"In the wilderness dealing with difficult situations": Knowledge exchange with care home staff in England on managing seizures and epilepsy - An initial exploration.

PURPOSE: With epilepsy increasingly affecting older adults, seizure-related care needs arise in new settings. Persons in these settings must receive optimal support and challenges identified for remediation. This may entail the epilepsy community researching in unfamiliar environments. One setting is care homes. Seizure-related ambulance incidents in them are common. We conducted the first qualitative study with care home staff to explore their experiences and challenges in managing suspected seizures. METHODS: Three online focus groups were organised for January 2024 to explore ambulance calls, post-incident procedures, and challenges faced by care home staff when managing seizures. Persons were eligible to participate if they worked as a care assistant, nurse or manager in a care home in North-West England. Different recruitment pathways were employed including direct approach, a managers' network, social media and a register of research interested homes. Focus group audio recordings were transcribed and analysed using Hamilton's Rapid Analysis. RESULTS: Recruitment was difficult; 13 care home staff from 12 different homes were ultimately recruited. Despite data saturation not being achieved, insights were gained regarding ambulance call decisions, paperwork navigation, and follow-up care challenges. Patients not having meaningful seizure action plans in place and regulatory restrictions were identified as factors that contributed to potentially avoidable calls for ambulance help being made. CONCLUSION: This study highlights systemic issues in care homes' seizure care, emphasizing the need for further research. The epilepsy community may need to innovate to better research within this increasingly important setting. This study offers insights into the effectiveness of different recruitment strategies.

Modelling Consciousness within Mental Monism: An Automata-Theoretic Approach.

Models of consciousness are usually developed within physical monist or dualistic frameworks, in which the structure and dynamics of the mind are derived from the workings of the physical brain. Little attention has been given to modelling consciousness within a mental monist framework, deriving the structure and dynamics of the mental world from primitive mental constituents only-with no neural substrate. Mental monism is gaining attention as a candidate solution to Chalmers' Hard Problem on philosophical grounds, and it is therefore timely to examine possible formal models of consciousness within it. Here, I argue that the austere ontology of mental monism places certain constraints on possible models of consciousness, and propose a minimal set of hypotheses that a model of consciousness (within mental monism) should respect. From those hypotheses, it would be possible to construct many formal models that permit universal computation in the mental world, through cellular automata. We need further hypotheses to define transition rules for particular models, and I propose a transition rule with the unusual property of deep copying in the time dimension.

Pharmacokinetics of serelaxin in patients with hepatic impairment: a single-dose, open-label, parallel group study.

AIMS: Serelaxin is a recombinant form of human relaxin-2 in development for treatment of acute heart failure. This study aimed to evaluate the pharmacokinetics (PK) of serelaxin in patients with hepatic impairment. Secondary objectives included evaluation of immunogenicity, safety and tolerability of serelaxin. METHODS: This was an open-label, parallel group study (NCT01433458) comparing the PK of serelaxin following a single 24 h intravenous (i.v.) infusion (30 µg kg(-1) day(-1) ) between patients with mild, moderate or severe hepatic impairment (Child-Pugh class A, B, C) and healthy matched controls. Blood sampling and standard safety assessments were conducted. Primary non-compartmental PK parameters [including area under the serum concentration-time curve AUC(0-48 h) and AUC(0-∞) and serum concentration at 24 h post-dose (C24h )] were compared between each hepatic impairment group and healthy controls. RESULTS: A total of 49 subjects (including 25 patients with hepatic impairment) were enrolled, of which 48 subjects completed the study. In all groups, the serum concentration of serelaxin increased over the first few hours of infusion, reached steady-state at 12-24 h and then declined following completion of infusion, with a mean terminal half-life of 7-8 h. All PK parameter estimates were comparable between each group of patients with hepatic impairment and healthy controls. No serious adverse events, discontinuations due to adverse events or deaths were reported. No serelaxin treatment-related antibodies developed during this study. CONCLUSIONS: The PK and safety profile of serelaxin were not affected by hepatic impairment. No dose adjustment is needed for serelaxin treatment of 48 h i.v. infusion in patients with hepatic impairment.

Patient-Specific Magnetic Catheters for Atraumatic Autonomous Endoscopy.

