Rapid Infliximab Infusion in the Pediatric Population.

OBJECTIVES: To compare infusion reaction rates between rapid infliximab (REMICADE, Janssen Biotech Inc) infusions and previous standard 2- to 3-hour infusions; additionally, to assess patient satisfaction and reduction in chair time associated with rapid infliximab infusions. METHODS: Pediatric rheumatology and gastroenterology patients receiving maintenance infliximab therapy using a standard 2- to 3-hour titrated infusion had the opportunity to enroll in the non-titrated rapid 1-hour infusion protocol following tolerance of induction dosing at 0, 2, and 6 weeks. Patients were included from December 1, 2017, to March 31, 2018, via retrospective chart review and patient satisfaction surveys. RESULTS: Data were collected on 55 patients receiving a total of 160 rapid infliximab infusions. There were 2 infusion reactions during the enrollment and data collection period, resulting in an overall infusion reaction rate of 1.3%. The patient satisfaction survey results showed all patients were at minimum satisfied with the information provided regarding rapid infliximab, decreased time spent in clinic, ease of scheduling, and overall process. CONCLUSIONS: Our data suggest rapid infliximab infusions are safe in pediatric rheumatology and gastroenterology patients receiving maintenance infliximab infusion therapy. The overall infusion reaction rate of 1.3% in this study is well below the accepted infusion reaction rate of standard-length infliximab infusions of 2% to 3%.

Simulation studies to understand sensitivity and timing characteristics of an optical property modulation-based radiation detection concept for PET.

The concept of using the modulation mechanisms of a material's optical properties for annihilation photon detection has been proposed as a potential method to significantly improve the coincidence time resolution (CTR) of positron emission tomography detectors. However, the possibility of detecting individual 511 keV photons with largely improved CTR using the proposed detection method has not yet been demonstrated, either experimentally or theoretically. In addition, the underlying physical picture of the optical modulation effects induced by annihilation photons has not been fully understood. In this work, we perform simulation studies including generation of the annihilation photon-induced ionization energy deposition trajectory, estimation of the charge carrier cascade time and temporal variance, simulation of the distribution of ionization-induced charge carrier density, and calculation of the strength of the modulation of two optical parameters: the absorption coefficient and the refractive index, as well as evaluation of the resulting optical intensity and phase change experienced by a probe laser beam. Our simulation results show that the average absorption coefficient modulation induced by individual 511 keV photon interactions is around 0.04 cm-1, and the average refractive index change is 3.6 × 10-5, leading to modulations in the probe laser intensity of around 0.1% and phase modulation of around 0.05 radians. We have also found that the ionization process induced by a single 511 keV photon interaction occurs within 2.3 ps with a temporal variance of 0.4 ps. The fundamental limit on CTR using the optical property modulation-based detection mechanism is estimated to be around 1.2 ps full width at half maximum. Our simulation results indicate that with proper experiment design, it is possible to detect the ionization produced by an individual 511 keV photon with significantly improved CTR using the optical property modulation-based detection concept.

Microsampling for quantitative bioanalysis, an industry update: output from an AAPS/EBF survey.

There is continuing interest in the development and application of various microsampling technologies for drug development. The AAPS bioanalytical community microsampling subgroup and the European Bioanalysis Forum conducted a survey of their members (39 individual organizations). This gives a snapshot of current practices and demonstrates that implementation of microsampling approaches is becoming increasingly commonplace, but not universal. Greater adoption was observed for nonclinical studies, particularly nonregulatory. A number of respondents reported that they have included microsampling data in regulatory submissions. Another important observation was that where microsampling is employed for clinical studies, dried blood approaches predominate, reflecting the interest in their use where they enable sample collection which is not feasible with standard approaches or to derive richer data sets.

Rectilinear Edge Selectivity Is Insufficient to Explain the Category Selectivity of the Parahippocampal Place Area.

The parahippocampal place area (PPA) is one of several brain regions that respond more strongly to scenes than to non-scene items such as objects and faces. The mechanism underlying this scene-preferential response remains unclear. One possibility is that the PPA is tuned to low-level stimulus features that are found more often in scenes than in less-preferred stimuli. Supporting this view, Nasr et al. (2014) recently observed that some of the stimuli that are known to strongly activate the PPA contain a large number of rectilinear edges. They further demonstrated that PPA response is modulated by rectilinearity for a range of non-scene images. Motivated by these results, we tested whether rectilinearity suffices to explain PPA selectivity for scenes. In the first experiment, we replicated the previous finding of modulation by rectilinearity in the PPA for arrays of 2-d shapes. However, two further experiments failed to find a rectilinearity effect for faces or scenes: high-rectilinearity faces and scenes did not activate the PPA any more strongly than low-rectilinearity faces and scenes. Moreover, the categorical advantage for scenes vs. faces was maintained in the PPA and two other scene-selective regions-the retrosplenial complex (RSC) and occipital place area (OPA)-when rectilinearity was matched between stimulus sets. We conclude that selectivity for scenes in the PPA cannot be explained by a preference for low-level rectilinear edges.

Techniques for quantitative LC-MS/MS analysis of protein therapeutics: advances in enzyme digestion and immunocapture.

