Effect of food on selumetinib pharmacokinetics and gastrointestinal tolerability in adolescents with neurofibromatosis type 1-related plexiform neurofibromas.

Background: Selumetinib is approved for the treatment of pediatric patients with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN) in multiple countries, including the USA (≥ 2 years). Until recently, individuals had to take selumetinib twice daily (BID) in a fasted state. This study evaluated the effect of a low-fat meal on selumetinib PK parameters and gastrointestinal (GI) tolerability in adolescent participants with NF1-PN. Methods: Eligible participants aged ≥ 12 to < 18 years took 25 mg/m2 selumetinib BID with a low-fat meal (T1) for 28 days, followed by a 7-day washout, and then administration in a fasted state (T2) for another 28 days. Primary objectives were to evaluate the effect of a low-fat meal on AUC0-12,ss and GI tolerability after multiple selumetinib doses in T1 versus T2. Key secondary objectives were additional PK parameters and adverse events (AEs). Results: At primary data cut-off, all 24 participants completed T1, and 23 participants completed T2. There were no significant differences in AUC0-12,ss between T1 and T2. In T1 and T2, 29.2% and 33.3% participants, respectively, reported ≥ 1 GI AE. No GI AEs Grade ≥ 3, or serious AEs, or GI AEs resulting in treatment interruptions, discontinuation, or dose reductions were reported in T1 and T2. Conclusions: Dosing selumetinib with a low-fat meal had no clinically relevant impact on selumetinib AUC0-12,ss nor GI tolerability in adolescents with NF1-PN. Trial registration ClinicalTrialsgov ID: NCT05101148.

Selumetinib in Japanese pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas: An open-label, phase I study.

Background: Plexiform neurofibromas (PN) are a manifestation of neurofibromatosis type 1 (NF1) that may cause morbidity and impact health-related quality of life (HRQoL). Selumetinib (ARRY-142886, AZD6244) is an orally available, selective, mitogen-activated protein kinase kinase 1/2 inhibitor approved for children with NF1 and symptomatic, inoperable PN in regions including the USA (aged ≥2 years), EU (≥3 years), and Japan (≥3 years). This open-label, single-arm, phase I study evaluated selumetinib in Japanese children with NF1 and symptomatic, inoperable PN. Methods: Eligible patients (aged 3-18 years) received oral selumetinib (25 mg/m2 twice daily) continuously in 28-day cycles in a fasted state. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics, efficacy, PN-related morbidities, and HRQoL. Results: Twelve patients (median age 13.3 years) were enrolled, received ≥1 selumetinib dose (data cutoff: cycle 13 day 1) with median follow-up of 11.5 months. All patients had baseline PN-related morbidities, most commonly disfigurement (91.7%) and pain (58.3%). Most frequently reported any-grade adverse events were dermatologic and gastrointestinal. Objective response rate was 33.3%; median duration of response was not reached. Most patients (83.3%) had target PN volume reduction versus baseline. No patients reported worsening of PN-related morbidities. Selumetinib was rapidly absorbed with moderate-to-high inter-patient variability in maximum plasma concentration and area under the concentration-time curve from time 0-6 hours. Conclusions: Consistent with results of the phase II SPRINT trial, 25 mg/m2 selumetinib twice daily was well tolerated with a manageable safety profile in Japanese children with NF1 and symptomatic, inoperable PN.

A Phase I, Open-label, Randomized, Crossover Study of the Relative Bioavailability of Capsule and Granule Formulations of Selumetinib.

PURPOSE: Selumetinib (ARRY-142886) is an oral, potent, and highly selective allosteric mitogen-activated protein kinase kinase 1/2 inhibitor approved for the treatment of pediatric patients (≥2 years of age) with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. This Phase I crossover study (NCT03649165) evaluated the pharmacokinetic properties and palatability of a new granule formulation of selumetinib. METHODS: Healthy volunteers were randomized to 1 of 2 sequences; selumetinib granule (25 mg) followed by selumetinib capsules (50 mg [2 × 25 mg]) and vice versa. The primary end point was the pharmacokinetic properties of the 2 formulations. Secondary end points included safety and tolerability of single selumetinib doses and palatability of the granule formulation. FINDINGS: Of the 24 enrolled volunteers (mean age, 33.2 years; range 23-44 years), all were male and 20 (83%) were Black/African American. Under fasted conditions for the granule versus capsule, geometric mean ratios for the dose-normalized Cmax and AUC0-∞ were 0.654 (90% CI, 0.581-0.736) and 0.865 (90% CI, 0.811-0.922), respectively. Absorption of selumetinib was similar between granule and capsule formulation, with a median time to Cmax of 1.73 hours and 1.14 hours, respectively. Adverse event incidence was low (n = 6 in both groups), and most events were mild. Palatability was acceptable, with volunteers indicating that they would take the granule formulation again. IMPLICATIONS: These findings support further research into the selumetinib granule formulation, with the aim of producing an alternative formulation for younger children or patients unable to swallow capsules. CLINICALTRIALS: gov identifier: NCT03649165.

Selumetinib Plus Adjuvant Radioactive Iodine in Patients With High-Risk Differentiated Thyroid Cancer: A Phase III, Randomized, Placebo-Controlled Trial (ASTRA).

