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Aim: Chemotherapy‐induced peripheral neuropathy (CIPN) is a major toxicity limiting the use of nab‐paclitaxel (Nab‐P) in treating patients with pancreatic cancer. The aim of this study was to identify the factors affecting CIPN using patient‐reported outcome measures and the minimally invasive volumetric absorptive microsampling (VAMS) technique. Methods: The maximum concentrations of paclitaxel (Cmax) were measured from 81 VAMS samples collected from 44 participants with pancreatic cancer. The association between CIPN development and demographic, clinical and pharmacokinetic factors was determined using univariable and multivariable logistic regression. The association between CIPN severity and the factors was evaluated using Spearman's rank correlation. The impact of Cmax and the number of treatment cycles on the severity was assessed using multivariable linear regression. Results: The development of CIPN was significantly associated with cumulative dose (odds ratio 1.005, 95% confidence interval [CI] 1.003‐1.007), treatment cycles (3.47, 2.25‐5.85), alkaline phosphate (0.992, 0.985‐0.998) and age (1.092, 1.020‐1.179), with an area under the receiver operating characteristic curve of 0.89 (95% CI 0.83‐0.95). The severity of CIPN significantly worsened with increasing cumulative dose (coefficient 0.58, 95% CI 0.44‐0.69), treatment cycles (0.57, 0.44‐0.68) and age (0.18, 0.00‐0.35). The severity of CIPN was predictable from treatment cycles (P =.0002) and Cmax (P =.01). Conclusion: The higher the cumulative dose of Nab‐P, treatment cycles and age, the more frequently and severely do the patients experience CIPN. In predicting the severity of CIPN using Cmax, minimally invasive VAMS is a feasible alternative to venous blood sampling. [ABSTRACT FROM AUTHOR]

Summary: Purposes Vactosertib is a new investigational inhibitor of activin receptor-like kinase 5. The objective of this study was to characterize vactosertib pharmacokinetics that are to be applied for subsequent clinical studies. Methods Vactosertib plasma concentration-time data were obtained from a multicenter, dose-escalation, first-in-human phase 1 study conducted in patients with advanced solid tumors. Each patient orally received a fixed dose of vactosertib with the range of 30 mg to 340 mg once daily under fasted condition. Pharmacokinetic analysis was performed using a non-compartmental method. Results Pharmacokinetic data were evaluable in 29 patients. Vactosertib was rapidly absorbed after the first dose with a median time to maximum concentration (tmax) of 1.2 h (interquartile range, 0.8–1.8 h) and quickly eliminated with a median terminal half-life (t1/2) of 3.2 h (2.2–4.2 h) over the dose range studied. Such trend was also observed after repeated doses for five days (median tmax, 1.5 h; median t1/2, 3.0 h). The area under the concentration-time curve within a dosing interval increased in proportion to dose. The median values of apparent clearance and volume of distribution were 29 L/h (21–44 L/h) and 133 L (77–222 L), respectively. The median accumulation ratio after repeated once-daily doses for five days was 0.87 (0.69–1.07). Conclusions Vactosertib pharmacokinetics were dose-proportional within tested dose range with negligible accumulation when administered once daily for five days. Considering the short half-life, it seems necessary to administer vactosertib twice- or thrice-daily to maintain its concentrations above minimum effective level over a dosing interval. [ABSTRACT FROM AUTHOR]

