EVIDENCE meta-analysis: evaluating minimal residual disease as an intermediate clinical end point for multiple myeloma.

ABSTRACT: Estimating progression-free survival (PFS) and overall survival superiority during clinical trials of multiple myeloma (MM) has become increasingly challenging as novel therapeutics have improved patient outcomes. Thus, it is imperative to identify earlier end point surrogates that are predictive of long-term clinical benefit. Minimal residual disease (MRD)-negativity is a common intermediate end point that has shown prognostic value for clinical benefit in MM. This meta-analysis was based on the US Food and Drug Administration guidance for considerations for a meta-analysis of MRD as a clinical end point and evaluates MRD-negativity as an early end point reasonably likely to predict long-term clinical benefit. Eligible studies were phase 2 or 3 randomized controlled clinical trials measuring MRD-negativity as an end point in patients with MM, with follow-up of ≥6 months following an a priori-defined time point of 12 ± 3 months after randomization. Eight newly diagnosed MM studies evaluating 4907 patients were included. Trial-level associations between MRD-negativity and PFS were R2WLSiv, 0.67 (95% confidence interval [CI], 0.43-0.91) and R2copula 0.84 (0.64 to >0.99) at the 12-month time point. The individual-level association between 12-month MRD-negativity and PFS resulted in a global odds ratio (OR) of 4.02 (95% CI, 2.57-5.46). For relapse/refractory MM, there were 4 studies included, and the individual-level association between 12-month MRD-negativity and PFS resulted in a global OR of 7.67 (4.24-11.10). A clinical trial demonstrating a treatment effect on MRD is reasonably likely to eventually demonstrate a treatment effect on PFS, suggesting that MRD may be an early clinical end point reasonably likely to predict clinical benefit in MM, that may be used to support accelerated approval and thereby, expedite the availability of new drugs to patients with MM.

Statin-induced Mitochondrial Priming Sensitizes Multiple Myeloma Cells to BCL2 and MCL-1 Inhibitors.

The BCL2 inhibitor venetoclax promotes apoptosis in blood cancer cells and is approved for treatment of chronic lymphocytic leukemia and acute myeloid leukemia. However, multiple myeloma cells are frequently more dependent on MCL-1 for survival, conferring resistance to venetoclax. Here we report that mevalonate pathway inhibition with statins can overcome resistance to venetoclax in multiple myeloma cell lines and primary cells. In addition, statins sensitize to apoptosis induced by MCL-1 inhibitor, S63845. In retrospective analysis of venetoclax clinical studies in multiple myeloma, background statin use was associated with a significantly enhanced rate of stringent complete response and absence of progressive disease. Statins sensitize multiple myeloma cells to venetoclax by upregulating two proapoptotic proteins: PUMA via a p53-independent mechanism and NOXA via the integrated stress response. These findings provide rationale for prospective testing of statins with venetoclax regimens in multiple myeloma. SIGNIFICANCE: BH3 mimetics including venetoclax hold promise for treatment of multiple myeloma but rational combinations are needed to broaden efficacy. This study presents mechanistic and clinical data to support addition of pitavastatin to venetoclax regimens in myeloma. The results open a new avenue for repurposing statins in blood cancer.

Evaluation of a semi-automated approach for FDG PET image analysis for routine clinical application in patients with multiple myeloma.

BACKGROUND: FDG PET/CT is a tool for assessing response to therapy in various cancers, and may provide an earlier biomarker of clinical response. We developed a novel semi-automated approach for analyzing FDG PET/CT images in patients with multiple myeloma (MM) to standardize FDG PET application. METHODS: Patients (n = 8) with relapsed/refractory MM from the Phase 2 study (NCT02899052) of venetoclax plus carfilzomib and dexamethasone underwent FDG PET/CT at baseline and up to two timepoints during treatment. Images were processed using an established automated segmentation algorithm, with the modification that a red marrow region in an unaffected lumbar vertebra was used to define background standardized uptake value normalized to lean body mass (SUL) threshold above which uptake was considered disease-specific uptake. This approach was compared to lesion segmentation, and to International Myeloma Working Group (IMWG) response criteria, including minimal residual disease (MRD). RESULTS: The two FDG PET analysis techniques agreed on evaluation of patient-level SULpeak for 67% of scans. In the metabolic response assessment per PET Response Criteria in Solid Tumors (PERCIST), the two techniques agreed in 75% of patients. Differences between techniques occurred in low-uptake lesions due to greater reader sensitivity to lesions with uptake marginally above background. PERCIST outcomes were generally in agreement with IMWC and MRD. CONCLUSIONS: This semi-automated analysis was in high agreement with standard approaches for detecting response to MM therapy. This proof-of-concept study suggests that larger studies should be conducted to confirm how FDG PET analysis may aid early response detection in MM.