Despite increasing interest in minimally invasive surgical techniques and related developments in flexible endoscopes and catheters, follow-the-leader motion remains elusive. Following the path of least resistance through a tortuous and potentially delicate environment without relying on interaction with the surrounding anatomy requires the control of many degrees of freedom. This typically results in large-diameter instruments. One viable solution to obtain dexterity without increasing size is via multiple-point magnetic actuation over the length of the catheter. The main challenge of this approach is planning magnetic interaction to allow the catheter to adapt to the surrounding anatomy during navigation. We design and manufacture a fully shape-forming, soft magnetic catheter of 80 mm length and 2 mm diameter, capable of navigating a human anatomy in a follow-the-leader fashion. Although this system could be exploited for a range of endoscopic or intravascular applications, here we demonstrate its efficacy for navigational bronchoscopy. From a patient-specific preoperative scan, we optimize the catheters' magnetization profiles and the shape-forming actuating field. To generate the required transient magnetic fields, a dual-robot arm system is employed. We fabricate three separate prototypes to demonstrate minimal contact navigation through a three-dimensional bronchial tree phantom under precomputed robotic control. We also compare a further four separate optimally designed catheters against mechanically equivalent designs with axial magnetization profiles along their length and only at the tip. Using our follow-the-leader approach, we demonstrate up to 50% more accurate tracking, 50% reduction in obstacle contact time during navigation over the state of the art, and an improvement in targeting error of 90%.

Fine-tuned long-acting interleukin-2 superkine potentiates durable immune responses in mice and non-human primate.

BACKGROUND: Recombinant human interleukin-2 (rhIL-2, aldesleukin) is Food and Drug Administration approved for the treatment of metastatic melanoma and renal cell carcinoma and has achieved durable response in a subset of patients. However, its utility as an immunotherapeutic drug is limited by undesirable activation of immune suppressive regulatory T cells (Tregs) and a short half-life requiring frequent high dose administration, leading to unacceptable toxicities. We have engineered MDNA11, a long-acting IL-2 superkine, to overcome these limitations by (1) modifying receptor selectivity in favor of anti-cancer immune cells to increase therapeutic efficacy and (2) fusion to human albumin to extend the pharmacokinetic (PK) profile, circumventing the need for frequent dosing. METHODS: MDNA11 was evaluated using in vitro and in vivo studies including: binding analyses to measure receptor affinity, IL-2 pathway signaling, PK studies in mice, and efficacy studies in syngeneic tumor models as single agent and in combination with immune checkpoint inhibitors. Finally, the safety and pharmacodynamic profile of MDNA11 was assessed in non-human primate (NHP). RESULTS: Binding studies with MDNA11 demonstrated increased affinity for IL-2Rß (CD122) and no binding to IL-2Rα (CD25). As a result, MDNA11 exhibits reduced/limited Treg stimulation while triggering an enhanced activation of natural killer and naïve CD8 T cells compared with rhIL-2. When administered to animals with pre-established tumors, MDNA11 controlled tumor growth in a monotherapy setting and in combination with anti-PD1 or anti-CTLA4 to induce durable tumor clearance with a once weekly dosing regimen. In a NHP model, MDNA11 was well tolerated while triggering durable and potent immune responses including expansion of lymphocytes without significant effect on Tregs and eosinophils, the latter been linked to an increased risk of vascular leak syndrome. CONCLUSION: MDNA11 is a next generation long-acting IL-2 immunotherapeutic with a highly favorable pharmacodynamic profile that translates to a strong therapeutic efficacy in preclinical tumor models and a strong and durable immune response in NHP.

Optimization and fabrication of programmable domains for soft magnetic robots: A review.

Driven by the aim of realizing functional robotic systems at the milli- and submillimetre scale for biomedical applications, the area of magnetically driven soft devices has received significant recent attention. This has resulted in a new generation of magnetically controlled soft robots with patterns of embedded, programmable domains throughout their structures. This type of programmable magnetic profiling equips magnetic soft robots with shape programmable memory and can be achieved through the distribution of discrete domains (voxels) with variable magnetic densities and magnetization directions. This approach has produced highly compliant, and often bio-inspired structures that are well suited to biomedical applications at small scales, including microfluidic transport and shape-forming surgical catheters. However, to unlock the full potential of magnetic soft robots with improved designs and control, significant challenges remain in their compositional optimization and fabrication. This review considers recent advances and challenges in the interlinked optimization and fabrication aspects of programmable domains within magnetic soft robots. Through a combination of improvements in the computational capacity of novel optimization methods with advances in the resolution, material selection and automation of existing and novel fabrication methods, significant further developments in programmable magnetic soft robots may be realized.

