RESUMEN
Off-the-shelf immunotherapeutics that suppress tumor growth and provide durable protection against relapse could enhance cancer treatment. We report preclinical studies on a CD33 x CD3 bivalent bispecific diabody, AMV564, that not only suppresses tumor growth, but also facilitates memory responses in a mouse model of acute myelogenous leukemia (AML). Mechanistically, a single 5-day treatment with AMV564 seems to reduce tumor burden by redirection of T cells, providing a time window for allogeneic or other T cells that innately recognize tumor antigens to become activated and proliferate. When the concentration of bispecific becomes negligible, the effector: target ratio has also shifted, and these activated T cells mediate long-term tumor control. To test the efficacy of AMV564 in vivo, we generated a CD33+ MOLM13CG bioluminescent human cell line and optimized conditions needed to control these cells for 62 days in vivo in NSG mice. Of note, not only did MOLM13CG become undetectable by bioluminescence imaging in response to infusion of human T cells plus AMV564, but also NSG mice that had cleared the tumor also resisted rechallenge with MOLM13CG in spite of no additional AMV564 treatment. In these mice, we identified effector and effector memory human CD4+ and CD8+ T cells in the peripheral blood immediately prior to rechallenge that expanded significantly during the subsequent 18 days. In addition to the anti-tumor effects of AMV564 on the clearance of MOLM13CG cells in vivo, similar effects were seen when primary CD33+ human AML cells were engrafted in NSG mice even when the human T cells made up only 2% of the peripheral blood cells and AML cells made up 98%. These studies suggest that AMV564 is a novel and effective bispecific diabody for the targeting of CD33+ AML that may provide long-term survival advantages in the clinic.
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Anticuerpos Biespecíficos , Complejo CD3 , Memoria Inmunológica , Leucemia Mieloide Aguda , Lectina 3 Similar a Ig de Unión al Ácido Siálico , Animales , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/tratamiento farmacológico , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/inmunología , Ratones , Complejo CD3/inmunología , Memoria Inmunológica/efectos de los fármacos , Línea Celular Tumoral , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacosRESUMEN
BACKGROUND AND OBJECTIVES: Monomethyl auristatin E (MMAE), the toxin linked to CD30-specific monoclonal antibody of Adcetris® (brentuximab vedotin), is a potent anti-microtubule agent. Brentuximab vedotin has been approved for the treatment of relapsed or refractory Hodgkin lymphoma and anaplastic large cell lymphoma. Cytochrome P450 (CYP) induction assessment of MMAE was conducted in human hepatocytes to assess DDI potentials and its translation to clinic. METHODS: MMAE was incubated at 1-1000 nM with cultured primary human hepatocytes for 72 h, and CYP1A2, CYP2B6, and CYP3A4 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction and CYP-specific probe substrate by liquid chromatography coupled with mass spectrometry, along with microtubule disruption by immunofluorescence staining using anti-ß-tubulin antibody and imaging. RESULTS: MMAE up to 10 nM had no significant effect on CYP1A2, CYP2B6, and CYP3A4 mRNA expression and activity, whereas at higher concentrations of 100- and 1000-nM MMAE, the CYP mRNA expression and activity were diminished substantially. Further investigation showed that the degree of CYP suppression was paralleled by that of microtubule disruption by MMAE, as measured by increase in the number of ß-tubulin-positive aggregates. At the clinical dose, the concentration of MMAE was 7 nM which did not show any significant CYP suppression or microtubule disruption in hepatocytes. CONCLUSIONS: MMAE was not a CYP inducer in human hepatocytes. However, it caused a concentration-dependent CYP mRNA suppression and activity. The CYP suppression was associated with microtubule disruption, supporting the reports that intact microtubule architecture is required for CYP regulations. The absence of CYP suppression and microtubule disruption in vitro at the clinical plasma concentrations of MMAE (< 10 nM) explains the lack of pharmacokinetic drug interaction between brentuximab vedotin and midazolam, a sensitive CYP3A substrate, reported in patients.