A Phase I First-in-Human Study of ABBV-383, a B-Cell Maturation Antigen × CD3 Bispecific T-Cell Redirecting Antibody, in Patients With Relapsed/Refractory Multiple Myeloma.

PURPOSE: ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study. METHODS: Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion. RESULTS: As of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose expansion [60 mg], n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively. CONCLUSION: ABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy's promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation.

Random number generation and the ability of mentally reconstructing context in patients with organic amnesia.

Studies investigating amnesic patients have shown the involvement of the medial temporal lobe during working memory (WM) tasks, especially when multiple items or features have to be associated. However, so far, no study has examined the relationship between episodic memory and WM components in patients with amnesia for comprehensive neuropsychological evaluation. Objective: The objective of this study was to investigate whether the null retention relates to deficits in the episodic buffer (EB) or the central executive (CE) components of WM. Methods: This study included 15 amnesic patients with mixed etiologies and 13 matched healthy controls. These 15 amnesic patients with mixed etiologies were divided into two subgroups: NUL subgroup (n=7) patients whose raw score was 0 (zero) on the Logical Memory delayed recall test and MOR subgroup (n=8) patients who recalled at least 1 item. The EB was assessed by complex span tasks, and the CE was assessed by random number generation (RNG) test. Results: EB tasks were impaired in both subgroups compared with controls. RNG was impaired in NUL (p=0.03), but not in MOR (p=0.99), subgroup. Conclusions: CE impairment hampers the retrieval mode action, preventing it from initiating the mental reconstruction of the context in which the to-be-remembered information was presented minutes ago.

Estudos que investigaram pacientes amnésicos demonstraram envolvimento do lobo temporal medial durante tarefas de memória de trabalho, especialmente quando vários itens ou características devem ser associados. No entanto, até o momento, não há estudos que tenham examinado a relação entre memória episódica e os subcomponentes da memória de trabalho em pacientes com amnésia por meio de avaliação neuropsicológica ampla. Objetivo: Investigar se a retenção nula está relacionada a déficits no buffer episódico ou nos componentes do executivo central da memória operacional. Métodos: Quinze pacientes amnésicos com etiologias mistas foram divididos em dois subgrupos: subgrupo NUL (n=7), de pacientes cuja pontuação bruta foi 0 (zero) na memória lógica tardia, e subgrupo MOR (n=8), de pacientes que recordaram pelo menos um item; além de 13 controles saudáveis pareados. O retentor episódico foi avaliado por tarefas de spam complexo e o executivo central com geração aleatória de números. Resultados: As tarefas do retentor episódico estavam prejudicadas em ambos os subgrupos em comparação com os controles. O teste de geração aleatória de números foi prejudicado em NUL (p=0,03), mas não no subgrupo MOR (p=0,99). Conclusões: O comprometimento do executivo central dificulta a ação do modo de recuperação, impedindo-o de iniciar a reconstrução mental do contexto em que a informação a ser lembrada foi apresentada, minutos antes.

Weak central coherence in adults with ASD: Evidence from eye-tracking and thematic content analysis of social scenes.

Central Coherence Weakness has been defined as a tendency for local rather than global processing that may underlie core deficits in Autism Spectrum Disorder (ASD). In social contexts it may be expressed in difficulties to integrate social cues arising from the recognition of emotions in faces or from the environment in order to understand people's interactions. A sample of 28 adults diagnosed with ASD Level 1 and 25 controls was submitted to a cartoon-like task with the instruction to describe social scenes and to Navon letter stimuli. Both quantitative measures and qualitative (thematic content analysis) procedures were used to assess performance. Heatmap and fixation preferences according to the stimuli quadrants were used to investigate eye-tracking patterns. A tendency to local processing, independently of the stimuli type, in the ASD participants was observed. Data from visual tracking by quadrants and from verbal reports suggest loss of social cues important for understanding context. Their reaction time and response duration were increased in relation to controls. The findings corroborate the idea that weak central coherence may be part of the cognitive phenotype in ASD.