The clinical efficacy of two semi-quantitative wound-swabbing techniques in identifying the causative organism(s) in infected cutaneous wounds.

A prospective randomised controlled trial of two paired wound-swabbing techniques (Levine versus Z) was conducted to establish which method was more effective in determining the presence of bacteria in clinically infected wounds. The Levine technique involves rotating the wound swab over a 1-cm(2) area of the wound; the Z technique involves rotating the swab between the fingers in a zigzag fashion across the wound without touching the wound edge. Fifty patients were recruited into the study with acute (42%) and chronic wounds (58%). Overall, the Levine technique detected significantly more organisms than the Z technique (P≤ 0· 001). When acute and chronic wounds were analysed separately, the Levine technique again detected more organisms in both acute (P≤ 0· 001) and chronic wounds (P≤ 0· 001). We conclude that the Levine technique is superior to the Z technique and this result may be because of the Levine technique's ability to express fluid from the wound bed and thereby sampling a greater concentration of microorganisms from both the surface and slightly below the surface of the wound.

Modelling the Spread of the Coronavirus: A View from Economics.

This article reviews the modelling of the spread in Australia of COVID-19 from the point of view of the discipline of Economics. After a brief overview of the epidemiological approach, we show that other modelling is needed for policy purposes and especially to provide a full understanding of the economic and social costs of disease control. We look at microeconomic aspects of infection, focusing on individual behaviour, the choices facing the individual and implications for policy. The use of a cost-benefit approach and macroeconomic aspects of the pandemic are examined together with the economic consequences of policy response.

Feasibility of Fiber Reinforcement Within Magnetically Actuated Soft Continuum Robots.

Soft continuum manipulators have the potential to replace traditional surgical catheters; offering greater dexterity with access to previously unfeasible locations for a wide range of interventions including neurological and cardiovascular. Magnetically actuated catheters are of particular interest due to their potential for miniaturization and remote control. Challenges around the operation of these catheters exist however, and one of these occurs when the angle between the actuating field and the local magnetization vector of the catheter exceeds 90°. In this arrangement, deformation generated by the resultant magnetic moment acts to increase magnetic torque, leading to potential instability. This phenomenon can cause unpredictable responses to actuation, particularly for soft, flexible materials. When coupled with the inherent challenges of sensing and localization inside living tissue, this behavior represents a barrier to progress. In this feasibility study we propose and investigate the use of helical fiber reinforcement within magnetically actuated soft continuum manipulators. Using numerical simulation to explore the design space, we optimize fiber parameters to enhance the ratio of torsional to bending stiffness. Through bespoke fabrication of an optimized helix design we validate a single, prototypical two-segment, 40 mm × 6 mm continuum manipulator demonstrating a reduction of 67% in unwanted twisting under actuation.

Evolutionary Inverse Material Identification: Bespoke Characterization of Soft Materials Using a Metaheuristic Algorithm.

The growing interest in soft robotics has resulted in an increased demand for accurate and reliable material modelling. As soft robots experience high deformations, highly nonlinear behavior is possible. Several analytical models that are able to capture this nonlinear behavior have been proposed, however, accurately calibrating them for specific materials and applications can be challenging. Multiple experimental testbeds may be required for material characterization which can be expensive and cumbersome. In this work, we propose an alternative framework for parameter fitting established hyperelastic material models, with the aim of improving their utility in the modelling of soft continuum robots. We define a minimization problem to reduce fitting errors between a soft continuum robot deformed experimentally and its equivalent finite element simulation. The soft material is characterized using four commonly employed hyperelastic material models (Neo Hookean; Mooney-Rivlin; Yeoh; and Ogden). To meet the complexity of the defined problem, we use an evolutionary algorithm to navigate the search space and determine optimal parameters for a selected material model and a specific actuation method, naming this approach as Evolutionary Inverse Material Identification (EIMI). We test the proposed approach with a magnetically actuated soft robot by characterizing two polymers often employed in the field: Dragon Skin™ 10 MEDIUM and Ecoflex™ 00-50. To determine the goodness of the FEM simulation for a specific set of model parameters, we define a function that measures the distance between the mesh of the FEM simulation and the experimental data. Our characterization framework showed an improvement greater than 6% compared to conventional model fitting approaches at different strain ranges based on the benchmark defined. Furthermore, the low variability across the different models obtained using our approach demonstrates reduced dependence on model and strain-range selection, making it well suited to application-specific soft robot modelling.

