggests further mechanistic understanding is required.

Clinical trial registration: NCT03373422 (date registered: November 23, 2017).

Background: The benefit of exogenous melatonin is based on its bioavailability, which depends on the galenic form, the route of administration, the dosage, and the individual absorption and rate of hepatic metabolism.

Objective: The objective of this study is to investigate the bioavailability of melatonin after administration of an oral prolonged-release tablet (PR form) and an immediate-release sublingual spray (IR form). The main metabolite of melatonin, 6-sulfatoxymelatonin (6-SMT), was also measured, which has not been done in previous studies. Its determination is important as an index of the hepatic transformation of melatonin.

Methods: In this single-center, open-label, randomized, crossover study, 14 healthy male volunteers received one tablet of the PR form (1.9 mg melatonin) or two sprays of the IR form (1 mg melatonin) during two visits separated by a washout period. Blood samples were collected over 7 and 9 h for the IR and PR form, respectively, to determine the main pharmacokinetic parameters.

Results: The observed kinetics were consistent with those expected for immediate and prolonged-release forms. Pulverization of the spray resulted in an early, high plasma melatonin peak (C_max: 2332 ± 950 pg/mL; T_max: 23.3 ± 6.5 min), whereas tablet intake produced a lower peak (C_max: 1151 ± 565 pg/mL; T_max: 64.2 ± 44.2 min; p < 0.001 for comparison of C_max and T_max) followed by a plasma melatonin plateau and a more prolonged decay over time. Plasma melatonin/6-SMT AUC_0-540/420 ratio was 0.09 for the PR form and 0.16 for the IR form. Both galenic forms were well tolerated.

Conclusions: The results suggest that the galenic forms containing melatonin assessed in this study are suitable for the treatment of certain sleep disorders such as sleep onset delay and transient nocturnal awakenings for the IR form and insomnia for the PR form.

Trial registry: Registration number: NCT04574141.

Background and objective: Human plasma is used for the generation of several life-saving drugs and contains valuable antibodies from the immunoglobulin classes IgG, IgM and IgA. Purified intravenous IgG solutions (IVIGs) form the majority of plasma-derived medicine to treat patients with various forms of immunodeficiencies. In conventional IVIG manufacturing processes, immunoglobulin classes IgM and IgA are often discarded as contaminants, but these antibody classes have been proven to be effective for the treatment of acute bacterial infections. Considering the increase in demand for human plasma-derived products and the ethical value of the raw material, a more resource-saving usage of human plasma is needed. Intensive research over the last decades showed that adverse reactions to IVIGs depend on the presence of thrombogenic factors, partially unfolded proteins, non-specific activation of the complement system, and blood group specific antibodies. Therefore, new IVIG preparations with reduced risks of adverse reactions are desirable.

Method: A new manufacturing process that yields two biologics was established and quality attributes of the new IVIG solution (Yimmugo^®) obtained from this process are presented.

Results: Here, we provide a biochemical characterization of Yimmugo^®, a new 10% IVIG preparation. It is derived from human blood plasma by a combined manufacturing process, where IgM and IgA are retained for the production of a new biologic (trimodulin, currently under investigation in phase III clinical trials). Several improvements have been implemented in the manufacturing of Yimmugo^® to reduce the risk of adverse reactions. Gentle and efficient mixing by vibration (called "vibromixing") during a process step where proteins are at risk to aggregate was implemented to potentially minimize protein damage. In addition, a dedicated process step for the removal of the complement system activator properdin was implemented, which resulted in very low anticomplementary activity levels. The absence of measurable thrombogenic activity in combination with a very high degree of functional monomeric antibodies predict excellent efficacy and tolerability.

Conclusion: Yimmugo^® constitutes a new high quality IVIG preparation derived from a novel manufacturing process that takes advantage of the full therapeutic immunoglobulin potential of human plasma.

Background: BAT1706 is a proposed biosimilar of bevacizumab, a vascular endothelial growth factor A (VEGF-A)-targeting biologic used to treat several different cancers, including metastatic colorectal cancer. A comprehensive physicochemical and functional similarity assessment is a key component of demonstrating biosimilarity between a reference biologic and a proposed biosimilar. Here we report the physicochemical and functional similarity of BAT1706 and reference bevacizumab sourced from both the United States (US-bevacizumab) and the European Union (EU-bevacizumab).