Autistic adults often report difficulties in interpreting social situations. These difficulties are commonly associated with a tendency to visually focus on specific parts of the situation (known as local processing) to the detriment of the whole situation. This way of looking at things has been given the name "weak central coherence," and may result in difficulties in understanding a situation or other people's behaviors. A group of ASD and controls were asked to describe two different types of image, one showing a common social situation, the other Navon figure. Eye-tracking technology was used to analyze how the participants looked at the images (which part of the image and for how long) and asked about what they had seen. The results showed that in the group of autistic participants there was a tendency to focus on the details in both types of images. The analysis of the verbal reports revealed that the interpretation of the social contexts by those with ASD was not what was expected, associated with a specific focus on details. These findings may be useful for a better understanding of some difficulties experienced by ASD in social contexts and contribute to therapeutic treatments.

Random number generation and the ability of mentally reconstructing context in patients with organic amnesia / Geração aleatória de números e a capacidade de reconstruir mentalmente o contexto em pacientes com amnésia orgânica

ABSTRACT. Studies investigating amnesic patients have shown the involvement of the medial temporal lobe during working memory (WM) tasks, especially when multiple items or features have to be associated. However, so far, no study has examined the relationship between episodic memory and WM components in patients with amnesia for comprehensive neuropsychological evaluation. Objective: The objective of this study was to investigate whether the null retention relates to deficits in the episodic buffer (EB) or the central executive (CE) components of WM. Methods: This study included 15 amnesic patients with mixed etiologies and 13 matched healthy controls. These 15 amnesic patients with mixed etiologies were divided into two subgroups: NUL subgroup (n=7) patients whose raw score was 0 (zero) on the Logical Memory delayed recall test and MOR subgroup (n=8) patients who recalled at least 1 item. The EB was assessed by complex span tasks, and the CE was assessed by random number generation (RNG) test. Results: EB tasks were impaired in both subgroups compared with controls. RNG was impaired in NUL (p=0.03), but not in MOR (p=0.99), subgroup. Conclusions: CE impairment hampers the retrieval mode action, preventing it from initiating the mental reconstruction of the context in which the to-be-remembered information was presented minutes ago.

RESUMO. Estudos que investigaram pacientes amnésicos demonstraram envolvimento do lobo temporal medial durante tarefas de memória de trabalho, especialmente quando vários itens ou características devem ser associados. No entanto, até o momento, não há estudos que tenham examinado a relação entre memória episódica e os subcomponentes da memória de trabalho em pacientes com amnésia por meio de avaliação neuropsicológica ampla. Objetivo: Investigar se a retenção nula está relacionada a déficits no buffer episódico ou nos componentes do executivo central da memória operacional. Métodos: Quinze pacientes amnésicos com etiologias mistas foram divididos em dois subgrupos: subgrupo NUL (n=7), de pacientes cuja pontuação bruta foi 0 (zero) na memória lógica tardia, e subgrupo MOR (n=8), de pacientes que recordaram pelo menos um item; além de 13 controles saudáveis pareados. O retentor episódico foi avaliado por tarefas de spam complexo e o executivo central com geração aleatória de números. Resultados: As tarefas do retentor episódico estavam prejudicadas em ambos os subgrupos em comparação com os controles. O teste de geração aleatória de números foi prejudicado em NUL (p=0,03), mas não no subgrupo MOR (p=0,99). Conclusões: O comprometimento do executivo central dificulta a ação do modo de recuperação, impedindo-o de iniciar a reconstrução mental do contexto em que a informação a ser lembrada foi apresentada, minutos antes.

A Phase II Study of Venetoclax in Combination With Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma.