A Synthetic Peptide CTL Vaccine Targeting Nucleocapsid Confers Protection from SARS-CoV-2 Challenge in Rhesus Macaques.

BACKGROUND: Persistent transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a COVID-19 pandemic. Several vaccines, conceived in 2020, that evoke protective spike antibody responses are being deployed in mass public health vaccination programs. Recent data suggests, however, that as sequence variation in the spike genome accumulates, some vaccines may lose efficacy. METHODS: Using a macaque model of SARS-CoV-2 infection, we tested the efficacy of a peptide-based vaccine targeting MHC class I epitopes on the SARS-CoV-2 nucleocapsid protein. We administered biodegradable microspheres with synthetic peptides and adjuvants to rhesus macaques. Unvaccinated control and vaccinated macaques were challenged with 1 × 108 TCID50 units of SARS-CoV-2, followed by assessment of clinical symptoms and viral load, chest radiographs, and sampling of peripheral blood and bronchoalveolar lavage (BAL) fluid for downstream analysis. RESULTS: Vaccinated animals were free of pneumonia-like infiltrates characteristic of SARS-CoV-2 infection and presented with lower viral loads relative to controls. Gene expression in cells collected from BAL samples of vaccinated macaques revealed a unique signature associated with enhanced development of adaptive immune responses relative to control macaques. CONCLUSIONS: We demonstrate that a room temperature stable peptide vaccine based on known immunogenic HLA class I bound CTL epitopes from the nucleocapsid protein can provide protection against SARS-CoV-2 infection in nonhuman primates.

Polymer, Additives, and Processing Effects on N95 Filter Performance.

The current severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) pandemic has highlighted the need for personal protective equipment, specifically filtering facepiece respirators like N95 masks. While it is common knowledge that polypropylene (PP) is the industry standard material for filtration media, trial and error is often required to identify suitable commercial precursors for filtration media production. This work aims to identify differences between several commercial grades of PP and demonstrate the development of N95 filtration media with the intent that the industry partners can pivot and help address N95 shortages. Three commercial grades of high melt flow index PP were melt blown at Oak Ridge National Laboratory and broadly characterized by several methods including differential scanning calorimetry (DSC), X-ray diffraction (XRD), and neutron scattering. Despite the apparent similarities (high melt flow and isotacticity) between PP feedstocks, the application of corona charging and charge enhancing additives improve each material to widely varying degrees. From the analysis performed here, the most differentiating factor appears to be related to crystallization of the polymer and the resulting electret formation. Materials with higher crystallization onset temperatures, slower crystallization rates, and larger number of crystallites form a stronger electret and are more effective at filtration.

MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial.

PURPOSE: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α. PATIENTS AND METHODS: We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design). RESULTS: Thirty-eight participants have been treated across six dose levels (28-160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment-related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD. CONCLUSIONS: MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC.

Half-life extension and non-human primate pharmacokinetic safety studies of i-body AD-114 targeting human CXCR4.

Single domain antibodies that combine antigen specificity with high tissue penetration are an attractive alternative to conventional antibodies. However, rapid clearance from the bloodstream owing to their small size can be a limitation of therapeutic single domain antibodies. Here, we describe and evaluate the conjugation of a single domain i-body, AD-114, which targets CXCR4, to a panel of half-life extension technologies including a human serum albumin-binding peptide, linear and branched PEG, and PASylation (PA600). The conjugates were assessed in murine, rat and cynomolgus monkey pharmacokinetic studies and showed that the branched PEG was most effective at extending circulating half-life in mice; however, manufacturing limitations of PEGylated test material precluded scale-up and assessment in larger animals. PA600, by comparison, was amenable to scale-up and afforded considerable half-life improvements in mice, rats and cynomolgus monkeys. In mice, the circulating half-life of AD-114 was extended from 0.18 h to 7.77 h following conjugation to PA600, and in cynomolgus monkeys, the circulating half-life of AD-114-PA600 was 24.27 h. AD-114-PA600 was well tolerated in cynomolgus monkeys at dose rates up to 100 mg/kg with no mortalities or drug-related clinical signs.

