RESUMEN
This phase 1/2 study assessed the safety, tolerability, and preliminary efficacy of the oral proteasome inhibitor (PI) ixazomib in patients with relapsed/refractory immunoglobulin light chain (AL) amyloidosis. Ixazomib was administered to adult patients with relapsed/refractory AL amyloidosis after 1 or more prior lines of therapy (including bortezomib) on days 1, 8, and 15 of 28-day cycles, for up to 12 cycles. Patients with less than partial response after 3 cycles received oral dexamethasone (40 mg, days 1-4) from cycle 4. A 3+3 dose-escalation phase was followed by 2 expansion cohorts (PI-naive and PI-exposed patients) at the maximum tolerated dose (MTD). Twenty-seven patients were enrolled: 11 during dose escalation (6 at 4.0 mg and 5 at 5.5 mg) and 16 during dose expansion (4.0 mg). Three patients experienced dose-limiting toxicities: 1 at 4.0 mg and 2 at 5.5 mg; the MTD was determined as 4.0 mg. Most common adverse events (AEs) included nausea, skin and subcutaneous tissue disorders (SSTD), diarrhea, and fatigue; grade 3 or higher AEs included dyspnea, fatigue, and SSTD. Overall, the hematologic response rate was 52% in patients treated at the MTD (n = 21). Organ responses were seen in 56% of patients (5 cardiac, 5 renal). Median hematologic progression-free survival was 14.8 months; 1-year progression-free and overall survival rates were 60% and 85%, respectively (median follow-up, 16.9 months). Weekly oral ixazomib appears to be active in patients with relapsed/refractory AL amyloidosis, with a generally manageable safety profile. The study was registered at clinicaltrials.gov as #NCT01318902 A phase 3 study is ongoing (#NCT01659658).
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Amiloidosis/tratamiento farmacológico , Amiloidosis/mortalidad , Compuestos de Boro/administración & dosificación , Glicina/análogos & derivados , Inhibidores de Proteasoma/administración & dosificación , Administración Oral , Anciano , Compuestos de Boro/efectos adversos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Glicina/administración & dosificación , Glicina/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteasoma/efectos adversos , Tasa de SupervivenciaRESUMEN
Background This phase II open-label, multicenter study evaluated the efficacy, safety, and tolerability of TAK-264 in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C (GCC). Methods Patients with advanced or metastatic pancreatic adenocarcinoma expressing GCC (H-score ≥ 10) received TAK-264 1.8 mg/kg on day 1 of a 21-day cycle as a 30-min intravenous infusion for up to 1 year or until disease progression or unacceptable toxicity. The primary objective was overall response rate (ORR [complete response + partial response (PR)]). Secondary objectives included evaluations of the safety and pharmacokinetic profile of TAK-264 (NCT02202785). Results 43 patients were enrolled and treated with 1.8 mg/kg TAK-264: 11, 15, and 17 patients with low, intermediate, and high GCC expression, respectively. Median number of treatment cycles received was two (range 1-10). The ORR was 3%, including one patient with intermediate GCC expression who achieved a PR. All patients experienced ≥1 adverse events (AE). The majority of patients experienced grade 1/2 AEs affecting the gastrointestinal tract. Fifteen (35%) patients experienced ≥grade 3 drug-related AEs; five (12%) patients had a serious AE. The most common (≥10% of patients) all-grade drug-related AEs were nausea (33%), fatigue (28%), neutropenia (23%), decreased appetite (23%), vomiting (16%), asthenia (16%), and alopecia (14%). Conclusions TAK-264 demonstrated a manageable safety profile; however, the low efficacy of TAK-264 observed in this study did not support further clinical investigation.
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Adenocarcinoma/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Inmunoconjugados/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/metabolismo , Receptores de Enterotoxina/metabolismo , Neoplasias PancreáticasRESUMEN
Renal impairment (RI) is a major complication of multiple myeloma (MM). This study aimed to characterize the single-dose pharmacokinetics (PK) of the oral proteasome inhibitor, ixazomib, in cancer patients with normal renal function [creatinine clearance (CrCl) ≥90 ml/min; n = 20), severe RI (CrCl <30 ml/min; n = 14), or end-stage renal disease requiring haemodialysis (ESRD; n = 7). PK and adverse events (AEs) were assessed after a single 3 mg dose of ixazomib. Ixazomib was highly bound to plasma proteins (~99%) in all renal function groups. Unbound and total systemic exposures of ixazomib were 38% and 39% higher, respectively, in severe RI/ESRD patients versus patients with normal renal function. Total ixazomib concentrations were similar in pre- and post-dialyser samples collected from ESRD patients; therefore, ixazomib can be administered without regard to haemodialysis timing. Except for anaemia, the incidence of the most common AEs was generally similar across groups, but grade 3 and 4 AEs were more frequent in the severe RI/ESRD groups versus the normal group (79%/57% vs. 45%), as were serious AEs (43%/43% vs. 15%). The PK and safety results support a reduced ixazomib dose of 3 mg in patients with severe RI/ESRD.