PURPOSE: Selumetinib can increase radioactive iodine (RAI) avidity in RAI-refractory tumors. We investigated whether selumetinib plus adjuvant RAI improves complete remission (CR) rates in patients with differentiated thyroid cancer (DTC) at high risk of primary treatment failure versus RAI alone. METHODS: ASTRA (ClinicalTrials.gov identifier: NCT01843062) is an international, phase III, randomized, placebo-controlled, double-blind trial. Patients with DTC at high risk of primary treatment failure (primary tumor > 4 cm; gross extrathyroidal extension outside the thyroid gland [T4 disease]; or N1a/N1b disease with ≥ 1 metastatic lymph node(s) ≥ 1 cm or ≥ 5 lymph nodes [any size]) were randomly assigned 2:1 to selumetinib 75 mg orally twice daily or placebo for approximately 5 weeks (no stratification). On treatment days 29-31, recombinant human thyroid-stimulating hormone (0.9 mg)-stimulated RAI (131I; 100 mCi/3.7 GBq) was administered, followed by 5 days of selumetinib/placebo. The primary end point (CR rate 18 months after RAI) was assessed in the intention-to-treat population. RESULTS: Four hundred patients were enrolled (August 27, 2013-March 23, 2016) and 233 randomly assigned (selumetinib, n = 155 [67%]; placebo, n = 78 [33%]). No statistically significant difference in CR rate 18 months after RAI was observed (selumetinib n = 62 [40%]; placebo n = 30 [38%]; odds ratio 1.07 [95% CI, 0.61 to 1.87]; P = .8205). Treatment-related grade ≥ 3 adverse events were reported in 25/154 patients (16%) with selumetinib and none with placebo. The most common adverse event with selumetinib was dermatitis acneiform (n = 11 [7%]). No treatment-related deaths were reported. CONCLUSION: Postoperative pathologic risk stratification identified patients with DTC at high risk of primary treatment failure, although the addition of selumetinib to adjuvant RAI failed to improve the CR rate for these patients. Future strategies should focus on tumor genotype-tailored drug selection and maintaining drug dosing to optimize RAI efficacy.

Effect of food on capsule and granule formulations of selumetinib.

Selumetinib is an oral, potent, and highly selective allosteric MEK1/2 inhibitor approved for the treatment of pediatric patients (aged ≥2 years) with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. A granule formulation of selumetinib is under development to improve dosing precision for younger pediatric patients who may be unable to swallow capsules. This phase I crossover study investigated the effect of food on the pharmacokinetic (PK) properties of selumetinib capsule and granule formulations. Healthy male volunteers were randomized to receive selumetinib granules (25 mg) or capsules (50 mg [2 × 25 mg]) under fasted or fed conditions (a low-fat meal). Plasma concentrations and PK parameters were determined less than or equal to 48 h postdose. Safety and tolerability were assessed. Across 24 volunteers, selumetinib was absorbed quickly, with a time to maximum concentration (Tmax ) ranging from ~1-3 h. Geometric mean ratios (90% confidence interval [CI]) for maximum plasma concentration (Cmax ) in the fed versus fasted state were 0.61 (90% CI 0.51-0.72) and 0.40 (90% CI 0.33-0.48) for the granule and capsule formulations, respectively, whereas geometric mean ratios (90% CI) for area under the plasma drug concentration-time curve in the fed versus fasted state were 0.97 (90% CI 0.91-1.02) and 0.62 (90% CI 0.55-0.70), respectively. Levels of less than 10% conversion to the N-desmethyl selumetinib metabolite were observed. Selumetinib was well-tolerated, with only a few adverse events of mild intensity reported. Selumetinib administration with a low-fat meal resulted in lower Cmax and longer Tmax for both formulations versus fasted conditions. However, area under the curve for selumetinib granules was similar under fasted and fed conditions. Overall, these findings support further development of this formulation for pediatric patients.

Legal abortion in childhood: the official discourse and the reality of a Brazilian case / Aborto legal en la infancia: el discurso oficial y la realidad de un caso brasileño / Aborto legal na infância: o discurso oficial e a realidade de um caso brasileiro

ABSTRACT Objective: to identify the ideological perspectives of official discourses in relation to sexual violence, childhood pregnancy and access to legal abortion based on a Brazilian case. Methods: a qualitative documentary study. Data collection was carried out in documents published on official Brazilian websites, between August and December 2020. The analytical categories of gender and generation supported data analysis. Results: a total of 39 documents were selected and three empirical categories were identified: Protection against violence in the legislation and the (re)production of injuries in reality; Facing sexual violence against children by the Brazilian State; Being a Brazilian girl: gender and generational oppressions. Final considerations: the ideological perspectives of official discourses in relation to the case showed a lack of compliance with advances in Brazilian legislation on issues related to child violence and adult-centric authoritarianism, with the imposition of gender and generation subalternity.

RESUMEN Objetivo: identificar las perspectivas ideológicas de los discursos oficiales en relación a la violencia sexual, el embarazo infantil y el acceso al aborto legal a partir de un caso brasileño. Métodos: estudio documental cualitativo. La recolección de datos se realizó en documentos publicados en sitios web oficiales brasileños, entre agosto y diciembre de 2020. Las categorías analíticas de género y generación apoyaron el análisis de datos. Resultados: se seleccionaron 39 documentos y se identificaron tres categorías empíricas: Protección contra la violencia en la legislación y la (re)producción de lesiones en la realidad; Enfrentando la violencia sexual contra los niños por parte del Estado brasileño; Ser niña brasileña: opresiones generacionales y de género. Consideraciones finales: las perspectivas ideológicas de los discursos oficiales en relación al caso mostraron una falta de adhesión a los avances de la legislación brasileña en temas relacionados con la violencia infantil y el autoritarismo adultocéntrico, con la imposición de la subalternidad de género y generacional.

RESUMO Objetivo: identificar as perspectivas ideológicas dos discursos oficiais em relação à violência sexual, à gravidez na infância e ao acesso ao aborto legal a partir de um caso brasileiro. Métodos: estudo documental qualitativo. A coleta de dados foi realizada em documentos publicados em sites oficiais brasileiros, entre agosto e dezembro de 2020. As categorias analíticas de gênero e geração deram suporte à análise dos dados. Resultados: foram selecionados 39 documentos e identificadas três categorias empíricas: A proteção contra a violência na legislação e a (re)produção dos agravos na realidade; O enfrentamento da violência sexual contra a criança pelo Estado brasileiro; Ser menina brasileira: opressões de gênero e geração. Considerações finais: as perspectivas ideológicas dos discursos oficiais em relação ao caso mostraram falta de adesão aos avanços na legislação brasileira nos temas relativos à violência infantil e autoritarismo adultocêntrico, com imposição de subalternidade de gênero e geração.

