FDA Approval: Blinatumomab Przepiorka, Donna; Ko, Chia-Wen; Deisseroth, Albert ...
Clinical cancer research,
09/2015, Letnik:
21, Številka:
18
Journal Article
Recenzirano
Odprti dostop
On December 3, 2014, the FDA granted accelerated approval of blinatumomab (Blincyto; Amgen, Inc.) for treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute ...lymphoblastic leukemia (R/R ALL). Blinatumomab is a recombinant murine protein that acts as a bispecific CD19-directed CD3 T-cell engager. The basis for the approval was a single-arm trial with 185 evaluable adults with R/R ALL. The complete remission (CR) rate was 32% 95% confidence interval (CI), 26%-40%, and the median duration of response was 6.7 months. A minimal residual disease response was achieved by 31% (95% CI, 25%-39%) of all patients. Cytokine release syndrome and neurologic events were serious toxicities that occurred. Other common (>20%) adverse reactions were pyrexia, headache, edema, febrile neutropenia, nausea, tremor, and rash. Neutropenia, thrombocytopenia, and elevated transaminases were the most common (>10%) laboratory abnormalities related to blinatumomab. A randomized trial is required in order to confirm clinical benefit.
There are several antibody therapeutics in preclinical and clinical development, industry-wide, for the treatment of central nervous system (CNS) disorders. Due to the limited permeability of ...antibodies across brain barriers, the quantitative understanding of antibody exposure in the CNS is important for the design of antibody drug characteristics and determining appropriate dosing regimens. We have developed a minimal physiologically-based pharmacokinetic (mPBPK) model of the brain for antibody therapeutics, which was reduced from an existing multi-species platform brain PBPK model. All non-brain compartments were combined into a single tissue compartment and cerebral spinal fluid (CSF) compartments were combined into a single CSF compartment. The mPBPK model contains 16 differential equations, compared to 100 in the original PBPK model, and improved simulation speed approximately 11-fold. Area under the curve ratios for minimal versus full PBPK models were close to 1 across species for both brain and plasma compartments, which indicates the reduced model simulations are similar to those of the original model. The minimal model retained detailed physiological processes of the brain while not significantly affecting model predictability, which supports the law of parsimony in the context of balancing model complexity with added predictive power. The minimal model has a variety of applications for supporting the preclinical development of antibody therapeutics and can be expanded to include target information for evaluating target engagement to inform clinical dose selection.
The International Conference on Harmonization E14 guidance for the clinical evaluation of QT/QTc interval prolongation requires almost all new drugs to undergo a dedicated clinical study, primarily ...in healthy volunteers, the so-called TQT study. Since 2005, when the E14 guidance was implemented in United States and Europe, close to 400 TQT studies have been conducted. In February 2012, the Cardiac Safety Research Consortium held a think tank meeting at Food and Drug Administration’s White Oak campus to discuss whether “QT assessment” can be performed as part of routine phase 1 studies. Based on these discussions, a group of experts convened to discuss how to improve the confidence in QT data from early clinical studies, for example, the First-Time-in-Human trial, through collection of serial electrocardiograms and pharmacokinetic samples and the use of exposure response analysis. Recommendations are given on how to design such “early electrocardiogram assessment,” and the limitation of not having a pharmacologic-positive control in these studies is discussed. A research path is identified toward collecting evidence to replace or provide an alternative to the dedicated TQT study.
Study Objective
To compare four common dosing regimens for vancomycin in preterm and term neonates by assessing the probability that each regimen would achieve the widely used therapeutic target ...serum trough concentrations of 5–15 mg/L and the newly suggested target of 15–20 mg/L.
Design
Retrospective population pharmacokinetic analysis using therapeutic drug monitoring data obtained from 1990–2007, with a subsequent simulation study performed on the pharmacokinetic model.
Setting
Tertiary‐care children's hospital.
Patients
One hundred thirty‐four preterm (66%) and term (34%) neonates, with a postnatal age of 1–121 days and postmenstrual age of 24.6–44 weeks.
Measurements and Main Results
Therapeutic drug monitoring data for vancomycin were used to develop a population pharmacokinetic model in the target population. Parameter estimates for the derived pharmacostatistical model were used to perform Monte Carlo simulations for four recommended dosing regimens: a standard dose for all neonates, postmenstrual age–based dosing, postmenstrual and postnatal age–based dosing, and serum creatinine–based dosing. Multivariate age‐weight distributions were established for term and preterm neonates using Centers for Disease Control and Prevention growth charts and intrauterine and postnatal growth charts from the literature, respectively. Each dosing regimen was treated as a separate scenario in which 200 replicates with 100 patients/replicate were simulated. The 5–15‐mg/L target trough serum concentration was achieved in 34% (90% confidence interval CI 20–53%), 42% (90% CI 31–55%), 52% (90% CI 43–60%), and 63% (90% CI 54–72%) of patients receiving the standard dose, postmenstrual age–based dose, postmenstrual and postnatal age–based dose, and serum creatinine–based dose, respectively. Serum creatinine–based dosing produced trough concentrations predominantly in the 5–15‐mg/L target range, with the smallest variability in both term and preterm neonates. As expected, when the target range was narrow and higher (15–20 mg/L), only 13–21% of patients were within the range across the four dosing regimens.