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Compuestos de Boro/farmacocinética , Glicina/análogos & derivados , Mieloma Múltiple/tratamiento farmacológico , Inhibidores de Proteasas/farmacocinética , Insuficiencia Renal/terapia , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Anemia/etiología , Proteínas Sanguíneas/metabolismo , Compuestos de Boro/administración & dosificación , Compuestos de Boro/metabolismo , Cálculo de Dosificación de Drogas , Femenino , Glicina/administración & dosificación , Glicina/metabolismo , Glicina/farmacocinética , Humanos , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Inhibidores de Proteasas/administración & dosificación , Diálisis RenalRESUMEN
AIM: The aim of the present study was to characterize the pharmacokinetics of the oral proteasome inhibitor, ixazomib, in patients with solid tumours and moderate or severe hepatic impairment, to provide posology recommendations. METHODS: Eligible adults with advanced malignancies for which no further effective therapy was available received a single dose of ixazomib on day 1 of the pharmacokinetic cycle; patients with normal hepatic function, moderate hepatic impairment or severe hepatic impairment received 4 mg, 2.3 mg or 1.5 mg, respectively. Blood samples for single-dose pharmacokinetic characterization were collected over 336 h postdose. After sampling, patients could continue to receive ixazomib on days 1, 8 and 15 in 28-day cycles. RESULTS: Of 48 enrolled patients (13, 15 and 20 in the normal, moderate and severe groups, respectively), 43 were pharmacokinetics-evaluable. Ixazomib was rapidly absorbed (median time to reach peak concentration was 0.95-1.5 h) and highly bound to plasma proteins, with a similar mean fraction bound (~99%) across the three groups. In patients with moderate/severe hepatic impairment (combined group), the geometric least squares mean ratios (90% confidence interval) for unbound and total dose-normalized area under the plasma concentration vs. time curve from time zero to the time of the last quantifiable concentration in reference to the normal hepatic function group were 1.27 (0.75, 2.16) and 1.20 (0.79, 1.82), respectively. Seven (15%) of the 48 patients experienced a grade 3 drug-related adverse event; there were no drug-related grade 4 adverse events. CONCLUSIONS: In patients with moderate/severe hepatic impairment, unbound and total systemic exposures of ixazomib were 27% and 20% higher, respectively, vs. normal hepatic function. A reduced ixazomib starting dose of 3 mg is recommended for patients with moderate or severe hepatic impairment.
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Compuestos de Boro/farmacocinética , Glicina/análogos & derivados , Hepatopatías/sangre , Neoplasias/sangre , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Compuestos de Boro/administración & dosificación , Compuestos de Boro/sangre , Femenino , Glicina/administración & dosificación , Glicina/sangre , Glicina/farmacocinética , Humanos , Hepatopatías/complicaciones , Hepatopatías/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Inhibidores de Proteasoma/administración & dosificación , Inhibidores de Proteasoma/sangre , Inhibidores de Proteasoma/farmacocinética , Adulto JovenRESUMEN
OBJECTIVES: To evaluate the efficacy and safety of adjunctive aripiprazole compared with standard antidepressant therapy (ADT) for older patients with major depressive disorder (MDD) who demonstrated an incomplete response to standard antidepressant monotherapy. METHODS: Data from three similar 14-week studies (an 8-week prospective ADT treatment phase and a 6-week randomized, double-blind phase) of aripiprazole augmentation were pooled for this post hoc analysis. Two age groups were defined: younger patients (aged 18-49 years) and older patients (aged 50-67 years). The older patient group was further divided into three subgroups: 50-55, 56-60, and 61-67 years. The efficacy endpoint was the mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from end of the prospective phase (Week 8) to endpoint (Week 14, last observation carried forward (LOCF)). Remission was defined as MADRS total score ≤10 at endpoint. RESULTS: Four hundred and nine older patients (placebo, n = 198; aripiprazole, n = 211) and 679 younger patients (placebo, n = 341; aripiprazole, n = 338) were included in this analysis. Older patients receiving aripiprazole demonstrated significantly greater improvement in MADRS total score versus placebo at Week 14 (-10.0 vs. -6.4; p < 0.001; LOCF), similar to the improvement seen in younger patients. Remission rates were significantly higher with aripiprazole versus placebo in older (32.5% vs. 17.1%; p < 0.001) and younger (26.9% vs. 16.4%; p < 0.001) patients. Akathisia was the most common adverse event in both the older (17.1%) and younger (26.0%) patient groups. CONCLUSIONS: Adjunctive aripiprazole was effective in improving depressive symptoms in older patients, 50-67 years, with MDD who have had an inadequate response to standard antidepressant medication.