BACKGROUND: Venetoclax is a selective BCL-2 inhibitor with clinical activity in relapsed/refractory multiple myeloma (RRMM). Combinations of venetoclax with agents that have complementary mechanisms of action may improve venetoclax efficacy in RRMM. This study evaluated venetoclax with pomalidomide and dexamethasone (VenPd) in RRMM. PATIENTS AND METHODS: This phase II open label study (NCT03567616) evaluated VenPd in patients with RRMM who had received ≥ 1 prior therapy and were refractory to lenalidomide. Venetoclax was administered orally daily for days 1 to 28, pomalidomide was administered orally daily for days 1 to 21, and dexamethasone was administered weekly for each 28-day cycle. The primary objective was to characterize the safety and tolerability of VenPd. The secondary objectives were to evaluate the efficacy and pharmacokinetics. The study was terminated early due to partial clinical hold and decision to pursue biomarker driven strategy. RESULTS: Eight patients were enrolled. Patients had a median age of 67.5 years. All patients received 400 mg venetoclax; 4 patients experienced dose-limiting toxicities and the dose was not escalated. All patients had a grade ≥ 3 adverse event, and the most common was neutropenia (n = 6); cytopenias were the most prevalent adverse events. Five patients (63%) had a confirmed response, and the median duration of response was 12.9 months. The median progression-free survival was 10.5 months. CONCLUSIONS: Given the limited enrollment, no clear safety or efficacy conclusions about VenPd can be drawn. Preliminary safety data, particularly the occurrence of cytopenias, can be used to guide dosing strategies for future combinations of venetoclax with immunomodulatory agents.

Numerical cognition in children with cerebral palsy.

Children with Cerebral Palsy (CP) often perform poorly in mathematics. It is not yet clear to what extent mathematics difficulties in this clinical condition are similar to those observed in developmental dyscalculia. To better elucidate this issue, we conducted an exploratory cross-sectional study with a sample of children and adolescents with congenital brain injuries and educational history of problems in Mathematics. Fifty students aged 7-15 years, of both genders (28 males) participated in the study, 31 with typical development (TD) and 19 of whom diagnosed with spastic CP. Nine had hemiplegia and ten diplegia. Assessment procedures included a neuropsychological battery covering numerical cognition (ZAREKI-R) and working memory (AWMA) skills, and a computerized task for comparing non-symbolic magnitudes as a measure of number sense. Despite average intelligence coefficient, participants with CP underperformed the TD in five of the 12 ZAREKI-R subtests, as well as in the number sense and working memory tasks. scores were lower among hemiplegic children compared to diplegic, numerical cognition was impaired in all CP group, unveiling a dyscalculia secondary to neurodevelopmental impairments. Therefore, we can consider that mathematical learning difficulties in CP as being heterogeneous and associated with the immaturity of neuropsychological functions, with consequences for the development of numerical cognition.

Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma.

Proteins in the antiapoptotic B-cell lymphoma 2 (BCL-2) family play a role in the pathophysiology of multiple myeloma (MM). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis of MM cells, and its efficacy may be potentiated through combination with agents that increase BCL-2 dependency or have complementary mechanisms of action. The safety, tolerability, pharmacokinetics, and antitumor activity of venetoclax in combination with carfilzomib and dexamethasone (VenKd) in adults with relapsed/refractory MM (RRMM) were investigated in this phase 2 dose-escalation study. Oral venetoclax (400 or 800 mg) was administered daily in combination with intravenous carfilzomib (27, 56, or 70 mg/m2) and oral dexamethasone (20 or 40 mg) in 4 dose-finding cohorts. The expansion cohort received venetoclax 800 mg, carfilzomib 70 mg/m2, and dexamethasone 40 mg. Forty-nine patients received treatment. Median prior lines of therapy was 1 (range, 1-3), and median time in the study was 27 months. The most common treatment-emergent adverse events were diarrhea (65%), fatigue (47%), nausea (47%), and lymphopenia (35%). Serious adverse events occurred in 26 (53%) patients. Of 3 treatment-emergent deaths, 1 was considered treatment related. The overall response rate was 80% in all patients, 92% in patients with t(11;14) (n = 13), and 75% in patients without (n = 36). The rate of complete response or better was 41%. Median progression-free survival was 22.8 months. Treatment with VenKd was well tolerated and showed promising response rates in this RRMM patient population, with greater responses observed in patients with t(11;14). This trial is registered at www.clinicaltrials.gov as #NCT02899052.

Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14).