Safety and efficacy outcomes of imatinib treatment were evaluated using extensive clinical data collected from a total of 1003 patients with newly diagnosed chronic myeloid leukemia in chronic phase between 2001 and 2018. By 12 months of imatinib treatment at a fixed dose of 400 mg/day, 45.4% of patients experienced at least one type of dose-limiting toxicities (DLTs). The DLTs that frequently occurred first were thrombocytopenia (40.0%), neutropenia/leukopenia (14.3%) and dermatological reactions (12.1%). Patients with lighter body weight (≤ 64 kg) and older age (> 43 years) experienced a markedly higher occurrence of first DLTs by 12 months than heavier and younger patients (57.9% vs. 30.1%, p < 0.001). On the other hand, 38.9% of patients achieved major molecular response (MMR) at 12 months at the fixed dose. Female patients achieved a greater rate of MMR than male patients (45.6% vs. 35.5%, p = 0.028). In conclusion, patients with light weight and old age are more vulnerable to DLTs, whereas female patients gain more efficacy benefit at the fixed dose. The authors suggest that the initial dose of imatinib should be reduced to 300 mg/day or lower for patients vulnerable to DLTs to diminish the risk of DLTs without compromising the achievement of MMR. [ABSTRACT FROM AUTHOR]

Purpose: Vactosertib, a novel inhibitor of transforming growth factor-β type Ι receptor, is under development for the treatment of various cancers. The objective of this study was to characterize the population pharmacokinetics of vactosertib in patients with solid tumors.Methods: Vactosertib population pharmacokinetics was assessed by nonlinear mixed-effects modelling of plasma concentration-time data obtained from a first-in-human phase 1 trial conducted in patients with advanced solid tumors. The final population pharmacokinetic model was constructed by assessing the effect of covariates on pharmacokinetic parameters including demographic characteristics, laboratory values, hepatic and renal function, and concomitant medications. The robustness of the final model was evaluated using a bootstrap method as well as visual predictive check based on Monte Carlo simulations and goodness-of-fit plots.Results: A total of 559 concentrations from 29 patients were available for pharmacokinetic analysis. A two-compartment linear model with first-order absorption and absorption lag time adequately described the population pharmacokinetics of vactosertib. The estimates of apparent clearance (CL/F) and volume of central compartment (Vc/F) were 31.9 L/h (inter-individual variability, 0.481) and 82.9 L (inter-individual variability, 0.534), respectively. The mixture model accounts for both typical absorption profile in the majority of patients and distinct profile in some patients with uncommon gastrointestinal conditions. Body mass index was significantly associated with Vc/F.Conclusions: The model developed in this study adequately describes the population pharmacokinetics of vactosertib in patients with advanced solid tumors. The pharmacokinetic characteristics assessed using the model would provide useful quantitative information to assist the future clinical development of vactosertib. [ABSTRACT FROM AUTHOR]

The present study aimed to assess the clinical impact of BCR‐ABL1 transcript levels determined at an earlier time point than the 3‐month early molecular response (EMR) in chronic‐phase chronic myeloid leukemia (CML‐CP) patients. BCR‐ABL1 transcript levels of CML‐CP patients (n = 258; median age, 43 [range, 18‐81] years) treated with various tyrosine kinase inhibitors (TKIs) were determined at 4 weeks (28 ± 3 days) and at every 3 months of treatment initiation. At 4 weeks, receiver operating characteristic curves revealed that cutoff values of BCR‐ABL1 transcripts for achieving major molecular responses (MMRs) by 12 and 60 months were 40.89% and 39.16%, respectively (95% CI, 0.658‐0.772 and 95% CI, 0.643‐0.758; P < 0.0001). With 40% of BCR‐ABL1 transcripts at 4 weeks (very early MR; VEMR), patients with VEMR achieved higher 3‐month EMR and 4‐week VEMR significantly associated with higher cumulative incidences of 5‐year MMR (89.1% vs 72.3%; P < 0.001) and 5‐year deep molecular response (DMR) (56.5% vs 29.4%; P = 0.001). Furthermore, event‐free survival (EFS)‐a (93.0% vs 84.8%; P = 0.068) and EFS‐b (71.1% vs 57.9%; P = 0.061) by 5 years were also marginally significant. VEMR and 3‐month EMR were achieved in 89 patients, with significantly superior outcomes. In multivariate analyses, lower leukocyte count (P = 0.008) and frontline second‐generation TKI therapy size (P < 0.001) were significantly associated with VEMR achievement, but not baseline BCR‐ABL1 level and CML duration. In conclusion, the 4‐week BCR‐ABL1 transcript levels including VEMR could be important to predict long‐term outcomes and may provide additional information about innate intrinsic sensitivity to CML among individuals. The very early molecular response assessment could be important to predict long‐term outcomes and may provide additional information about innate intrinsic sensitivity to individual CML clone. As it also allows for the prediction of DMR, VEMR can be used as one of the important tools to select candidates for treatment‐free remission. [ABSTRACT FROM AUTHOR]