Population pharmacokinetics and exposure-response of selumetinib and its N-desmethyl metabolite in pediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas.

PURPOSE: Selumetinib (ARRY-142886) is a potent, selective, MEK1/2 inhibitor approved in the US for the treatment of children (≥ 2 years) with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN). We characterized population pharmacokinetics (PK) of selumetinib and its active N-desmethyl metabolite, evaluated exposure-safety/efficacy relationships, and assessed the proposed therapeutic dose of 25 mg/m2 bid based on body surface area (BSA) in this patient population. METHODS: Population PK modeling and covariate analysis (demographics, formulation, liver enzymes, BSA, patients/healthy volunteers) were based on pooled PK data from adult healthy volunteers (n = 391), adult oncology patients (n = 83) and pediatric patients with NF1-PN (n = 68). Longitudinal selumetinib/metabolite exposures were predicted with the final model. Exposure-safety/efficacy analyses were applied to pediatric patients (dose levels: 20, 25, 30 mg/m2 bid). RESULTS: Selumetinib and metabolite concentration-time courses were modeled using a joint compartmental model. Typical selumetinib plasma clearance was 11.6 L/h (95% CI 11.0-12.2 L/ h). Only BSA had a clinically relevant (> 20%) impact on exposure, supporting BSA-based administration in children. Selumetinib and metabolite exposures in responders (≥ 20% PN volume decrease from baseline) and non-responders were largely overlapping, with medians numerically higher in responders. No clear relationships between exposure and safety events were established; exposure was not associated with key adverse events (AEs) including rash acneiform, diarrhea, vomiting, and nausea. CONCLUSION: Findings support continuous selumetinib 25 mg/m2 bid in pediatric patients. Importantly, the updated dosing nomogram ensures that patients will receive a clinically active, yet tolerable, dose regardless of differences in BSA and allows dose reductions, if necessary.

Mobile application of the Terminology Subset for Coping with Domestic Violence Against Children / Aplicación móvil del Subconjunto Terminológico para Enfrentar la Violencia Doméstica contra los Niños / Aplicativo móvel do Subconjunto Terminológico para o Enfrentamento da Violência Doméstica Contra a Criança

ABSTRACT Objective: to describe the development of a mobile application for the International Classification Terminology Subset for Nursing Practice for Coping with Domestic Violence Against Children. Methods: an applied research of technological development, based on the Analysis, Design, Development, Implementation and Evaluation model and on the terminological subset based on the Theory of Nursing Praxis Intervention in Collective Health framework. Results: the application is divided into: 1) "Definition": characterizes the phenomenon of violence against children; 2) "Assistance": electronic record of nursing care; 3) "Diagnosis Consultation"; 4) "Intervention Consultation": nursing diagnoses, outcomes, and interventions related to children and their families, subdivided into Strengthening and Weariness group. Final considerations: built from scientific research, the application has the potential to support nursing care, presenting, in an organized and systematic manner, nursing diagnoses, outcomes, and interventions, in addition to enabling the registration of cases under monitoring.

RESUMEN Objetivos: describir el desarrollo de la aplicación móvil para el Subconjunto Terminológico de la Clasificación Internacional de Prácticas de Enfermería para Enfrentar la Violencia Doméstica contra los Niños. Métodos: investigación de desarrollo tecnológico aplicado, basado en el modelo Analysis, Design, Development, Implementation and Evaluation y en el subconjunto terminológico basado en el marco de la Teoría de la Intervención Práxica en Enfermería en Salud Pública. Resultados: la aplicación se divide en: 1) "Definición": caracteriza el fenómeno de la violencia contra los niños; 2) "Asistencia": registro electrónico de cuidados de enfermería; 3) "Consultar Diagnósticos"; 4) "Consultar Intervenciones": diagnósticos, resultados e intervenciones de enfermería referidas al niño y la familia, subdivididas en grupos de Fortalecimiento/Desgaste. Consideraciones finales: construida a partir de la investigación científica, la aplicación tiene el potencial de apoyar la atención de las enfermeras, presentando de manera organizada y sistemática los diagnósticos, resultados e intervenciones de enfermería, además de posibilitar el registro de los casos en seguimiento.

RESUMO Objetivos: descrever o desenvolvimento do aplicativo móvel para o Subconjunto Terminológico da Classificação Internacional para a Prática de Enfermagem para o Enfrentamento da Violência Doméstica Contra a Criança. Métodos: pesquisa aplicada de desenvolvimento tecnológico, fundamentada no modelo Analysis, Design, Development, Implementation and Evaluation e no subconjunto terminológico embasado no referencial da Teoria de Intervenção Práxica da Enfermagem em Saúde Coletiva. Resultados: o aplicativo divide-se em: 1) "Definição": caracteriza o fenômeno da violência contra crianças; 2) "Atendimentos": registro eletrônico do atendimento de enfermagem; 3) "Consultar Diagnósticos"; 4) "Consultar Intervenções": diagnósticos, resultados e intervenções de enfermagem referentes à criança e à família, subdivididos nos grupos de Fortalecimentos ou Desgastes. Considerações finais: construído a partir de uma pesquisa científica, o aplicativo tem o potencial de apoiar o atendimento das enfermeiras, apresentando, de forma organizada e sistematizada, os diagnósticos, resultados e intervenções de enfermagem, além de possibilitar o registro dos casos em acompanhamento.

Effect of food on the pharmacokinetics of the WEE1 inhibitor adavosertib (AZD1775) in patients with advanced solid tumors.