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Antidepresivos/uso terapéutico , Antipsicóticos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Piperazinas/uso terapéutico , Quinolonas/uso terapéutico , Adolescente , Adulto , Anciano , Análisis de Varianza , Antipsicóticos/efectos adversos , Aripiprazol , Trastorno Depresivo Mayor/psicología , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piperazinas/efectos adversos , Estudios Prospectivos , Escalas de Valoración Psiquiátrica , Quinolonas/efectos adversos , Adulto JovenRESUMEN
The testis-specific gene Jingwei (jgw) is a newly evolved short-chain dehydrogenase/reductase in Drosophila. Preliminary substrate screening indicated that JGW prefers long-chain primary alcohols as substrates, including several exotic alcohols such as farnesol and geraniol. Using steady-state kinetics analyses and molecular docking, we not only confirmed JGW's substrate specificity, but also demonstrated that the new enzymatic activities of JGW evolved extensively after exon-shuffling from a preexisting enzyme. Analysis of JGW orthologs in sister species shows that subsequent evolutionary changes following the birth of JGW altered substrate specificities and enzyme stabilities. Our results lend support to a general mechanism for the evolution of a new enzyme, in which catalytic chemistry evolves first followed by diversification of substrate utilization.
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Proteínas de Drosophila/genética , Drosophila melanogaster/enzimología , Drosophila melanogaster/genética , Evolución Molecular , Ácido Graso Sintasas/genética , Ácido Graso Sintasas/metabolismo , Proteínas Mutantes Quiméricas/genética , NADH NADPH Oxidorreductasas/genética , NADH NADPH Oxidorreductasas/metabolismo , Testículo/enzimología , Alcohol Deshidrogenasa/química , Alcohol Deshidrogenasa/genética , Sustitución de Aminoácidos/genética , Animales , Biocatálisis/efectos de los fármacos , Dominio Catalítico , Simulación por Computador , Detergentes/farmacología , Proteínas de Drosophila/química , Estabilidad de Enzimas/efectos de los fármacos , Ácido Graso Sintasas/química , Concentración de Iones de Hidrógeno/efectos de los fármacos , Masculino , Proteínas Mutantes Quiméricas/química , NADH NADPH Oxidorreductasas/química , Especificidad de Órganos/efectos de los fármacos , Especificidad de Órganos/genética , Estructura Terciaria de Proteína , Homología Estructural de Proteína , Especificidad por Sustrato/efectos de los fármacosRESUMEN
In 2 identical multicenter, double-blind, placebo-controlled trials, an 8-week prospective treatment phase to ensure inadequate response to standard antidepressants was followed with 6 weeks of aripiprazole (2-20 mg/d) or placebo, plus a standard antidepressant. This pooled analysis involving 737 patients across the 2 studies evaluated the metabolic effects of adjunctive aripiprazole in patients with major depressive disorder. Outcomes included mean change from end of prospective treatment phase to endpoint in body weight, waist circumference, fasting levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides (TG), fasting plasma glucose, and glycosylated hemoglobin (hemoglobin A1C). Logistic regression determined whether baseline variables were associated with weight gain or whether weight change was associated with clinical outcome. Statistically significant increases occurred in mean body weight (adjunctive aripiprazole, +1.73 kg, vs adjunctive placebo, +0.38 kg; P < 0.001). Significantly more subjects receiving adjunctive aripiprazole had clinically relevant (> or = 7%) weight gain versus placebo (5.2% vs 0.6%; P < 0.001). More patients treated with adjunctive aripiprazole shifted body mass index category group from normal to overweight and from overweight to obese than those treated with adjunctive placebo. Body mass index, sex, age, Montgomery-Asberg Depression Rating Scale score, fasting TG, fasting glucose, and standard antidepressants were not clinically meaningful predictors of weight gain with adjunctive aripiprazole, and change in weight had no correlation with clinical outcome. Adjunctive aripiprazole produced no significant changes versus placebo in mean waist circumference, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, TG, fasting plasma glucose, or hemoglobin A1C. Also, there was no apparent change in the incidence of National Cholesterol Education Program-defined abnormal metabolic measures after treatment with aripiprazole.