Ultra-fast absorption of amorphous pure drug aerosols via deep lung inhalation.

A deficiency of most current drug products for treatment of acute conditions is slow onset of action. A promising means of accelerating drug action is through rapid systemic drug administration via deep lung inhalation. The speed of pulmonary drug absorption depends on the site of aerosol deposition within the lung and the dissolution rate and drug content of the deposited particles. Alveolar delivery of fast-dissolving, pure drug particles should in theory enable very rapid absorption. We have previously shown that heating of thin drug films generates vapor-phase drug that subsequently cools and condenses into pure drug particles of optimal size for alveolar delivery. Here we present a hand held, disposable, breath-actuated device incorporating this thermal aerosol technology, and its application to the delivery of alprazolam, an anti-panic agent, and prochlorperazine, an anti-emetic with recently discovered anti-migraine properties. Thermal aerosol particles of these drugs exist in an amorphous state, which results in remarkably rapid drug absorption from the lung into the systemic circulation, with peak left ventricular concentrations achieved within 20 s, even quicker than following rapid (5 s) intravenous infusion. Absorption of the thermal aerosol is nearly complete, with >80% absolute bioavailability found in both dogs and human normal volunteers.

Development of a Pitch Discrimination Screening Test for Preschool Children.

BACKGROUND: There is a critical need for tests of auditory discrimination for young children as this skill plays a fundamental role in the development of speaking, prereading, reading, language, and more complex auditory processes. Frequency discrimination is important with regard to basic sensory processing affecting phonological processing, dyslexia, measurements of intelligence, auditory memory, Asperger syndrome, and specific language impairment. PURPOSE: This study was performed to determine the clinical feasibility of the Pitch Discrimination Test (PDT) to screen the preschool child's ability to discriminate some of the acoustic demands of speech perception, primarily pitch discrimination, without linguistic content. The PDT used brief speech frequency tones to gather normative data from preschool children aged 3 to 5 yrs. RESEARCH DESIGN: A cross-sectional study was used to gather data regarding the pitch discrimination abilities of a sample of typically developing preschool children, between 3 and 5 yrs of age. The PDT consists of ten trials using two pure tones of 100-msec duration each, and was administered in an AA or AB forced-choice response format. STUDY SAMPLE: Data from 90 typically developing preschool children between the ages of 3 and 5 yrs were used to provide normative data. DATA ANALYSIS: Nonparametric Mann-Whitney U-testing was used to examine the effects of age as a continuous variable on pitch discrimination. The Kruskal-Wallis test was used to determine the significance of age on performance on the PDT. Spearman rank was used to determine the correlation of age and performance on the PDT. RESULTS: Pitch discrimination of brief tones improved significantly from age 3 yrs to age 4 yrs, as well as from age 3 yrs to the age 4- and 5-yrs group. Results indicated that between ages 3 and 4 yrs, children's auditory discrimination of pitch improved on the PDT. The data showed that children can be screened for auditory discrimination of pitch beginning with age 4 yrs. CONCLUSIONS: The PDT proved to be a time efficient, feasible tool for a simple form of frequency discrimination screening in the preschool population before the age where other diagnostic tests of auditory processing disorders can be used.

Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients.