PURPOSE: To support future dosing recommendations, the effect of food on the pharmacokinetics of adavosertib, a first-in-class, small-molecule reversible inhibitor of WEE1 kinase, was assessed in patients with advanced solid tumors. METHODS: In this Phase I, open-label, randomized, two-period, two-sequence crossover study, the pharmacokinetics of a single 300 mg adavosertib dose were investigated in fed versus fasted states. RESULTS: Compared with the fasted state, a high-fat, high-calorie meal (fed state) decreased adavosertib maximum plasma concentration (Cmax) by 16% and systemic exposure (area under the plasma concentration-time curve [AUC]) by 6%; AUC0-t decreased by 7% and time to maximum plasma concentration was delayed by 1.97 h (P = 0.0009). The 90% confidence interval of the geometric least-squares mean treatment ratio for AUC and AUC0-t was contained within the no-effect limits (0.8-1.25), while that of Cmax crossed the lower bound of the no-effect limits. Adverse events (AEs) related to adavosertib treatment were reported by 20 (64.5%) of the 31 patients treated in this study. Grade ≥ 3 AEs were reported by four (12.9%) patients (one in the fed state, three in the fasted state); two of these AEs were considered treatment-related by the investigator. Three serious AEs were reported in three (9.7%) patients; these were not considered treatment-related. No patients discontinued because of treatment-related AEs, and no new safety signals were reported. CONCLUSION: A high-fat meal did not have a clinically relevant effect on the systemic exposure of adavosertib, suggesting that adavosertib can be administered without regard to meals.

Acupuncture as Part of Iatrogenic Facial Nerve Palsy Rehabilitation-First Report.

BACKGROUND: Facial paresis is one of the complications after treatment for vestibular schwannoma (VS). Acupuncture has been used for Bell palsy but not in iatrogenic facial paresis. The objective of this study is to measure the efficacy of using acupuncture for iatrogenic facial nerve palsy and patients' satisfaction. METHODS: This is a single-center retrospective study with patients from 2007-2019 received treatment for newly diagnosed or recurrent VS. Some patients who suffered facial paresis after surgery had self-initiated acupuncture. All patients who had facial paresis were included. Their facial nerve status before and immediately after surgery, postoperative 6 months and 12 months, were recorded. Those who received acupuncture also answered 6- and 12-month patient satisfaction surveys over the phone. Adverse effects were also assessed. RESULTS: There were 123 patients in this period. Of these, 29 patients had iatrogenic facial paresis and 23 of them received acupuncture. There was significant improvement of facial paresis for the acupuncture group compared with the nonacupuncture group at 6 and 12 months. More than 80% of patients who received acupuncture were satisfied. They had motor improvement and experienced less pain and tightness. No adverse effects were reported. CONCLUSIONS: Acupuncture for postresection VS facial paresis seemed to speed up its recovery. Both patients' recovery and satisfaction were good after acupuncture, and it seemed to be a safe procedure in trained hands.

Impact of Disease and Treatment Response in Drug-Drug Interaction Studies: Osimertinib and Simvastatin in Advanced Non-Small Cell Lung Cancer.

A phase I, open-label study (NCT02197234) assessed the effects of osimertinib on simvastatin exposure in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer and disease progression post-EGFR tyrosine kinase inhibitor treatment. Here, we report on a retrospective analysis of two patients (patients 1 and 2) who had liver metastases and high simvastatin exposure prior to osimertinib treatment, which changed following treatment. Patients received single oral doses of simvastatin 40 mg on day (D) 1 and D31, and osimertinib 80 mg once daily on D3-32. At baseline, both patients had abnormal liver function tests (LFTs; Child-Pugh scores of 6 and 8, respectively), significant liver metastasis, and, after a single simvastatin dose, had higher (~ 10-fold) exposure compared with all other patients. Following 31 days of continuous osimertinib treatment, simvastatin exposures (area under the plasma concentration-time curve from zero to infinity (AUC) and maximum plasma concentration (Cmax )) and LFTs, such as alanine transaminase, aspartate aminotransferase, and bilirubin normalized to population mean values. Additionally, ~ 50% and ~ 80% reductions in liver metastases were observed on computed tomography scans in patients 1 and 2, respectively. High simvastatin exposure on D1 likely resulted from impairment of hepatic first pass metabolism due to liver metastases. Reduction in hepatic disease burden due to osimertinib treatment likely resulted in liver function returning to normal levels.

Comparing 3 Different Techniques of Patella Fracture Fixation and Their Complications.

INTRODUCTION: Patella fractures managed by fixation with metal implants often cause local soft tissue irritation and necessitate implant removal. An alternative is to utilize suture-based fixation methods. We have adopted suture and hybrid fixation in the routine management of patella fractures. Here, we compare the results of 3 fixation techniques. MATERIALS AND METHODS: Eighty-seven eligible patients underwent patella fracture fixation over a 3-year period. As determined by fracture configuration, patients received (1) suture fixation (transosseous sutures and figure-of-eight tension banding with FiberWire), (2) hybrid fixation (transosseous FiberWire sutures and metal tension banding), or (3) metal fixation. Primary outcome measures included reoperation rate and soft tissue irritation. Secondary outcomes included surgical complications, radiological, and functional parameters. RESULTS: Reoperation rate was highest for metal fixation (25/57, 43.9%) and lowest for suture fixation (2/13, 15.4%). Soft tissue irritation necessitating implant removal was the predominant reason for reoperation and was significantly less prevalent following suture fixation (1/13, 7.7%, P < .01). Hybrid fixation resulted in similar rates of soft tissue irritation (6/17, 35.3%) and implant removal (7/17, 41.2%) as compared to metal fixation. There was a significant increase in patella baja (13/17, 76.5%) and reduction in Insall-Salvati ratio (0.742; 95% confidence interval: 0.682-0.802) following hybrid fixation as compared to the other 2 fixation methods (P < .05). DISCUSSION: Suture fixation results in the least amount of soft tissue irritation and lowest reoperation rate, but these advantages are negated with the addition of a metal tension band wire. Hybrid fixation also unbalances the extensor mechanism. CONCLUSION: Patients should be counseled as to the expected sequelae of their fixation method. Suture fixation is the favored means to fix distal pole fractures of the patella. An additional metal tension band loop may confer additional stability but should be applied with caution.

Pharmacokinetic Study of Osimertinib in Cancer Patients with Mild or Moderate Hepatic Impairment.