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Antidepresivos/efectos adversos , Trastorno Depresivo Mayor/tratamiento farmacológico , Enfermedades Metabólicas/inducido químicamente , Obesidad/inducido químicamente , Piperazinas/efectos adversos , Quinolonas/efectos adversos , Adolescente , Adulto , Anciano , Aripiprazol , Biomarcadores/sangre , Glucemia/efectos de los fármacos , Índice de Masa Corporal , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/psicología , Método Doble Ciego , Quimioterapia Combinada , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/sangre , Modelos Logísticos , Masculino , Enfermedades Metabólicas/sangre , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Obesidad/sangre , Estudios Prospectivos , Escalas de Valoración Psiquiátrica , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Factores de Riesgo , Resultado del Tratamiento , Circunferencia de la Cintura , Aumento de Peso , Adulto JovenRESUMEN
BACKGROUND: Novel efficacious treatments with long-term tolerability are needed for transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. This phase 2 study evaluated the safety and efficacy of all-oral ixazomib-cyclophosphamide-dexamethasone (ICd) followed by single-agent ixazomib maintenance. PATIENTS AND METHODS: Patients were randomised (1:1) to receive 4.0 mg of ixazomib, 300 (Arm A) or 400 (Arm B) mg/m2 of cyclophosphamide (days 1, 8, and 15), and 40 mg of dexamethasone (days 1, 8, 15, and 22) as induction (up to 13 × 28-day cycles), followed by single-agent ixazomib maintenance (28-day cycles) until progressive disease, death, or unacceptable toxicity. Primary end-point was complete response (CR) + very good partial response (VGPR) rate for ICd induction. RESULTS: Seventy patients were enrolled (n = 36 Arm A; n = 34 Arm B); median age was 73 years (range, 61-87). At data cut-off, 66% of patients had completed 13 induction cycles followed by ixazomib maintenance. Median overall treatment duration was 19 cycles (range, 1-29); 21% of patients discontinued treatment during induction and 3% during maintenance due to adverse events (AEs). During induction, among 67 response-evaluable patients, CR+VGPR rate was 25%, and overall response rate (ORR) was 73%. Including the maintenance phase, CR+VGPR rate was 33%, and ORR was 76%. Median progression-free survival was 23.5 months (median follow-up: 26.1 months). The most common all-grade AE was neutropenia (31%). Grade ≥3 AEs were reported by 73% of patients. Five on-study deaths occurred (not treatment-related). CONCLUSIONS: ICd treatment followed by ixazomib maintenance is tolerable and active in elderly, transplant-ineligible NDMM patients. TRIAL REGISTRATION NUMBER: NCT02046070.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Compuestos de Boro/administración & dosificación , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Glicina/análogos & derivados , Mieloma Múltiple/tratamiento farmacológico , Administración Oral , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Australia , Compuestos de Boro/efectos adversos , Contraindicaciones de los Procedimientos , Ciclofosfamida/efectos adversos , Dexametasona/efectos adversos , Progresión de la Enfermedad , Determinación de la Elegibilidad , Europa (Continente) , Femenino , Glicina/administración & dosificación , Glicina/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Supervivencia sin Progresión , Factores de Tiempo , Estados UnidosRESUMEN
Model-informed drug development (MIDD) was central to the development of the oral proteasome inhibitor ixazomib, facilitating internal decisions (switch from body surface area (BSA)-based to fixed dosing, inclusive phase III trials, portfolio prioritization of ixazomib-based combinations, phase III dose for maintenance treatment), regulatory review (model-informed QT analysis, benefit-risk of 4 mg dose), and product labeling (absolute bioavailability and intrinsic/extrinsic factors). This review discusses the impact of MIDD in enabling patient-centric therapeutic optimization during the development of ixazomib.