PURPOSE: Venetoclax is an oral BCL-2 inhibitor with single-agent activity in patients with relapsed or refractory multiple myeloma (RRMM) with t(11;14) translocation. Venetoclax efficacy in RRMM may be potentiated through combination with agents including bortezomib, dexamethasone, and daratumumab. METHODS: This phase I study (NCT03314181) evaluated venetoclax with daratumumab and dexamethasone (VenDd) in patients with t(11;14) RRMM and VenDd with bortezomib (VenDVd) in cytogenetically unselected patients with RRMM. Primary objectives included expansion-phase dosing, safety, and overall response rate. Secondary objectives included further safety analysis, progression-free survival, duration of response, time to progression, and minimal residual disease negativity. RESULTS: Forty-eight patients were enrolled, 24 each in parts 1 (VenDd) and 2 (VenDVd). There was one dose-limiting toxicity in part 1 (grade 3 febrile neutropenia, 800 mg VenDd). Common adverse events with VenDd and VenDVd included diarrhea (63% and 54%) and nausea (50% and 50%); grade ≥ 3 adverse events were observed in 88% in the VenDd group and 71% in the VenDVd group. One treatment-emergent death occurred in part 2 (sepsis) in the context of progressive disease, with no other infection-related deaths on study with medians of 20.9 and 20.4 months of follow-up in parts 1 and 2, respectively. The overall response rate was 96% with VenDd (all very good partial response or better [≥ VGPR]) and 92% with VenDVd (79% ≥ VGPR). The 18-month progression-free survival rate was 90.5% (95% CI, 67.0 to 97.5) with VenDd and 66.7% (95% CI, 42.5 to 82.5) with VenDVd. CONCLUSION: VenDd and VenDVd produced a high rate of deep and durable responses in patients with RRMM. These results support continued evaluation of venetoclax with daratumumab regimens to treat RRMM, particularly in those with t(11;14).

Expanding the Repertoire for "Large Small Molecules": Prodrug ABBV-167 Efficiently Converts to Venetoclax with Reduced Food Effect in Healthy Volunteers.

Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.

Executive functions in children with dyslexia.

INTRODUCTION: This study aimed to verify whether children with dyslexia have difficulties in executive functions (shifting, working memory, inhibition). METHODS: A sample of 47 children (ages 8-13 years) participated in the study: 24 who were dyslexic and 23 controls with typical development. A battery of neuropsychological tests was used. RESULTS: Results revealed executive function difficulties among the dyslexic children when compared with controls, encompassing selective attention modulation processes, shifting, and inhibitory control. These difficulties appeared to be affected by phonological working memory deficits, typically associated with dyslexia. CONCLUSION: Our findings support the consensus among scholars regarding the central involvement of phonological skill dysfunctions in dyslexia.

Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Subjects with Hepatic Impairment.

INTRODUCTION: Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of hepatic insufficiency on venetoclax pharmacokinetics. METHODS: A phase I study was carried out in 24 women with normal hepatic function or mild, moderate, or severe hepatic impairment (based on Child-Pugh scores), who received a single 50 mg dose of venetoclax with a low-fat meal. Blood samples were collected up to 120 h after venetoclax administration. Pharmacokinetic parameters were estimated using non-compartmental methods. RESULTS: Venetoclax maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) in subjects with mild or moderate hepatic impairment were similar to subjects with normal hepatic function. Mean venetoclax AUC in subjects with severe hepatic impairment was 2.3- to 2.7-fold higher than in subjects with normal hepatic function. The half-life of venetoclax in subjects with severe hepatic impairment was approximately two-fold longer than in subjects with normal hepatic function and subjects with mild or moderate hepatic impairment. Unbound fractions of venetoclax in subjects with mild, moderate, and severe hepatic impairment were similar to the subjects with normal hepatic function. No significant adverse safety events were reported. CONCLUSIONS: No venetoclax dosage adjustment is required in subjects with mild or moderate hepatic impairment. In subjects with severe hepatic impairment, a 50% dose reduction of venetoclax is recommended to account for higher exposures and the longer half-life.

Executive functions in children with dyslexia / Funções executivas em crianças com dislexia

ABSTRACT This study aimed to verify whether children with dyslexia have difficulties in executive functions (shifting, working memory, inhibition). Methods: A sample of 47 children (ages 8-13 years) participated in the study: 24 who were dyslexic and 23 controls with typical development. A battery of neuropsychological tests was used. Results: Results revealed executive function difficulties among the dyslexic children when compared with controls, encompassing selective attention modulation processes, shifting, and inhibitory control. These difficulties appeared to be affected by phonological working memory deficits, typically associated with dyslexia. Conclusion: Our findings support the consensus among scholars regarding the central involvement of phonological skill dysfunctions in dyslexia.

