Abstract Purpose The metabolism of olaparib, a potent inhibitor of poly(ADP-ribose) polymerase (PARP) with demonstrated efficacy in patients with BRCA -mutated ovarian cancer, is mediated by ...cytochrome P450 (CYP) enzymes (predominantly CYP3A4/5). We assessed the potential of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) to alter the pharmacokinetic (PK) profile of olaparib following single oral tablet doses. Methods Two Phase I, open-label, non-randomized trials were conducted in patients with advanced solid tumors. In Study 7, patients received olaparib alone and co-administered with itraconazole; in Study 8, a separate group of patients received olaparib alone and co-administered with rifampin. No interaction between itraconazole and olaparib was concluded if two-sided 90% CIs for the treatment ratios of AUC and/or AUC0–t and Cmax fell within the bioequivalence range of 0.80–1.25. An interaction between rifampin and olaparib was concluded if the lower limit of the 90% CI for the treatment ratios was <0.5 (ie, >50% decrease in olaparib AUC or Cmax in the presence of rifampin compared with olaparib alone). Findings In Study 7 (N = 59; 17 male, 42 female), 56 and 53 patients were evaluable for PK analysis following treatment with olaparib alone and olaparib plus itraconazole, respectively; in Study 8 (N = 22; 4 male, 18 female), all patients were evaluable. Co-administration of olaparib with itraconazole resulted in a statistically significant increase in the relative bioavailability of olaparib: Cmax treatment ratio, 1.42 (90% CI, 1.33–1.52); mean AUC treatment ratio, 2.70 (90% CI, 2.44–2.97). Mean CL/F and Vz /F were reduced (8.16 vs 3.05 L/h and 192 vs 75.1 L), although mean t½ was unchanged (15.0 vs 15.6 hours). Co-administration of olaparib with rifampin resulted in a statistically significant decrease in the relative bioavailability of olaparib: Cmax treatment ratio, 0.29 (90% CI, 0.24–0.33); mean AUC treatment ratio, 0.13 (90% CI, 0.11–0.16). CL/F and Vz /F were increased when olaparib and rifampin were co-administered (6.36 vs 48.3 L/h and 112 vs 1076 L); however, mean t½ was unchanged (13.0 vs 15.8 hours). Safety data for olaparib following tablet dosing were consistent with the known safety profile. Implications Exposure to olaparib was significantly increased when co-administered with the potent CYP3A4 inhibitor itraconazole, and significantly decreased when co-administered with the potent CYP3A4 inducer rifampin, compared with olaparib alone. Potent CYP3A4 enzyme inhibitors and inducers should be avoided during olaparib treatment. ClinicalTrials.gov identifiers: NCT01900028 (Study 7) and NCT01929603 (Study 8).
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.
Violence is increasing worldwide mainly among the most socially vulnerable groups such as women, elderly people, children and adolescents. In addition to the justice sector, many other areas and ...workers are involved and they are becoming even more important for addressing violence. One such area is the health sector. This article aims to identify the creative potential of videos that aim to tackle issues involving domestic violence against children which are categorized based on generation (age) and gender. A search was conducted between 2013 and 2014 on official sites and video channels of institutions that deal with child-related topics. We used the webQDA software to conduct our analysis and for reference purposes we used "Generation" and "Gender" as categories. We collected 40 video campaigns, of which ten were analyzed qualitatively. Upon analyzing complete scenes and parts of scenes we were able to see both inter/intra -generational and inter/intra-gender violence and its consequences for children. The videos allowed for critical reflections to be made on the educational processes and training used to combat violence against children in the context of "Generations" and "Genders".
Abstract Purpose Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective allosteric mitogen-activated protein kinase 1/2 inhibitor with a short t1/2 . The purpose of this study was to ...characterize the effect of selumetinib on cardiac repolarization and a potential exposure–QT effect relationship. Methods A double-blind (selumetinib), randomized, 3-period crossover study was conducted to assess the effects of a single oral dose of selumetinib (75 mg) on the QTc interval compared with placebo, using moxifloxacin as an open-label positive control, in healthy male subjects aged 18 to 45 years. QT intervals were evaluated by using the Fridericia formula (QTcF) and the Bazett formula. Further analysis was conducted by using nonlinear mixed effects modeling to characterize any relationship between selumetinib exposure and QTc and was used to predict the effect if selumetinib 150 mg was administered. All adverse events were characterized and recorded. Findings A total of 54 healthy male subjects were enrolled, and 48 completed all treatments. Mean age was 27 years; four subjects were of Hispanic or Latino ethnicity, and 53.7% were White and 46.3% were Black. The BMI of subjects ranged from 19.4 to 29.6 kg/m2 . After a single oral dose of selumetinib 75 mg, the highest upper bound of the 2-sided 90% CI for placebo-corrected, baseline-adjusted QTcF (ΔΔQTcF) over the 24-hour postdose measurement interval was 2.5 milliseconds, which was well below the 10-millisecond upper bound for concluding no effect. The relationship between ΔΔQTcF and selumetinib concentrations was adequately described by using a nonlinear mixed effect model. The mean estimated ∆∆QTcF interval prolongation based on the geometric mean Cmax of 75 mg selumetinib was 2.38 milliseconds (90% CI, 1.25 to 3.52), which was in good agreement with the statistical analysis results. The model also predicted mean ∆∆QTcF interval prolongations of 4.70 milliseconds (90% CI, 2.46 to 6.95) after a single supratherapeutic dose of selumetinib 150 mg, indicating the upper bound of 2-sided 90% CIs for ΔΔQTcF are predicted to be <10 milliseconds. Selumetinib, administered as a single 75 mg oral dose, was generally safe and well tolerated. Implications Selumetinib 75 mg did not cause any QT/QTc interval prolongation in these healthy subjects, and selumetinib is not expected to have a clinically relevant effect on cardiac repolarization in patients at the anticipated therapeutic dose of 75 mg. The model also demonstrated the low potential for any QTc effects of selumetinib at doses higher than the standard therapeutic dose.
There is widespread recognition that the existing global systems for innovation and access to medicines need reform. Billions of people do not have access to the medicines they need, and market ...failures prevent new drugs from being developed for diseases that primarily affect the global poor. The World Health Organization's Consultative Expert Working Group on Research and Development: Financing and Coordination (CEWG) analyzed numerous proposals for reform. The aim of this article is to build on these previous inquiries.
We conducted a structured analysis that grouped proposals into five broad opportunities for global policy reform to help researchers and decision makers to meaningfully evaluate each proposal in comparison with similar proposals. Proposals were also analyzed along three important dimensions—potential health impact, financial implications, and political feasibility—further facilitating the comparison and application of this information.
Upon analysis, no one solution was deemed a panacea, as many (often competing) considerations need to be taken into account. However, some proposals, particularly product development partnership and prizes, appeared more promising and feasible at this time and deserve further attention.
More research is needed into the effectiveness of these mechanisms and their transferability across jurisdictions.
to describe the development of a mobile application for the International Classification Terminology Subset for Nursing Practice for Coping with Domestic Violence Against Children.
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.
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.
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.
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.
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.
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.
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.
to analyze the narratives of sexually abused women in childhood, identifying issues related to gender and generation.
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.
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.
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.
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.
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.
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.
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.
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.
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