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Compuestos de Boro/uso terapéutico , Glicina/análogos & derivados , Inhibidores de Proteasoma/uso terapéutico , Animales , Disponibilidad Biológica , Compuestos de Boro/farmacocinética , Compuestos de Boro/farmacología , Ensayos Clínicos Fase III como Asunto , Desarrollo de Medicamentos , Glicina/farmacocinética , Glicina/farmacología , Glicina/uso terapéutico , Humanos , Modelos Teóricos , Mieloma Múltiple/tratamiento farmacológico , Inhibidores de Proteasoma/farmacocinética , Inhibidores de Proteasoma/farmacologíaRESUMEN
BACKGROUND: In patients with ulcerative colitis (UC), fecal calprotectin (FC) concentrations correlate with endoscopic inflammation evidence. This study investigated the effect of vedolizumab induction on FC concentrations and whether FC concentrations could be a reliable surrogate measure of disease status. METHODS: Data from the placebo-controlled, phase 3 trial GEMINI 1 were used to evaluate week-6 relationships between outcomes (including clinical remission, mucosal healing [MH], and endoscopic remission) and both absolute FC concentration values and relative FC concentration changes from baseline (%FC0-6). Sensitivity and specificity were calculated by cross-tabulation; the value of week-6 FC concentration as surrogate biomarker was measured with Youden J statistic computed for various cut points. RESULTS: GEMINI 1 induction phase enrolled 895 patients. Fecal calprotectin concentration decreases were deeper in patients with clinical remission, MH, and/or endoscopic remission than in patients without. The best week-6 indicator of clinical or endoscopic remission in this data set was absolute FC concentration ≤150 µg/g. The surrogate biomarker values (based on areas under the curve) for the best-performing cut points (FC0-6 reduction >90%, FC ≤150 µg/g) were fair (range, 0.70-0.77, total population). More patients met the ≤150 µg/g cut point with vedolizumab than with placebo. Baseline FC concentrations were not correlated with clinical outcomes. CONCLUSIONS: Fecal calprotectin concentration reductions were greater with vedolizumab induction than with placebo. Week-6 FC concentrations had only fair surrogate biomarker value for endoscopic status. Our data suggest that, while FC may reflect inflammatory burden, FC concentration after vedolizumab induction may not be a robust biomarker of mucosal inflammation.
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Biomarcadores/metabolismo , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Heces/química , Fármacos Gastrointestinales/uso terapéutico , Complejo de Antígeno L1 de Leucocito/metabolismo , Índice de Severidad de la Enfermedad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/uso terapéutico , Colitis Ulcerosa/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Curva ROC , Inducción de Remisión , Adulto JovenRESUMEN
BACKGROUND: Patients with major depressive disorder (MDD) who fail to achieve complete remission with antidepressant therapy may benefit from augmentation therapy with an atypical antipsychotic. METHOD: A pooled analysis was performed on 2 identical 14-week studies (8-week prospective antidepressant therapy treatment phase followed by 6-week randomized double-blind phase) evaluating the efficacy of adjunctive aripiprazole (2-20 mg/day) in DSM-IV-TR-defined MDD patients with an inadequate response to antidepressant therapy. Primary efficacy endpoint was the mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from end of the prospective phase (week 8) to end of randomized phase (week 14, last observation carried forward). Subgroup analyses were performed. The key secondary endpoint was mean change in Sheehan Disability Scale (SDS) mean score. RESULTS: At endpoint, mean change in MADRS total score was significantly greater with adjunctive aripiprazole (-8.7) than with adjunctive placebo (-5.7; p < .001). Except for a differential treatment-by-sex interaction, change in MADRS total scores were consistently greater with adjunctive aripiprazole than with adjunctive placebo, regardless of race, age, episode duration, prior antidepressant therapy response, number of historical treatment failures, severity of depressive symptoms, and antidepressant. At endpoint, MADRS remission rates were significantly greater with adjunctive aripiprazole than with placebo (25.7% vs. 15.4%; p < .001). Adjunctive aripiprazole also demonstrated significantly greater improvements in mean change from baseline in SDS total score than adjunctive placebo (-1.2 vs. -0.6; p = .001). CONCLUSION: Augmentation of antidepressant therapy with the atypical antipsychotic aripiprazole resulted in significant efficacy benefits across a range of subgroups of patients with MDD. Further study of a treatment-by-sex interaction is needed. TRIAL REGISTRATION: www.clinicaltrials.gov Identifiers: NCT00095823 and NCT00095758.
RESUMEN
PURPOSE: This phase 1 dose-escalation portion of the study evaluated the safety, pharmacokinetics (PK), and antitumor activity of TAK-264 in Asian patients with advanced gastrointestinal (GI) carcinoma or metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma expressing guanylyl cyclase C (GCC). MATERIALS AND METHODS: Adult patients with advanced GI malignancies expressing GCC (H-score ≥ 10) received TAK-264 on day 1 of 3-week cycles as 30-minute intravenous infusions for up to 1 year or until disease progression or unacceptable toxicity. The primary objectives were to evaluate the safety profile including dose-limiting toxicities (DLTs) during cycle 1, determine the maximum tolerated dose (MTD), and characterize the PK profile of TAK-264. RESULTS: Twelve patients were enrolled and treated with 1.2 mg/kg (n=3), 1.5 mg/kg (n=3), or 1.8 mg/kg TAK-264 (n=6). Median number of treatment cycles received was two (range, 1 to 10). None of the patients experienced a DLT and the MTD was not determined. Ten patients (83%) experienced adverse events (AEs). The most common were neutropenia, anorexia, and nausea (each reported by four patients). Five patients (42%) experienced grade ≥ 3 AEs consisting of tumor hemorrhage and hypertension, ascites, adrenal insufficiency, neutropenia and asthenia. Serum exposure to TAK-264 increased proportionally with the dose and the median half-life was approximately 5.5-6.6 days. No patients experienced an objective response. CONCLUSION: TAK-264 demonstrated a manageable safety profile with limited antitumor activity consistent with studies conducted in Western patients with advanced GI malignancies. TAK-264 exposure increased proportionally with the dose.