Osimertinib, an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), undergoes significant hepatic elimination. In this phase 1 study, we assessed the effects of mild and moderate hepatic impairment on the pharmacokinetics (PK) of osimertinib in patients with malignant solid tumors. In part A, patients with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment, according to the Child-Pugh classification, received a single 80 mg oral dose of osimertinib. Standard PK measures were assessed. In part B, patients could continue osimertinib treatment if deemed clinically appropriate. We compared these study results with a population PK analysis including other osimertinib clinical studies. Geometric mean osimertinib plasma concentrations were lower in patients with mild (n = 7) or moderate hepatic impairment (n = 5) versus normal hepatic function (n = 10): C max was reduced to 51% and 61%, respectively; area under the curve was reduced to 63% and 68%, respectively. PK results for the metabolites were similar. No apparent differences in the safety profile were found between patients with normal hepatic function and patients with mild or moderate hepatic impairment. Comparison of these study results with National Cancer Institute-Organ Dysfunction Working Group criteria from population PK analysis showed osimertinib exposure was not affected by hepatic impairment. No dose adjustment is required for osimertinib when treating patients with mild or moderate hepatic impairment. No apparent differences in the safety of osimertinib were found between patients with normal hepatic function and mild or moderate hepatic impairment.

Absolute Bioavailability of Osimertinib in Healthy Adults.

Osimertinib is a third-generation, central nervous system-active, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) selective for EGFR-TKI sensitizing and T790M resistance mutations. This phase 1, open-label study (NCT02491944) investigated absolute bioavailability and pharmacokinetics (PK) of oral and intravenous (IV) osimertinib. Ten healthy subjects (21-61 years) received a single oral 80-mg dose concomitantly with a 100 µg (containing 1 µCi) IV microtracer dose of [14 C]osimertinib. Oral and IV PK were determined simultaneously for osimertinib and its active metabolites, AZ5104 and AZ7550. High-performance liquid chromatography and accelerator mass spectrometry were used to characterize IV dose PK. Geometric mean absolute oral bioavailability of osimertinib was 69.8% (90% confidence interval, 66.7, 72.9). Oral osimertinib was slowly absorbed (median time to maximum plasma concentration [tmax ] 7.0 hours). Following tmax , plasma concentrations fell in an apparent monophasic manner. IV clearance and volume of distribution were 16.8 L/h and 1285 L, respectively. Arithmetic mean elimination half-life estimates were 59.7, 52.6, and 72.6 hours for osimertinib, AZ5104, and AZ7550, respectively (oral dosing), and 54.9, 68.4, and 99.7 hours for [14 C]osimertinib, [14 C]AZ5104, and [14 C]AZ7550, respectively (IV dosing). Oral osimertinib was well absorbed. Simultaneous IV and oral PK analysis proved useful for complete understanding of osimertinib PK and showed that the first-pass effect was minimal for osimertinib.

Effect of multiple-dose osimertinib on the pharmacokinetics of simvastatin and rosuvastatin.

AIM: We report on two Phase 1, open-label, single-arm studies assessing the effect of osimertinib on simvastatin (CYP3A substrate) and rosuvastatin (breast cancer resistance protein substrate [BCRP] substrate) exposure in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer who have progressed after treatment with an EGFR tyrosine kinase inhibitor, to determine, upon coadministration, whether osimertinib could affect the exposure of these agents. METHODS: Fifty-two patients in the CYP3A study (pharmacokinetic [PK] analysis, n = 49), and 44 patients in the BCRP study were dosed (PK analysis, n = 44). In the CYP3A study, patients received single doses of simvastatin 40 mg on Days 1 and 31, and osimertinib 80 mg once daily on Days 3-32. In the BCRP study, single doses of rosuvastatin 20 mg were given on Days 1 and 32, and osimertinib 80 mg once daily on Days 4-34. RESULTS: Geometric least squares mean (GLSM) ratios (90% confidence intervals) of simvastatin plus osimertinib for area under the plasma concentration-time curves from zero to infinity (AUC) were 91% (77-108): entirely contained within the predefined no relevant effect limits, and Cmax of 77% (63, 94) which was not contained within the limits. GLSM ratios of rosuvastatin plus osimertinib for AUC were 135% (115-157) and Cmax were 172 (146, 203): outside the no relevant effect limits. CONCLUSIONS: Osimertinib is unlikely to have any clinically relevant interaction with CYP3A substrates and has a weak inhibitory effect on BCRP. No new safety concerns were identified in either study.

The effect of itraconazole and rifampicin on the pharmacokinetics of osimertinib.

AIMS: We investigated the effects of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampicin) on the pharmacokinetics of the epidermal growth factor receptor-tyrosine kinase inhibitor osimertinib, in patients with advanced non-small cell lung cancer in two Phase I, open-label, two-part clinical studies. Part one of both studies is reported. METHODS: In the itraconazole study (NCT02157883), patients received single-dose osimertinib 80 mg on Days 1 and 10 and itraconazole (200 mg twice daily) on Days 6-18 orally. In the rifampicin study (NCT02197247), patients received osimertinib 80 mg once daily on Days 1-77 and rifampicin 600 mg once daily on Days 29-49. RESULTS: In the itraconazole study (n = 36), the geometric least squares mean (GMLSM) ratios (osimertinib plus itraconazole/osimertinib alone) for Cmax and AUC were 80% (90% CI 73, 87) and 124% (90% CI 115, 135), respectively, below the predefined no-effect upper limit of 200%. In the rifampicin study (n = 40), the GMLSM ratios (osimertinib plus rifampicin/osimertinib alone) for Css,max and AUCτ were 27% (90% CI 24, 30) and 22% (90% CI 20, 24), respectively, below the predefined no-effect lower limit of 50%. The induction effect of rifampicin was apparent within 7 days of initiation; osimertinib Css,max and AUCτ values returned to pre-rifampicin levels within 3 weeks of rifampicin discontinuation. No new osimertinib safety findings were observed. CONCLUSIONS: Osimertinib can be co-administered with CYP3A4 inhibitors, but strong CYP3A inducers should be avoided if possible.

