Background: BRAF V600E mutation is present in a subset of pediatric brain tumors. Vemurafenib is an oral, selective ATP-competitive inhibitor of BRAF V600E kinase. The goal of this multi-center study conducted through the Pacific Pediatric Neuro-Oncology Consortium (PNOC) was to determine the recommended phase 2 dose (RP2D) and dose limiting toxicities (DLTs) in children < 18 years with recurrent or progressive BRAF V600E mutant brain tumors. Results: Nineteen eligible patients were enrolled. Eleven patients had received three or more prior therapies. Data reported are from the start of treatment for the first patient (April 30 2014) through August 31 2019. The RP2D was defined as 550 mg/m 2 twice daily after DLT criteria adjustment for rash. Related grade ≥ 3 adverse events included secondary keratoacanthoma (n = 1); rash (n =16); and fever (n = 5). Subjects received a median of 23 cycles (range 3-63). Four patients remain www.oncotarget.com
The primary objective of this work was to characterize the pharmacokinetics (PK) of gentamicin across the whole pediatric age spectrum from premature neonates to young adults with a single model by identifying significant clinical predictors. A nonlinear mixed‐effect population PK model was developed with retrospective therapeutic drug‐monitoring data. A total of 6459 drug concentration measurements from 3370 hospitalized patients were collected for model building (n = 2357) and evaluation (n = 1013). In agreement with previously reported models, a 2‐compartment model with first‐order elimination best described the drug PK. Patient‐specific factors significantly impacting gentamicin clearance included fat‐free mass, postmenstrual age, and serum creatinine (SCr). Based on our model, the deviation of the individual SCr from the age‐dependent expected mean SCr value (SCrM) can result in a 40% lower clearance in a patient with renal impairment than that in a patient with normal kidney function, with SCrM:SCr ratios between 0.16 and 3.2 in this study. Consistent with the known age‐dependent changes of the proportion of extracellular water in body weight, the inclusion of the impact of extracellular water maturation on the central volume of distribution was found to improve the model fitting significantly. In comparison with other published models, model evaluation suggested the developed model was the least biased and physiologically most representative. These results will be used to inform individualized initial dosing strategies and serve as a prior PK model for Bayesian updating and forecasting as individual clinical observations become available.
The primary objective of this work was to characterize the pharmacokinetics (PK) of systemic clofarabine (clofara) in pediatric allogeneic hematopoietic cell transplantation (HCT) recipients receiving either nucleoside monotherapy or a dual nucleoside analog preparative regimen. Fifty-one children (median age, 4.9 years; range, .25 to 14.9 years) undergoing allogeneic HCT for a variety of malignant and nonmalignant disorders underwent PK assessment. Plasma samples were collected over the 4 to 5 days of clo-fara treatment and quantified for clo-fara, using a validated liquid chromatography/tandem mass spectrometry assay. Nonlinear mixed-effects modeling was used to develop the population PK model, including identification of covariates that influenced drug disposition. In agreement with previously published models, a 2-compartment PK model with first-order elimination best described the PK of clo-fara. Final parameter estimates for clo-fara were consistent with previous reports and were as follows: clearance (CL), 23 L/h/15 kg; volume of the central compartment, 42 L/15 kg; volume of peripheral compartment, 47 L/15 kg; and intercompartmental CL, 9.8 L/h/15 kg. Unexplained variability was acceptable at 33%, and the additive residual error (reflective of the assay) was estimated to be 0.36 ng/mL. Patient-specific factors significantly impacting clo-fara CL included actual body weight and age. The covariate model was able to estimate clo-fara CL with good precision in children spanning a wide age range from infancy to early adulthood and demonstrates the need for variable dosing in children of different ages. For example, the dose required for a 6-month and 1-year old was approximately 43% and 17% lower, respectively, than the typical 40 mg/m 2 dose to achieve the median AUC 0-24 of 1.04 mg¢h/L in the study population. Despite the known renal elimination of clofara, no significant clinical parameters for renal function were retained in the final model (P> .05). Coadministration of fludarabine with clo-fara did not alter the CL of clo-fara (P> .05). These results will help inform individualized dosing strategies for clo-fara to improve clinical outcomes and limit drug-related adverse events in children undergoing HCT.
Atrial fibrosis plays a significant role in the development of atrial fibrillation (AF). Previously, we showed that mitsugumin 53 (MG53) regulates TGF-β1 signaling pathway-induced atrial fibrosis. Recent studies have shown that caveolin-1 (CAV1) is an important anti-fibrosis signaling mediator that inhibits the TGF-β1 signaling pathway. Here, we further study the mechanism underlying the related action of MG53 and CAV1. We demonstrate that CAV1 expression was decreased while MG53 expression was increased in atrial tissue from AF patients. In cultured atrial fibroblasts, MG53 depletion by siRNA caused CAV1 upregulation and TGF-β1/SMAD2 signaling pathway downregulation, while MG53 overexpression via adenovirus had the opposite effect. CAV1 inactivated the TGF-β1/SMAD2 signaling pathway. In addition, using an Ang II-induced fibrosis model, we show that MG53 regulates TGF-β1 signaling via CAV1. Therefore, CAV1 is critical for the MG53 regulation of TGF-β1 signaling pathway-induced atrial fibrosis in AF. These findings reveal the related underlying mechanism of action of MG53 and CAV1 and provide a potential therapeutic target for fibrosis and AF.
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