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Anticuerpos Monoclonales/uso terapéutico , Neoplasias Gastrointestinales/tratamiento farmacológico , Receptores de Enterotoxina/metabolismo , Anciano , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Femenino , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/metabolismo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: The oral proteasome inhibitor ixazomib has been approved by regulatory authorities around the world, including in the United States and the European Union, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy, based on the pivotal phase III TOURMALINE-MM1 study. OBJECTIVE: The objective of this study was to quantitatively characterize the benefit-risk profile of ixazomib in relapsed/refractory MM in support of the approved dose and schedule. METHODS: We report early-phase study data and exposure-response analyses of TOURMALINE-MM1 data that support the selection of the recommended ixazomib dose and schedule. RESULTS: Single-agent ixazomib studies showed a favorable efficacy/safety profile with weekly versus twice-weekly dosing; a phase I/II study of ixazomib in combination with lenalidomide and dexamethasone (IRd) identified a weekly ixazomib dose that offered an acceptable efficacy/safety profile. In IRd exposure-response analyses from TOURMALINE-MM1, ixazomib systemic exposure was not a significant predictor of progression-free survival or probability of response. Significant associations were observed between ixazomib exposure and the probability of grade ≥3 anemia and thrombocytopenia, and grade ≥2 diarrhea, fatigue, nausea, peripheral neuropathy, and rash. Additionally, higher ixazomib exposure was associated with lower lenalidomide relative dose intensity. CONCLUSIONS: These analyses support a favorable benefit-risk profile for weekly ixazomib 4.0 mg on days 1, 8, and 15 of 28-day cycles, which was selected for the phase III TOURMALINE registration program. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov NCT00932698, NCT00963820, NCT01217957, NCT01564537.
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Compuestos de Boro/administración & dosificación , Glicina/análogos & derivados , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inhibidores de Proteasoma/administración & dosificación , Antineoplásicos/administración & dosificación , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Glicina/administración & dosificación , Humanos , Masculino , Mieloma Múltiple/mortalidadRESUMEN
BACKGROUND AND AIMS: A positive relationship between vedolizumab trough serum concentrations and clinical outcomes in patients with ulcerative colitis [UC] or Crohn's disease [CD] has been reported. Here we further explore exposure-efficacy relationships for vedolizumab induction therapy in post hoc analyses of GEMINI study data. METHODS: Vedolizumab trough concentrations at Week 6 or 10 were grouped in quartiles and clinical outcome rates calculated. Exposure-efficacy relationships at Week 6 and potential baseline covariate effects were explored using logistic regression and individual predicted cumulative average concentration through Week 6 [Caverage] as exposure measure. RESULTS: Higher vedolizumab concentrations were associated with higher clinical remission rates; the exposure-efficacy relationship was steeper for UC than CD. Unadjusted analyses overestimated the relationship, more so for CD. From covariate-adjusted models, average probability of remission at Week 6 increased by approximately 15% for UC and 10% for CD between Caverage values of 35 and 84 µg/ml [5th and 95th percentiles, respectively]. On average, patients with higher albumin, lower faecal calprotectin [UC only], lower C-reactive protein [CD only], and no previous tumour necrosis factor-α [TNFα] antagonist use had a higher remission probability. Previous TNFα antagonist use had the greatest impact; remission probability was approximately 10% higher in treatment-naïve patients. CONCLUSIONS: Higher vedolizumab serum concentrations were associated with higher remission rates after induction therapy in patients with moderately to severely active UC or CD. This relationship is affected by several factors, including previous TNFα antagonist use. Prospective studies are needed to assess vedolizumab dose individualisation and optimisation.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/sangre , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Heces/química , Femenino , Fármacos Gastrointestinales/administración & dosificación , Humanos , Complejo de Antígeno L1 de Leucocito/análisis , Masculino , Persona de Mediana Edad , Inducción de Remisión/métodos , Albúmina Sérica/análisis , Resultado del Tratamiento , Adulto JovenRESUMEN
Theoretical Microscopic Titration Curves (THEMATICS) may be used to identify chemically important residues in active sites of enzymes by characteristic deviations from the normal, sigmoidal Henderson-Hasselbalch titration behavior. Clusters of such deviant residues in physical proximity constitute reliable predictors of the location of the active site. Originally the residues with deviant predicted behavior were identified by human observation of the computed titration curves. However, it is preferable to select the unusual residues by mathematically well-defined criteria, in order to reduce the chance of error, eliminate any possible biases, and substantially speed up the selection process. Here we present some simple statistical tests that constitute such selection criteria. The first derivatives of the predicted titration curves resemble distribution functions and are normalized. The moments of these first derivative functions are computed. It is shown that the third and fourth moments, measures of asymmetry and kurtosis, respectively, are good measures of the deviations from normal behavior. Results are presented for 44 different enzymes. Detailed results are given for 4 enzymes with 4 different types of chemistry: arginine kinase from Limulus polyphemus (horseshoe crab); beta-lactamase from Escherichia coli; glutamate racemase from Aquifex pyrophilus; and 3-isopropylmalate dehydrogenase from Thiobacillus ferrooxidans. The relationship between the statistical measures of nonsigmoidal behavior in the predicted titration curves and the catalytic activity of the residue is discussed.