LC-MS/MS has been investigated to quantify protein therapeutics in biological matrices. The protein therapeutics is digested by an enzyme to generate surrogate peptide(s) before LC-MS/MS analysis. One challenge is isolating protein therapeutics in the presence of large number of endogenous proteins in biological matrices. Immunocapture, in which a capture agent is used to preferentially bind the protein therapeutics over other proteins, is gaining traction. The protein therapeutics is eluted for digestion and LC-MS/MS analysis. One area of tremendous potential for immunocapture-LC-MS/MS is to obtain quantitative data where ligand-binding assay alone is not sufficient, for example, quantitation of antidrug antibody complexes. Herein, we present an overview of recent advance in enzyme digestion and immunocapture applicable to protein quantitation.

Simultaneous perceptual and response biases on sequential face attractiveness judgments.

Face attractiveness is a social characteristic that we often use to make first-pass judgments about the people around us. However, these judgments are highly influenced by our surrounding social world, and researchers still understand little about the mechanisms underlying these influences. In a series of 3 experiments, we use a novel sequential rating paradigm that enables us to measure biases in attractiveness judgments from the previous face and the previous rating. Our results reveal 2 simultaneous and opposing influences on face attractiveness judgments that arise from past experience of faces: a response bias in which attractiveness ratings shift toward a previously given rating and a stimulus bias in which attractiveness ratings shift away from the mean attractiveness of the previous face. Further, we provide evidence that the contrastive stimulus bias (but not the assimilative response bias) is strengthened by increasing the duration of the previous stimulus, suggesting an underlying perceptual mechanism. These results demonstrate that judgments of face attractiveness are influenced by information from our evaluative and perceptual history and that these influences have measurable behavioral effects over the course of just a few seconds.

Phase I study to assess the pharmacokinetics and the effect on cardiac repolarization of amrubicin and amrubicinol in patients with advanced solid tumors.

PURPOSE: To evaluate the pharmacokinetics and cardiac repolarization effect (measured by QT/QTc interval) of amrubicin and its active metabolite amrubicinol in non-Japanese patients with advanced solid tumors. METHODS: Patients received amrubicin 40 mg/m(2)/day as a 5-min infusion on days 1-3 of a 21-day cycle. During cycle 1, serial blood and plasma samples were collected on days 1-9 and time-matched triplicate electrocardiograms on the "off-drug" visit (1-5 days prior to start of treatment) and days 1-9. RESULTS: Twenty-four patients were treated. Amrubicinol reached peak concentration 2-4 h after amrubicin administration and had a terminal half-life of 53 h. Distribution of amrubicinol into erythrocytes was fivefold greater than into plasma. The molar ratio of amrubicinol to amrubicin in blood was 0.67 on day 3. The presence of an NQO1 polymorphism did not alter drug exposure. The upper bound of the one-sided 95 % confidence interval for the time-matched, baseline-adjusted change from the off-drug day in QTcI (individual correction) was <10 ms at all times and was only >10 ms (10.20 ms) at a single time point for QTcF (Fridericia correction). No relationship was observed between blood amrubicin or amrubicinol concentrations and QTcF changes. All QTcF measurements were <480 ms, and none increased by >60 ms from baseline. CONCLUSIONS: Data suggest that amrubicinol is an important active metabolite in humans and that both compounds were not associated with clinically relevant QTc interval prolongation at the dose regimen studied.

Nonclinical dose formulation: out of specification investigations.

Nonclinical safety studies are required to follow applicable Good Laboratory Practice (GLP) regulations. Nonclinical dose formulations are required to be analyzed to confirm the analyte concentration, homogeneity, and stability. Analytical samples that fall outside of the acceptance criteria are considered out of specification (OOS), and an investigation should be conducted. The US FDA has issued a guidance document for GMP studies on conducting OOS investigations. However, no regulatory guidance has been issued regarding nonclinical safety study (GLP) OOS investigations, which often vary in regard to content, assessment, and impact statements. There is opportunity to improve the quality of OOS investigations by defining expectations and providing guidance in several areas including root cause assessment, impact statements, and acceptable paths forward. This paper will provide recommendations of best practices for nonclinical dose formulation OOS investigations.

Nonclinical dose formulation analysis method validation and sample analysis.

Nonclinical dose formulation analysis methods are used to confirm test article concentration and homogeneity in formulations and determine formulation stability in support of regulated nonclinical studies. There is currently no regulatory guidance for nonclinical dose formulation analysis method validation or sample analysis. Regulatory guidance for the validation of analytical procedures has been developed for drug product/formulation testing; however, verification of the formulation concentrations falls under the framework of GLP regulations (not GMP). The only current related regulatory guidance is the bioanalytical guidance for method validation. The fundamental parameters for bioanalysis and formulation analysis validations that overlap include: recovery, accuracy, precision, specificity, selectivity, carryover, sensitivity, and stability. Divergence in bioanalytical and drug product validations typically center around the acceptance criteria used. As the dose formulation samples are not true "unknowns", the concept of quality control samples that cover the entire range of the standard curve serving as the indication for the confidence in the data generated from the "unknown" study samples may not always be necessary. Also, the standard bioanalytical acceptance criteria may not be directly applicable, especially when the determined concentration does not match the target concentration. This paper attempts to reconcile the different practices being performed in the community and to provide recommendations of best practices and proposed acceptance criteria for nonclinical dose formulation method validation and sample analysis.