PURPOSE: To evaluate the basic pharmacokinetic (PK) characteristics of imatinib mesylate and assess the relationship between the PK and pharmacodynamic (PD) properties of the drug. PATIENTS AND METHODS: The PK and PD properties of imatinib were investigated during a phase I trial that included 64 adult patients with Philadelphia chromosome-positive leukemias. Patients received imatinib orally once or twice daily. PK parameters of imatinib, derived from the plasma concentration-time curves, were determined. PD response, defined as the WBC after 1 month of treatment with imatinib, was used to develop an efficacy model. A maximum inhibition-effect model was used to describe the relationship between reduction in WBC and drug exposure parameters. RESULTS: Imatinib exposure was dose proportional after oral administration for the dose range of 25 to 1,000 mg. There was a 1.5- to three-fold drug accumulation after repeated once-daily dosing. Mean plasma trough concentration was 0.57 microg/mL (approximately 1 micromol/L) 24 hours after administration of 350 mg of imatinib at steady-state, which exceeds the 50% inhibitory concentration required to inhibit proliferation of Bcr-Abl-positive leukemic cells. Analysis of PK/PD relationships indicates that the initial hematologic response depends on the administered dose for patients with chronic myeloid leukemia. CONCLUSION: Drug exposure (area under the concentration-time curve) is dose proportional for the dose range of 25 to 1,000 mg, and there is a 1.5- to three-fold drug accumulation at steady-state after once-daily dosing. Analysis of the relationship between PD (WBC reduction) and PK parameters at steady-state indicates that a dose of 400 mg or greater is required for maximal PD effect.

Clinical pharmacokinetics of imatinib.

Imatinib is a potent and selective inhibitor of the protein tyrosine kinase Bcr-Abl, platelet-derived growth factor receptors (PDGFRalpha and PDGFRbeta) and KIT. Imatinib is approved for the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST), which have dysregulated activity of an imatinib-sensitive kinase as the underlying pathogenetic feature. Pharmacokinetic studies of imatinib in healthy volunteers and patients with CML, GIST and other cancers show that orally administered imatinib is well absorbed, and has an absolute bioavailability of 98% irrespective of oral dosage form (solution, capsule, tablet) or dosage strength (100 mg, 400 mg). Food has no relevant impact on the rate or extent of bioavailability. The terminal elimination half-life is approximately 18 hours. Imatinib plasma concentrations predictably increase by 2- to 3-fold when reaching steady state with 400mg once-daily administration, to 2.6 +/- 0.8 microg/mL at peak and 1.2 +/- 0.8 microg/mL at trough, exceeding the 0.5 microg/mL (1 micromol/L) concentrations needed for tyrosine kinase inhibition in vitro and leading to normalisation of haematological parameters in the large majority of patients with CML irrespective of baseline white blood cell count. Imatinib is approximately 95% bound to human plasma proteins, mainly albumin and alpha1-acid glycoprotein. The drug is eliminated predominantly via the bile in the form of metabolites, one of which (CGP 74588) shows comparable pharmacological activity to the parent drug. The faecal to urinary excretion ratio is approximately 5:1. Imatinib is metabolised mainly by the cytochrome P450 (CYP) 3A4 or CYP3A5 and can competitively inhibit the metabolism of drugs that are CYP3A4 or CYP3A5 substrates. Interactions may occur between imatinib and inhibitors or inducers of these enzymes, leading to changes in the plasma concentration of imatinib as well as coadministered drugs. Hepatic and renal dysfunction, and the presence of liver metastases, may result in more variable and increased exposure to the drug, although typically not necessitating dosage adjustment. Age (range 18-70 years), race, sex and bodyweight do not appreciably impact the pharmacokinetics of imatinib.

Ethnic sensitivity assessment - pharmacokinetic comparability between Japanese and non-Japanese healthy subjects on selected mAbs.

OBJECTIVE: Ethnic sensitivity studies (ESSs), where safety and pharmacokinetics (PK) are assessed in Japanese subjects, are routinely conducted according to Japanese regulatory requirement before the subsequent clinical studies. The necessity of ESSs is questionable in case of mAbs, where inherent IgG characteristics are considered ethnically insensitive. This report investigated PK profiles and immunogenicity (IG) following a single administration of mAbs in Japanese and non-Japanese healthy subjects. RESEARCH DESIGN AND METHODS: PK and IG comparison between Japanese and non-Japanese healthy subjects was made on mAbs data available from public domain and unpublished internal reports. PK comparison was made based on statistical approach as well as assumed typical IgG profile using modeling and simulation. RESULTS: When compared directly, most mAbs showed no difference between ethnic groups. When profiles of various mAbs were fit to an assumed typical IgG PK model, the majority of mAbs follow the expected behavior regardless of ethnicities. Deviations from this behavior did not appear to be due to inherent ethnic differences. When the incidence of IG was assessed, only Adalimumab showed apparent ethnic difference. CONCLUSIONS: The overall lack of observational difference may facilitate discussion of mAbs' early clinical development in Japan, including the utility of dedicated ESSs.