Asunto(s)
Enzimas/química , Enzimas/metabolismo , Isomerasas de Aminoácido/química , Isomerasas de Aminoácido/metabolismo , Animales , Arginina Quinasa/química , Arginina Quinasa/metabolismo , Bacterias/enzimología , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Sitios de Unión , Catálisis , Escherichia coli/enzimología , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Cangrejos Herradura , Cinética , Microscopía/métodos , Modelos Estadísticos , beta-Lactamasas/química , beta-Lactamasas/metabolismoRESUMEN
BACKGROUND: The oral proteasome inhibitor ixazomib is under phase 3 clinical investigation in multiple myeloma (MM) in combination with lenalidomide-dexamethasone. This study was conducted to investigate the pharmacokinetic and safety profiles of ixazomib, administered with lenalidomide-dexamethasone, in East Asian patients with relapsed/refractory MM. METHODS: Adult patients with measurable disease who had received 1-3 prior lines of therapy received oral ixazomib on days 1, 8, and 15, lenalidomide (25 mg) on days 1-21, and dexamethasone (40 mg) on days 1, 8, 15, and 22, in 28-day cycles. Primary objectives were to characterize ixazomib plasma pharmacokinetics, determine the recommended phase 2/3 dose, and evaluate safety and tolerability. RESULTS: Forty-three patients were enrolled. No dose-limiting toxicities were reported for the first six patients receiving ixazomib (4.0 mg), confirming this as the recommended phase 2/3 dose. Ixazomib was rapidly absorbed with a median T max of 1.5 h on day 1 and 2.0 h on day 15 of cycle 1 and had a geometric mean terminal half-life of 6.1 days. Twenty-one (49%) patients had at least one drug-related grade ≥3 adverse event (AE); the most common were neutropenia (19%), diarrhea (14%), and thrombocytopenia (12%). Twenty-eight of 43 (65%) response-evaluable patients had at least a partial response. The recommended phase 2/3 dose for ixazomib was determined to be 4.0 mg. CONCLUSIONS: The all-oral combination of ixazomib plus lenalidomide-dexamethasone appeared active and well tolerated at 4.0 mg. Consequently, East Asian patients enrolled in phase 3 studies are receiving the same ixazomib dose as patients in other regions. TRIAL REGISTRATION: This study is registered at NCT01645930.
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Antineoplásicos/uso terapéutico , Compuestos de Boro/uso terapéutico , Dexametasona/uso terapéutico , Glicina/análogos & derivados , Mieloma Múltiple/tratamiento farmacológico , Talidomida/análogos & derivados , Adulto , Anciano , Antineoplásicos/farmacocinética , Asia , Compuestos de Boro/farmacocinética , Dexametasona/farmacocinética , Femenino , Glicina/farmacocinética , Glicina/uso terapéutico , Humanos , Lenalidomida , Masculino , Persona de Mediana Edad , Recurrencia , Talidomida/farmacocinética , Talidomida/uso terapéuticoRESUMEN
One of the major challenges in genomics is to understand the function of gene products from their 3D structures. Computational methods are needed for the high-throughput prediction of the function of proteins from their 3D structure. Methods that identify active sites are important for understanding and annotating the function of proteins. Traditional methods exploiting either sequence similarity or structural similarity can be unreliable and cannot be applied to proteins with novel folds or low homology with other proteins. Here, we present a machine-learning application that combines computed electrostatic, evolutionary, and pocket geometric information for high-performance prediction of catalytic residues. Input features consist of our structure-based theoretical microscopic anomalous titration curve shapes (THEMATICS) electrostatics data, enhanced with sequence-based phylogenetic information from INTREPID and topological pocket information from ConCavity. Our THEMATICS-based input features are augmented with an additional metric, the theoretical buffer range. With the integration of the three different types of input, each of which performs admirably on its own, significantly better performance is achieved than that of any of these methods by itself. This combined method achieves 86.7%, 92.5%, and 93.8% recall of annotated functional residues at 5, 8, and 10% false-positive rates, respectively.