The Effect of Food or Omeprazole on the Pharmacokinetics of Osimertinib in Patients With Non-Small-Cell Lung Cancer and in Healthy Volunteers.

Two phase 1, open-label studies assessed the impact of food or gastric pH modification (omeprazole) on the exposure and safety/tolerability of osimertinib and its metabolites. The food effect study was an open-label, 2-period crossover study in patients with advanced non-small-cell lung cancer, randomized into 2 treatment sequences: single-dose osimertinib 80 mg in a fed then fasted state or fasted then fed. The gastric pH study was an open-label, 2-period fixed sequence study assessing the effect of omeprazole on osimertinib exposure in healthy male volunteers. In period 1, volunteers received omeprazole 40 mg (days 1-4), then omeprazole 40 mg plus osimertinib 80 mg (day 5). In period 2, volunteers received osimertinib 80 mg alone (single dose). Blood samples were collected at prespecified time points for pharmacokinetic analyses. Safety/tolerability was also assessed. In the food effect study 38 patients were randomized to fed/fasted (n = 18) or fasted/fed (n = 20) sequences with all patients completing treatment. Coadministration with food did not affect osimertinib exposure (geometric least-squares mean ratios [90% confidence intervals]: 106.05% [94.82%, 118.60%] [area under the plasma concentration time curve from zero to 72 hours] and 92.75% [81.40%, 105.68%] [maximum plasma concentration]). In the gastric pH study (n = 68 received treatment, n = 47 completed the study), coadministration with omeprazole did not affect osimertinib exposure (geometric least-squares mean ratios 106.66% [100.26%, 113.46%] [area under the concentration-time curve], 101.65% [94.65%, 109.16%] [peak concentration]). Osimertinib was well tolerated in both studies. Osimertinib may be administered without regard to food. Dose restriction is not required in patients whose gastric pH may be altered by concomitant agents or medical conditions. ClinicalTrials.gov: NCT02224053, NCT02163733.

Gender and generation perspectives in the narratives of sexually abused women in childhood / As perspectivas de gênero e geração nas narrativas de mulheres abusadas sexualmente na infância / Las perspectivas de género y de generación en las narrativas de mujeres abusadas sexualmente en la infancia

ABSTRACT Objective: to analyze the narratives of sexually abused women in childhood, identifying issues related to gender and generation. Method: descriptive research with a qualitative approach, based on 214 reports selected from the Brazilian campaign #primeiroassedio (first harassment), which took place on Twitter social network, collected from a structured instrument. Thematic content analysis was used. Results: girls were the main victims of sexual abuse. The perpetrators were mostly male and people they knew. Five categories emerged from the narratives: Sexual abuse in the aggressors' discourse; The child as the object of sexual pleasure; Violated childhood; Victims' guilty feelings; and Repercussions of sexual abuse experienced in childhood. Conclusion: sexual abuse often occurs in the family context and, even if sometimes veiled, the submission of girls' power in gender relations and of children in generation relationships is evident. Analyzing sexual abuse under the categories of gender and generation contributes to an in-depth understanding of the phenomenon, directing practices more effectively to their coping.

RESUMO Objetivo: analisar as narrativas de mulheres abusadas sexualmente na infância identificando questões relacionadas ao gênero e à geração. Método: pesquisa descritiva de abordagem qualitativa, realizada a partir de 214 relatos selecionados da campanha brasileira #primeiroassedio, ocorrida na rede social Twitter, coletados a partir de instrumento estruturado. Utilizou-se análise de conteúdo temática. Resultados: as meninas foram as principais vítimas de abuso sexual. Os perpetradores eram majoritariamente do sexo masculino e conhecidos. Das narrativas, emergiram cinco categorias: o abuso sexual no discurso dos agressores; a criança como objeto do prazer sexual; a infância violentada; o sentimento de culpa das vítimas e as repercussões do abuso sexual vivido na infância. Conclusão: o abuso sexual frequentemente acontece no contexto intrafamiliar e, mesmo que às vezes velado, identifica-se a subalternidade de poder das meninas nas relações de gênero e das crianças nas relações de geração. Analisar o abuso sexual sob as categorias gênero e geração contribui para uma compreensão aprofundada do fenômeno, direcionando as práticas de forma mais efetiva para o seu enfrentamento.

RESUMEN Objetivo: analizar las narrativas de mujeres abusadas sexualmente en la infancia, identificando cuestiones relacionadas al género y a la generación. Método: investigación descriptiva de enfoque cualitativo, realizada a partir de 214 relatos seleccionados de la campaña brasilera #primeiroassedio, ocurrida en la red social Twitter, recogidos a partir de un instrumento estructurado. Se utilizó un análisis de contenido temático. Resultados: las niñas fueron las principales víctimas de abuso sexual. Los perpetradores eran mayoritariamente del sexo masculino y conocidos. De las narrativas, surgieron cinco categorías: el abuso sexual en el discurso de los agresores; el niño como objeto del placer sexual; infancia violentada; el sentimiento de culpa de las víctimas; y repercusiones del abuso sexual vivido en la infancia. Conclusión: el abuso sexual frecuentemente acontece en el contexto intrafamiliar y, mismo que a veces velado, se identifica la subalternidad de poder de las niñas en las relaciones de género y de las niñas en las relaciones de generación. Analizar el abuso sexual sobre las categorías de género y generación contribuye para una comprensión profundizada del fenómeno, dirigido a las prácticas de forma más efectiva para su enfrentamiento.