RESUMO O objetivo deste estudo foi verificar se crianças com dislexia têm dificuldades nas habilidades de funções executivas (shifting, memória operacional e inibição). Métodos: Uma amostra de 47 crianças (idades entre 8 e 13 anos) participaram do estudo: 24 crianças disléxicas e 23 crianças com desenvolvimento típico. Uma bateria de avaliação neuropsicológica foi usada. Results: Os resultados revelaram dificuldades nas funções executivas nas crianças disléxicas quando comparadas com as controle, envolvendo processos de modulação de atenção seletiva, shifting e controle inibitório. Essas dificuldades parecem ser afetadas pelos déficits na memória operacional fonológica, tipicamente associada à dislexia. Conclusion: Assim, nossos achados suportam o consenso de que a disfunção central da dislexia está nas habilidades fonológicas.

Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors.

INTRODUCTION: Venetoclax, a substrate of cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), is approved for the treatment of patients with chronic lymphocytic leukemia who have received at least one prior therapy. This study evaluated the effect of azithromycin, a commonly used antibiotic in cancer patients and a P-gp inhibitor, on the pharmacokinetics of venetoclax. METHODS: In this single-center, open-label, nonfasting, two-period study, 12 healthy female subjects received a single 100 mg dose of venetoclax on day 1 of period 1 and day 3 of period 2. Subjects received azithromycin 500 mg on day 1 and 250 mg once daily on days 2 through 5. Serial blood samples for the determination of venetoclax concentrations were collected after dosing in both periods. Safety was evaluated throughout the study. RESULTS: Following coadministration of venetoclax with multiple doses of azithromycin, venetoclax maximum concentration and area under the curve to infinite time were 25% and 35% lower, respectively, compared to venetoclax administered alone. Venetoclax half-life and time to maximum concentration remained relatively unchanged when administered with azithromycin. Venetoclax was well tolerated with no serious adverse events reported. CONCLUSIONS: The modest changes in venetoclax exposures when given with azithromycin indicate that no dose adjustment would be needed when venetoclax is coadministered with azithromycin or other drugs with P-gp inhibitory potential. Azithromycin represents an alternative to other antimicrobial agents with higher potential to alter venetoclax pharmacokinetics such as clarithromycin, erythromycin, and ciprofloxacin. FUNDING: AbbVie in collaboration with Genentech/Roche.

Clinical evaluation of P-glycoprotein inhibition by venetoclax: a drug interaction study with digoxin.

1. Venetoclax is a novel, small molecule B-cell lymphoma-2 (BCL-2) inhibitor that has demonstrated clinical efficacy in a variety of haematological malignancies. Since venetoclax is an inhibitor of P glycoprotein (P-gp) transporter, a study was conducted in healthy, female volunteers to evaluate the effect of venetoclax on the pharmacokinetics of digoxin, a P-gp probe substrate. 2. Volunteers received a single oral dose of digoxin (0.5 mg) with or without a single oral dose of venetoclax (100  mg). Serial blood samples were obtained for pharmacokinetic assessments of digoxin and venetoclax and serial urine samples were obtained for measurement of digoxin concentrations. Safety was assessed throughout the study. 3. Coadministration of digoxin and venetoclax increased digoxin maximum observed plasma concentration (Cmax) by 35% and area under the plasma-concentration time curve (AUC0-∞) by 9%. Digoxin half-life, renal clearance and the fraction excreted unchanged in urine remained relatively similar. The results of this study indicate that venetoclax can increase the concentrations of P-gp substrates. Narrow therapeutic index P-gp substrates should be administered six hours prior to venetoclax to minimise the potential interaction.

Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Healthy Chinese Subjects.