Method: A large range of product attributes, including primary and higher order structure, post-translational modifications, purity, stability, and potency, were characterized for BAT1706 and EU/US-bevacizumab using sensitive state-of-the-art analytical techniques. Up to 18 lots of US- and 29 lots of EU-bevacizumab, and 10 unique drug substance lots of BAT1706, were assessed.

Result: BAT1706 was shown to have an identical amino acid sequence and an indistinguishable higher-order structure compared with EU/US-bevacizumab. BAT1706 and EU/US-bevacizumab also exhibited similar post-translational modifications, glycan profiles, and charge variants. Potency, assessed using a wide range of bioassays, was also shown to be comparable between BAT1706 and EU/US-bevacizumab, with statistical equivalence demonstrated for VEGF-A binding and neutralizing activity.

Conclusion: Overall, this extensive comparability exercise demonstrated BAT1706 to match EU/US-bevacizumab in terms of all physicochemical and functional attributes assessed.

Background and objectives: Risk assessment related to bioequivalence study outcome is critical for effective planning from the early stage of drug product development. The objective of this research was to evaluate the associations between solubility and acido-basic parameters of an active pharmaceutical ingredient (API), study conditions and bioequivalence outcome.

Methods: We retrospectively analyzed 128 bioequivalence studies of immediate-release products with 26 different APIs. Bioequivalence study conditions and acido-basic/solubility characteristics of APIs were collected and their predictive potential on the study outcome was assessed using a set of univariate statistical analyses.

Results: There was no difference in bioequivalence rate between fasting and fed conditions. The highest proportion of non-bioequivalent studies was for weak acids (10/19 cases, 53%) and neutral APIs (23/95 cases, 24%). Lower non-bioequivalence occurrence was observed for weak bases (1/15 cases, 7%) and amphoteric APIs (0/16 cases, 0%). The median dose numbers at pH 1.2 and pH 3 were higher and the most basic acid dissociation constant (pKa) was lower in the non-bioequivalent group of studies. Additionally, APIs with low calculated effective permeability (cPeff) or low calculated lipophilicity (clogP) had lower non-bioequivalence occurrence. Results of the subgroup analysis of studies under fasting conditions were similar as for the whole dataset.

Conclusion: Our results indicate that acido-basic properties of API should be considered in bioequivalence risk assessment and reveal which physico-chemical parameters are most relevant for the development of bioequivalence risk assessment tools for immediate-release products.

Background and objective: At present, the therapies of dilated cardiomyopathy concentrated on the symptoms of heart failure and related complications. The study is to evaluate the clinical efficacy of a combination of various conventional and adjuvant drugs in treating dilated cardiomyopathy via network meta-analysis.

Methods: The study was reported according to the PRISMA 2020 statement. From inception through 27 June 2022, the PubMed, Embase, Cochrane library, and Web of Science databases were searched for randomized controlled trials on medicines for treating dilated cardiomyopathy. The quality of the included studies was evaluated according to the Cochrane risk of bias assessment. R4.1.3 and Revman5.3 software were used for analysis.

Results: There were 52 randomized controlled trials in this study, with a total of 25 medications and a sample size of 3048 cases. The network meta-analysis found that carvedilol, verapamil, and trimetazidine were the top three medicines for improving left ventricular ejection fraction (LVEF). Ivabradine, bucindolol, and verapamil were the top 3 drugs for improving left ventricular end-diastolic dimension (LVEDD). Ivabradine, L-thyroxine, and atorvastatin were the top 3 drugs for improving left ventricular end-systolic dimension (LVESD). Trimetazidine, pentoxifylline, and bucindolol were the top 3 drugs for improving the New York Heart Association classification (NYHA) cardiac function score. Ivabradine, carvedilol, and bucindolol were the top 3 drugs for reducing heart rate (HR).

Conclusion: A combination of different medications and conventional therapy may increase the clinical effectiveness of treating dilated cardiomyopathy. Beta-blockers, especially carvedilol, can improve ventricular remodeling, cardiac function, and clinical efficacy in patients with dilated cardiomyopathy (DCM). Hence, they can be used if patients tolerate them. If LVEF and HR do not meet the standard, ivabradine can also be used in combination with other treatments. However, since the quality and number of studies in our research were limited, large sample size, multi-center, and high-quality randomized controlled trials are required to corroborate our findings.