Validação do Subconjunto Terminológico da Classificação Internacional para a Prática de Enfermagem - CIPE® - para o Enfrentamento da Violência Doméstica Infantil / Validation of a Subset of Terms for the International Classification of Nursing Practice ICNP® for Coping with Domestic Violence Against Children

Introdução: O fenômeno da violência é responsável por diversos agravos e sequelas em milhões de pessoas e vem crescendo entre os grupos mais vulneráveis socialmente, tais como os idosos, as mulheres e as crianças. O objeto de estudo foram os Diagnósticos, Resultados e Intervenções de Enfermagem, e o fenômeno escolhido foi a violência doméstica contra a criança. Objetivo: Construir um Subconjunto Terminológico da Classificação Internacional para a Prática de Enfermagem CIPE® para o Enfrentamento da Violência Doméstica Contra a Criança. Método: O referencial teórico-metodológico foi baseado no materialismo histórico-dialético a partir da Teoria de Intervenção Práxica da Enfermagem em Saúde Coletiva (TIPESC). Para os dados primários, utilizou-se a base terminológica de Albuquerque 2014 e dos Diagnósticos, Resultados e Intervenções avaliados por 32 juízas/especialistas na FASE 1, e por 13 na FASE 2, por meio de questionário eletrônico. A análise dos dados foi baseada no Índice de Validade de Conteúdo (IVC). Foram validados os itens com IVC > 0,79. Dados secundários foram obtidos na revisão integrativa da literatura. O estudo foi aprovado pelo Comitê de Ética em Pesquisa da Escola de Enfermagem da Universidade de São Paulo, parecer 1.433.634 (CAAEE 52639416.1.0000.5392). Resultados e discussão: Foram validados 14 Diagnósticos/Resultados de Fortalecimentos e Promoção (9 relativos à criança e 5 relativos à família) e 46 de Desgastes, Causas, Manifestações e Consequências (30 relativos à criança e 16 relativos à família). Quanto às Intervenções, foram 19 de Fortalecimentos e Promoção, 63 de Desgastes, Causas, Manifestações e Consequências e 18 aplicáveis a ambos os grupos. Desenvolveu-se uma proposta de utilização do Subconjunto Terminológico com base em um raciocínio crítico em Saúde Coletiva. Dentre as facilidades para a atuação da(o)s enfermeira(o)s, estão reconhecer seu papel, agir em integração com os demais trabalhadores, poder contar com uma rede de serviços integrada e ter suporte da instituição. Dentre as dificuldades, estão falta de clareza sobre o seu papel, receio de invadir a privacidade da família, medo, insegurança, lacunas na formação, falta de uma rede de serviços integrada, deficit de trabalhadores, sobrecarga de trabalho e falta de tempo. Experiências exitosas partiram das visitas domiciliárias que permitiram às(aos) enfermeira(o)s estreitar vínculos com as famílias, fazer atendimentos sem preconceitos e/ou julgamentos e prevenir a negligência contra a criança acompanhando mulheres desde a gestação e nos primeiros anos de vida das crianças. Conclusão: Este Subconjunto, alinhado aos conhecimentos da Saúde Coletiva, não tem foco apenas nos agravos, mas também na prevenção da violência e na promoção de ações emancipatórias dos sujeitos. Acredita-se que ele tem o potencial de sistematizar uma linguagem específica para a Enfermagem e também ser uma linguagem que se comunique com outras áreas e profissionais da rede de proteção às crianças e suas famílias. É dever dos gestores e das instâncias governamentais se comprometerem com ações que têm se mostrado efetivas no enfrentamento da violência doméstica contra a criança. É preciso rever as condições de trabalho da(o)s enfermeira(o)s para que estas possam desenvolver ações que, de fato, tenham real impacto na transformação dos fenômenos sociais e nas respostas às necessidades de saúde das crianças e suas famílias.

Introduction: Violence accounts for various injuries and sequelae among million of people and has grown among the most socially vulnerable groups, such as the elderly, women and children. The object of this study includes Nursing Diagnosis, Outcomes and Interventions, while domestic violence against children was the phenomenon chosen. Objective: To construct a Subset of Terms for the International Classification for Nursing Practice - ICNP® for Coping with Domestic Violence Against Children. Method: The theoreticalmethodological reference was historical-dialectical materialism based on the Theory of Nursing Praxis Intervention in Collective Health (TIPESC). Primary data were composed of the terminological basis by Albuquerque 2014 and the Diagnoses, Outcomes, and Interventions assessed by 32 experts in PHASE 1 and 13 experts in PHASE 2 using an electronic questionnaire. Data analysis was based on the Content Validity Index (CVI). Items with CVI > 0.79 were validated. Secondary data were obtained from an integrative literature review. The study was approved by the Institutional Review Board at the University of São Paulo, School of Nursing, report 1,433,634 (CAAEE 52639416.1.0000.5392). Results and discussion: The following were validated: 14 Diagnoses/Outcomes concerning Strengthening and Promotion (9 concerning children and 5 concerning families) and 46 concerning Weariness, Causes, Manifestations and Consequences (30 concerning children and 16 concerning families). In regard to Interventions, 19 were related to Strengthening and Promotion, 63 were related Weariness, Causes, Manifestations and Consequences and 18 were applicable to both groups. A proposal to use this subset of terms was developed based on critical rationale in Collective Health. The aspects that facilitate the work of nurses include acknowledging their role, working together with the remaining health workers, having an integrated service network and the institutions support. Difficulties include lack of clarity regarding nurses roles, being afraid of invading the familys privacy, fear, insecurity, gaps in education, lack of an integrated service network, understaffing, overwork, and lack of time. Successful experiences took place in home visits, in which nurses were able to establish bonds with families, leaving aside prejudice and/or judgment, and prevent child neglect by monitoring women from pregnancy to the childrens first years of life. Conclusion: This Subset, aligned with Collective Health knowledge, does not focus on health conditions only, but also on preventing violence and promoting individuals emancipatory actions. It is believed that it has the potential to systematize a specific language for Nursing and also be a language that communicates with other fields and workers within the network that protects children and their families. Managers and governmental agencies should engage in actions that have been proven effective to cope with domestic violence against children. The working conditions of nurses should be reconsidered so that they may implement actions that have a real impact on the transformation of social phenomena and respond to the health needs of children and their families.