Asunto(s)
Inteligencia Artificial , Dominio Catalítico , Genómica/métodos , Anotación de Secuencia Molecular/métodos , Proteínas/química , Algoritmos , Aminoácidos/química , Biología Computacional , Glicósido Hidrolasas/química , Conformación Molecular , Pliegue de Proteína , Proteínas/genética , Relación Estructura-ActividadRESUMEN
OBJECTIVE: To evaluate the efficacy of adjunctive aripiprazole to standard antidepressant therapy (ADT) for patients with DSM-IV major depressive disorder with anxious/atypical features at baseline. METHOD: Data from 2 identical 14-week studies (an 8-week prospective ADT treatment phase and a 6-week randomized, double-blind phase) of aripiprazole augmentation were pooled to evaluate efficacy and safety in the 2 subgroups. The primary efficacy endpoint was mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from end of ADT treatment to end of randomized treatment (last observation carried forward). Anxious depression was defined by a Hamilton Rating Scale for Depression anxiety/somatization factor score ≥ 7, and atypical depression was defined by previously described criteria on the Inventory of Depressive Symptomatology-Self-Report. Both anxious and atypical subtypes were defined based on symptoms at entry into prospective ADT (week 0). Patients were enrolled between June 2004 and April 2006 in one study and from September 2004 to December 2006 in the other (total randomized population, N = 742; anxious/nonanxious population, N = 740; atypical/nonatypical population, N = 737). RESULTS: Completion rates were between 84% and 90% and comparable across all subgroups, with low discontinuations due to adverse events. Patients receiving adjunctive aripiprazole demonstrated significantly greater improvement in MADRS total score versus patients receiving adjunctive placebo, starting at week 1 or week 2 and continuing through to endpoint (anxious: -8.72 vs. -6.17, p ≤ .001; nonanxious: -8.61 vs. -4.97, p ≤ .001; atypical: -9.31 vs. -5.15, p ≤ .001; nonatypical: -8.08 vs. -6.22, p < .05). At endpoint, remission rates were also significantly higher with adjunctive aripiprazole versus adjunctive placebo (p < .05) in all subgroups. Treatment emergent adverse event profile was similar in all subgroups and comparable to the total population. Reporting of akathisia and weight gain on aripiprazole treatment did not differ between subgroups. CONCLUSION: Adjunctive aripiprazole is an effective treatment for patients with major depression presenting with either anxious or atypical features. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00095823 and NCT00095758.
Asunto(s)
Antidepresivos/uso terapéutico , Antipsicóticos/uso terapéutico , Trastornos de Ansiedad/diagnóstico , Trastorno Depresivo Mayor/tratamiento farmacológico , Piperazinas/uso terapéutico , Quinolonas/uso terapéutico , Adulto , Acatisia Inducida por Medicamentos/etiología , Antidepresivos/efectos adversos , Antipsicóticos/efectos adversos , Trastornos de Ansiedad/psicología , Aripiprazol , Peso Corporal/efectos de los fármacos , Comorbilidad , Trastorno Depresivo Mayor/clasificación , Trastorno Depresivo Mayor/diagnóstico , Trastorno Depresivo Mayor/psicología , Método Doble Ciego , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Inventario de Personalidad , Piperazinas/efectos adversos , Quinolonas/efectos adversos , Resultado del TratamientoRESUMEN
New directions in computational methods for the prediction of protein function are discussed. THEMATICS, a method for the location and characterization of the active sites of enzymes, is featured. THEMATICS, for Theoretical Microscopic Titration Curves, is based on well-established finite-difference Poisson-Boltzmann methods for computing the electric field function of a protein. THEMATICS requires only the structure of the subject protein and thus may be applied to proteins that bear no similarity in structure or sequence to any previously characterized protein. The unique features of catalytic sites in proteins are discussed. Discussion of the chemical basis for the predictive powers of THEMATICS is featured in this paper. Some results are given for three illustrative examples: HIV-1 protease, human apurinic/apyrimidinic endonuclease, and human adenosine kinase.