Conclusion
Monte Carlo simulations based on our population pharmacokinetic model suggest that vancomycin dosing guidelines based on serum creatinine concentration have a greater likelihood of achieving trough concentrations in the 5–15‐mg/L range compared with other evaluated dosing regimens. None of the four dosing regimens is suitable to produce target trough concentration of 15–20 mg/L in an acceptable number of patients.
Quadrupolar Asymmetry (QA), which has been a rampant problem for rod-type Radio Frequency Quadrupole (RFQ) Linacs, arises due to the geometry of resonant structure. A systematic parametric simulation ...study has been performed to unravel their effect on Figure of Merit (FoM) quantities namely Quality Factor (Q), Shunt Impedance (Rsh) and Quadrupolar Asymmetry (QA). A novel stem and cavity shape is proposed, which caters to the profile of electromagnetic fields of the resonant structure. A design methodology is formulated, which demonstrates that Quadrupolar Asymmetry can be annihilated, and a symmetric electric field can be produced in all four quadrants of rod-type RFQ accelerator.
Acetaminophen, caffeine, phenytoin, ranitidine, and theophylline are widely used in pediatric pharmacotherapy, but only very limited information is available on the pharmacokinetics of these ...medications in premature neonates. As pharmacokinetic studies in this population are hampered by limitations in the number and volume of plasma samples, we developed an LC-MS/MS assay for the simultaneous determination of these medications in small volume human plasma specimens for pharmacokinetic evaluations in neonates.
Sample preparation was performed by protein precipitation with methanol after addition of internal standard to 50 µl of plasma specimen. After chromatographic separation on a C18 column using gradient elution, analytes were detected using a triple quadrupole mass spectrometer that was operated in positive ion mode with electrospray ionization.
All 5 analytes could be simultaneously quantified in human plasma. The linear quantification range comprised 12.2 to 25,000 ng/ml for acetaminophen, phenytoin, and ranitidine, 24.4 to 25,000 ng/ml for theophylline, and 48.8 to 25,000 ng/ml for caffeine with accuracies ranging from 87.5 to 115.0%. The intra-day and inter-day precision (%CV) was between 2.8 and 11.8% and 4.5 and 13.5%, respectively.
An accurate, sensitive, and reliable LC-MS/MS method was developed and validated to simultaneously quantify 5 drugs frequently used in neonatal pharmacotherapy.
In vaccine efficacy trials, inaccurate counting of infection cases leads to systematic under-estimation—or “dilution”—of vaccine efficacy. In particular, if a sufficient fraction of observed cases ...are false positives, apparent efficacy will be greatly reduced, leading to unwarranted no-go decisions in vaccine development. Here, we propose a range of replicate testing strategies to address this problem, considering the additional challenge of uncertainty in both infection incidence and diagnostic assay specificity/sensitivity. A strategy that counts an infection case only if a majority of replicate assays return a positive result can substantially reduce efficacy dilution for assays with non-systematic (i.e., “random”) errors. We also find that a cost-effective variant of this strategy, using confirmatory assays only if an initial assay is positive, yields a comparable benefit. In clinical trials, where frequent longitudinal samples are needed to detect short-lived infections, this “confirmatory majority rule” strategy can prevent the accumulation of false positives from magnifying efficacy dilution. When widespread public health screening is used for viruses, such as SARS-CoV-2, that have non-differentiating features or may be asymptomatic, these strategies can also serve to reduce unneeded isolations caused by false positives.
Abstract
Smartphones and wearables are widely recognised as the foundation for novel Digital Health Technologies (DHTs) for the clinical assessment of Parkinson’s disease. Yet, only limited progress ...has been made towards their regulatory acceptability as effective drug development tools. A key barrier in achieving this goal relates to the influence of a wide range of sources of variability (SoVs) introduced by measurement processes incorporating DHTs, on their ability to detect relevant changes to PD. This paper introduces a conceptual framework to assist clinical research teams investigating a specific Concept of Interest within a particular Context of Use, to identify, characterise, and when possible, mitigate the influence of SoVs. We illustrate how this conceptual framework can be applied in practice through specific examples, including two data-driven case studies.
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