Validação do Subconjunto Terminológico da Classificação Internacional para a Prática de Enfermagem - CIPE® - para o Enfrentamento da Violência Doméstica Infantil / Validation of a Subset of Terms for the International Classification of Nursing Practice ICNP® for Coping with Domestic Violence Against Children

Introdução: O fenômeno da violência é responsável por diversos agravos e sequelas em milhões de pessoas e vem crescendo entre os grupos mais vulneráveis socialmente, tais como os idosos, as mulheres e as crianças. O objeto de estudo foram os Diagnósticos, Resultados e Intervenções de Enfermagem, e o fenômeno escolhido foi a violência doméstica contra a criança. Objetivo: Construir um Subconjunto Terminológico da Classificação Internacional para a Prática de Enfermagem CIPE® para o Enfrentamento da Violência Doméstica Contra a Criança. Método: O referencial teórico-metodológico foi baseado no materialismo histórico-dialético a partir da Teoria de Intervenção Práxica da Enfermagem em Saúde Coletiva (TIPESC). Para os dados primários, utilizou-se a base terminológica de Albuquerque 2014 e dos Diagnósticos, Resultados e Intervenções avaliados por 32 juízas/especialistas na FASE 1, e por 13 na FASE 2, por meio de questionário eletrônico. A análise dos dados foi baseada no Índice de Validade de Conteúdo (IVC). Foram validados os itens com IVC > 0,79. Dados secundários foram obtidos na revisão integrativa da literatura. O estudo foi aprovado pelo Comitê de Ética em Pesquisa da Escola de Enfermagem da Universidade de São Paulo, parecer 1.433.634 (CAAEE 52639416.1.0000.5392. Resultados e discussão: Foram validados 14 Diagnósticos/Resultados de Fortalecimentos e Promoção (9 relativos à criança e 5 relativos à família) e 46 de Desgastes, Causas, Manifestações e Consequências (30 relativos à criança e 16 relativos à família). Quanto às Intervenções, foram 19 de Fortalecimentos e Promoção, 63 de Desgastes, Causas, Manifestações e Consequências e 18 aplicáveis a ambos os grupos. Desenvolveu-se uma proposta de utilização do Subconjunto Terminológico com base em um raciocínio crítico em Saúde Coletiva. Dentre as facilidades para a atuação da(o)s enfermeira(o)s, estão reconhecer seu papel, agir em integração com os demais trabalhadores, poder contar com uma rede de serviços integrada e ter suporte da instituição. Dentre as dificuldades, estão falta de clareza sobre o seu papel, receio de invadir a privacidade da família, medo, insegurança, lacunas na formação, falta de uma rede de serviços integrada, deficit de trabalhadores, sobrecarga de trabalho e falta de tempo. Experiências exitosas partiram das visitas domiciliárias que permitiram às(aos) enfermeira(o)s estreitar vínculos com as famílias, fazer atendimentos sem preconceitos e/ou julgamentos e prevenir a negligência contra a criança acompanhando mulheres desde a gestação e nos primeiros anos de vida das crianças. Conclusão: Este Subconjunto, alinhado aos conhecimentos da Saúde Coletiva, não tem foco apenas nos agravos, mas também na prevenção da violência e na promoção de ações emancipatórias dos sujeitos. Acredita-se que ele tem o potencial de sistematizar uma linguagem específica para a Enfermagem e também ser uma linguagem que se comunique com outras áreas e profissionais da rede de proteção às crianças e suas famílias. É dever dos gestores e das instâncias governamentais se comprometerem com ações que têm se mostrado efetivas no enfrentamento da violência doméstica contra a criança. É preciso rever as condições de trabalho da(o)s enfermeira(o)s para que estas possam desenvolver ações que, de fato, tenham real impacto na transformação dos fenômenos sociais e nas respostas às necessidades de saúde das crianças e suas famílias.

Introduction: Violence accounts for various injuries and sequelae among million of people and has grown among the most socially vulnerable groups, such as the elderly, women and children. The object of this study includes Nursing Diagnosis, Outcomes and Interventions, while domestic violence against children was the phenomenon chosen. Objective: To construct a Subset of Terms for the International Classification for Nursing Practice - ICNP® for Coping with Domestic Violence Against Children. Method: The theoreticalmethodological reference was historical-dialectical materialism based on the Theory of Nursing Praxis Intervention in Collective Health (TIPESC). Primary data were composed of the terminological basis by Albuquerque 2014 and the Diagnoses, Outcomes, and Interventions assessed by 32 experts in PHASE 1 and 13 experts in PHASE 2 using an electronic questionnaire. Data analysis was based on the Content Validity Index (CVI). Items with CVI > 0.79 were validated. Secondary data were obtained from an integrative literature review. The study was approved by the Institutional Review Board at the University of São Paulo, School of Nursing, report 1,433,634 (CAAEE 52639416.1.0000.5392). Results and discussion: The following were validated: 14 Diagnoses/Outcomes concerning Strengthening and Promotion (9 concerning children and 5 concerning families) and 46 concerning Weariness, Causes, Manifestations and Consequences (30 concerning children and 16 concerning families). In regard to Interventions, 19 were related to Strengthening and Promotion, 63 were related Weariness, Causes, Manifestations and Consequences and 18 were applicable to both groups. A proposal to use this subset of terms was developed based on critical rationale in Collective Health. The aspects that facilitate the work of nurses include acknowledging their role, working together with the remaining health workers, having an integrated service network and the institutions support. Difficulties include lack of clarity regarding nurses roles, being afraid of invading the familys privacy, fear, insecurity, gaps in education, lack of an integrated service network, understaffing, overwork, and lack of time. Successful experiences took place in home visits, in which nurses were able to establish bonds with families, leaving aside prejudice and/or judgment, and prevent child neglect by monitoring women from pregnancy to the childrens first years of life. Conclusion: This Subset, aligned with Collective Health knowledge, does not focus on health conditions only, but also on preventing violence and promoting individuals emancipatory actions. It is believed that it has the potential to systematize a specific language for Nursing and also be a language that communicates with other fields and workers within the network that protects children and their families. Managers and governmental agencies should engage in actions that have been proven effective to cope with domestic violence against children. The working conditions of nurses should be reconsidered so that they may implement actions that have a real impact on the transformation of social phenomena and respond to the health needs of children and their families.