Abstract: Radotinib is a second‐generation BCR‐ABL1 tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia in chronic phase (CP‐CML). Here, using the data from a Phase 3 study conducted in patients with newly diagnosed CP‐CML, the dose–efficacy as well as dose–safety relationship analyses were performed to determine a safe and effective initial dosage regimen of radotinib. A significant positive association was detected between the starting dose of radotinib adjusted for body weight (Dose/BW) and the probability of dose‐limiting toxicity (≥grade 3 hematologic and nonhematologic toxicity) (P = 0.003). In contrast, a significant inverse association was discovered between Dose/BW and the probability of major molecular response (BCR‐ABL1/ABL1 ≤ 0.1%) when controlled for sex (P = 0.033). Moreover, frequent dose interruptions and reductions secondary to radotinib toxicities occurred in the Phase 3 study, resulting in nearly half (44%) of patients receiving a reduced dose at a 12‐month follow‐up. In conclusion, the results of this study demonstrate the need for initial radotinib dose attenuation to improve the long‐term efficacy and safety of radotinib. Hence, the authors suggest a new upfront radotinib dose of 400 mg once daily be tested in patients with newly diagnosed CP‐CML. [ABSTRACT FROM AUTHOR]

Background: An optimal therapy for the treatment of pneumonia caused by drug-resistant Acinetobacter baumannii remains unclear. This study aims to compare various antimicrobial strategies and to determine the most effective therapy for pneumonia using a network meta-analysis.Methods: Systematic search and quality assessment were performed to select eligible studies reporting one of the following outcomes: all-cause mortality, clinical cure, and microbiological eradication. The primary outcome was all-cause mortality. A network meta-analysis was conducted with a Bayesian approach. Antimicrobial treatments were ranked based on surface under the cumulative ranking curve (SUCRA) value along with estimated median outcome rate and corresponding 95% credible intervals (CrIs). Two treatments were considered significantly different if a posterior probability of superiority (P) was greater than 97.5%.Results: Twenty-three studies evaluating 15 antimicrobial treatments were included. Intravenous colistin monotherapy (IV COL) was selected as a common comparator, serving as a bridge for developing the network. Five treatments ranked higher than IV COL (SUCRA, 57.1%; median all-cause mortality 0.45, 95% CrI 0.41-0.48) for reducing all-cause mortality: sulbactam monotherapy (SUL, 100.0%; 0.18, 0.04-0.42), high-dose SUL (HD SUL, 85.7%; 0.31, 0.07-0.71), fosfomycin plus IV COL (FOS + IV COL, 78.6%; 0.34, 0.19-0.54), inhaled COL plus IV COL (IH COL + IV COL, 71.4%; 0.39, 0.32-0.46), and high-dose tigecycline (HD TIG, 71.4%; 0.39, 0.16-0.67). Those five treatments also ranked higher than IV COL (SUCRA, 45.5%) for improving clinical cure (72.7%, 72.7%, 63.6%, 81.8%, and 90.9%, respectively). Among the five treatments, SUL (P = 98.1%) and IH COL + IV COL (P = 99.9%) were significantly superior to IV COL for patient survival and clinical cure, respectively. In terms of microbiological eradication, FOS + IV COL (P = 99.8%) and SUL (P = 98.9%) were significantly superior to IV COL.Conclusions: This Bayesian network meta-analysis demonstrated the comparative effectiveness of fifteen antimicrobial treatments for drug-resistant A. baumannii pneumonia in critically ill patients. For survival benefit, SUL appears to be the best treatment followed by HD SUL, FOS + IV COL, IH COL + IV COL, HD TIG, and IV COL therapy, in numerical order. [ABSTRACT FROM AUTHOR]