Venetoclax has been approved in the United States, Europe, Canada, and Australia for appropriate patients with difficult-to-treat chronic lymphocytic leukemia (CLL). The objective of this phase 1 study was to evaluate the pharmacokinetics of venetoclax in Chinese subjects to inform the dose selection of venetoclax in a phase 2 study of patients with relapsed/refractory (R/R) CLL in China. Twelve healthy first-generation Han Chinese subjects received a single 100-mg dose of venetoclax following a low-fat breakfast. Pharmacokinetic parameters were estimated using noncompartmental methods. After a single dose of venetoclax in healthy Chinese subjects, the median time to peak concentration was 6 hours (range, 4 to 6 hours), and the mean ± SD Cmax , AUCinf , and terminal half-life were 1.0 ± 0.32 µg/mL, 12.6 ± 5.4 µg·h/mL, and 18.4 ± 2.97 hours, respectively. On average, venetoclax Cmax and AUCinf values were 94% and 66% higher, respectively, in Chinese subjects compared with those observed historically for non-Asian subjects receiving the same dose. Based on these pharmacokinetic results and the established exposure-response relationship of venetoclax in non-Asian CLL subjects, a 400-mg once-daily dosage regimen was selected for evaluating the venetoclax pharmacokinetics, efficacy, and safety in the venetoclax phase 2 open-label study in Chinese subjects with R/R CLL.

Neupsilin-Inf em um modelo de avaliação neuropsicológica breve para centros de saúde / Neupsilin-Inf in a model of brief neuropsychological assesment for health centers / Neupsilin-Inf en un modelo de evaluación neuropsicológica breve para centros de salud

Este estudo teve como objetivo analisar o uso do NEUPSILIN-Inf num modelo de avaliação neuropsicológica breve em crianças atendidas em um serviço assistencial. As etapas seguidas no modelo de avaliação neuropsicológica breve são: sala de espera, grupo de crianças e avaliação neuropsicológica individual. A análise da aplicabilidade do NEUPSILIN-Inf na detecção de déficits cognitivos foi realizada comparando o desempenho de 171 crianças com possíveis transtornos do neurodesenvolvimento a 358 crianças da amostra de normatização, tendo a média marginal do escore ajustado pela idade. Em todas as tarefas do NEUPSILIN-Inf, o grupo clínico mostrou desempenho inferior. O conjunto de dados do modelo de avaliação pode gerar hipóteses diagnósticas, como deficiência intelectual, possíveis quadros de transtornos da aprendizagem ou específicos de linguagem. Frente à alta escassez de atendimento público para crianças com possíveis transtornos do neurodesenvolvimento, este pode ser um modelo economicamente eficiente para centros de saúde em diversas regiões do Brasil. (AU)

This study aimed to analyze the use of NEUPSILIN-Inf in a model of brief neuropsychological assessment for children attending a helthcare service. The steps followed in the brief neuropsychological assessment model are waiting room, children's group, and individual assessment. The analysis of this model's efficacy in detecting cognitive deficits through NEUPSILIN-Inf was conducted by comparing the performance of 171 children with possible developmental disorders to 358 children from the normative sample of NEUPSILIN-Inf. The clinical group showed lower performance in all NEUPSILIN-Inf 's tasks. The set of data derived from the evaluation model can underlie diagnostic hypotheses, such as intellectual disabilities, learning disorders or specific language impairment. Taking into account the restrictive public care for children with possible developmental disorders, this model can be considered a cost-effective possibility to be accomplished by health centers in different Brazilian regions. (AU)

Este estudio tuvo como objetivo analizar el uso de NEUPSILIN-Inf como un modelo de evaluación neuropsicológica breve para niños, atendidos en un servicio de asistencia pública. Las etapas seguidas para evaluación neuropsicológica breve fueron: sala de espera, grupo de niños, evaluación neuropsicológica individual. El análisis de aplicabilidad NEUPSILIN-Inf para detectar déficits cognitivos, fue realizado comparando el rendimiento de 171 niños con posibles trastornos de neuro-desarrollo y 358 niños de la muestra de normalización, obteniendo la media marginal del resultado, ajustado por la edad. En todas las tareas del NEUPSILIN-Inf, el grupo clínico tuvo un rendimiento inferior. El conjunto de datos del modelo de evaluación puede generar hipótesis diagnósticas, como deficiencia intelectual, posibles trastornos de aprendizaje o específicos de lenguaje. Ante la escasez de atendimiento público para niños con posibles trastornos de neurodesarrollo, este modelo puede ser eficiente desde el punto de vista económico en centros de salud en varias regiones de Brasil. (AU)