A fixed dose regimen for tyrosine kinase inhibitors (TKIs) is postulated to be responsible for variable safety outcomes in the treatment of chronic myelogenous leukemia (CML). The objective of this study was to explore an optimal dosing regimen for a TKI, radotinib, to improve its safety profile. Clinical data were obtained from a Phase 2 study of fixed-dose radotinib in 77 Asian patients with CML. The magnitude of radotinib dose adjusted for patient’s body weight (Dose/BW) and the probability of dose-limiting toxicity (DLT) demonstrated a positive association (Logit[P] = 0.86*[Dose/BW]-4.45,p = 0.001). There was a significant difference in the Kaplan-Meier curves for time to first DLT between the patient subgroups of Dose/BW <6 and ≥6 mg/kg (259versus83 days). Consequently, a two-tier weight-based dosing regimen may improve the safety of radotinib: 300 mg or 400 mg twice daily for patients weighing ≤65 or >65 kg, respectively. [ABSTRACT FROM AUTHOR]

Background: To assess the cardiovascular (CV) risk associated with the use of incretin-based therapy in adult patients with type 2 diabetes mellitus (T2DM) primary prevention group with low CV risks. Methods: The clinical studies on incretin-based therapy published in medical journals until August 2014 were comprehensively searched using MEDLINE, EMBASE and CENTRAL with no language restriction. The studies were systemically reviewed and evaluated for CV risks using a meta-analysis approach and where they meet the following criteria: clinical trial, incidence of predefined CV disease, T2DM with no comorbidities, age > 18 years old, duration of at least 12 weeks, incretin-based therapy compared with other antihyperglycaemic agents or placebo. Statistical analyses were performed using a Mantel-Haenszel (M-H) test. The odds ratios (OR) and their 95% confidence interval (CI) were estimated and displayed for comparison. Results: A total of 75 studies comprising 45,648 patients with T2DM were selected. The pooled estimate demonstrated no significance in decreased CV risk with incretin-based therapy versus control (M-H OR, 0.90; 95% CI, 0.81–1.00). Conclusions: This meta-analysis suggests that incretin-based therapy show no significant protective effect on CV events in T2DM primary prevention group with low CV risks. Prospective randomized controlled trials are required to confirm the results of this analysis. [ABSTRACT FROM AUTHOR]

The conservative single-layered wound dressing system is decomposed when mixed in polyvinyl alcohol (PVA) solution, which means it cannot be used with a temperature-sensitive drug. The goal of this investigation was to make an amniotic membrane extract (AME)-loaded double-layered wound dressing with an improved healing result compared to the conservative single-layered wound dressing systems. The double-layered wound dressing was developed with PVA/sodium alginate using a freeze-melting technique; one layer was PVA layer and the other was the drug-loaded sodium alginate layer. Its gel properties were assessed compared to single-layered wound dressings. Moreover, in vivo wound-healing effects and histopathology were calculated compared to commercial products. The double-layered wound dressing gave a similar gel fraction and Young's module as single-layered wound bandages developed with only PVA, and a similar inflammation ability and WVTR as single-layered wound dressings developed with PVA and sodium alginate. Our data indicate that these double-layered wound bandages were just as swellable, but more elastic and stronger than single-layered wound dressings comprised of the same polymers and quantities, possibly giving an acceptable level of moisture and accumulation of exudates in the wound zone. Compared to the commercial product, the double-layered wound dressing comprising 6.7% PVA, 0.5% sodium alginate and 0.01% AME significantly enhanced the wound-healing effect in the wound-healing test. Histological investigations showed that superior full-thickness wound-healing effects compared to the commercial product. Therefore, the double-layered wound dressing would be an outstanding wound-dressing system with improved wound healing and good gel property. [ABSTRACT FROM AUTHOR]