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Sistema Enzimático del Citocromo P-450/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Inmunoconjugados/farmacología , Microtúbulos/efectos de los fármacos , Oligopéptidos/farmacología , Antineoplásicos/farmacología , Brentuximab Vedotina , Células Cultivadas , Interacciones Farmacológicas , Humanos , Microtúbulos/metabolismo , ARN Mensajero/metabolismoRESUMEN
Antibody-drug conjugates (ADCs) represent an innovative therapeutic approach that provides novel treatment options and hope for patients with cancer. By coupling monoclonal antibodies (mAbs) to cytotoxic small-molecule payloads with a plasma-stable linker, ADCs offer the potential for increased drug specificity and fewer off-target effects than systemic chemotherapy. As evidence for the potential of these therapies, many new ADCs are in various stages of clinical development. Because their structure poses unique challenges to pharmacokinetic and pharmacodynamic characterization, it is critical to recognize the differences between ADCs and conventional chemotherapy in the design of ADC clinical development strategies. Although some properties may be determined mainly by either the mAb or the small-molecule portion, the behavior of these agents is not always predictable. Furthermore, because the absorption, distribution, metabolism, and excretion (ADME) of ADCs are influenced by all 3 of its components (mAb, linker, and payload), it is important to characterize the intact molecule, any target-mediated catabolic clearance of the mAb, and the ADME properties of the small-molecule payload. Here we describe key issues in the clinical development of ADCs, including considerations for designing first-in-human studies for ADCs. We discuss some difficulties of ADC pharmacokinetic characterization and current approaches to overcoming these challenges. Finally, we consider all aspects of clinical pharmacology assessment required during drug development, using examples from the literature to illustrate the discussion.
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Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos/administración & dosificación , Inmunoconjugados/administración & dosificación , Neoplasias/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacología , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Diseño de Fármacos , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/farmacología , Neoplasias/inmunologíaRESUMEN
Brentuximab vedotin, a CD30-directed antibody-drug conjugate (ADC), is approved for treating certain patients with CD30-expressing hematologic malignancies. Its primary mechanism of action is the targeted delivery of a microtubule-disrupting agent, monomethyl auristatin E (MMAE), to CD30-expressing cells. A population pharmacokinetic (PopPK) analysis was conducted to characterize the PK of ADC and unconjugated MMAE in patients with CD30-expressing hematologic malignancies by compartmental analysis and to evaluate the effects of covariates on PK of the ADC. A nonlinear mixed-effects modeling approach was used to evaluate data from 314 patients in 5 clinical studies. ADC PK was described by a linear, 3-compartment model with first-order elimination. MMAE PK was described by a semimechanistic, linear, 2-compartment model with first-order elimination. The estimated typical values for a 75-kg male patient were 1.56 L/d and 4.29 L for ADC systemic clearance (CL) and volume of central compartment (V1), respectively, with weight effect exponents of 0.698 and 0.503, respectively. Typical V1 in 75-kg females was 87% of that in males, with no impact on systemic ADC exposure. Typical values of MMAE clearance (CLM ) and volume of central compartment (V4) were 55.7 L/d and 79.8 L, respectively, with weight effect exponents fixed to 0.75 and 1.0, respectively. This is the first PopPK model of brentuximab vedotin to semimechanistically link the PK of ADC and that of the unconjugated small molecule MMAE. Both ADC and MMAE PK data were adequately described by the final integrated model, which supports weight-based dosing of brentuximab vedotin in adult patients with CD30-expressing hematologic malignancies.
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Antineoplásicos/farmacocinética , Neoplasias Hematológicas/metabolismo , Inmunoconjugados/farmacocinética , Antígeno Ki-1/metabolismo , Modelos Biológicos , Oligopéptidos/farmacocinética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Brentuximab Vedotina , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identified in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen. METHODS: We conducted a phase 1 open-label study at ten cancer centres in the USA. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed small-cell lung cancer or large-cell neuroendocrine tumours with progressive measurable disease (according to Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) previously treated with one or two chemotherapeutic regimens, including a platinum-based regimen. We assigned patients to dose-escalation or expansion cohorts, ranging from 0·05 mg/kg to 0·8 mg/kg rovalpituzumab tesirine intravenously every 3 weeks or every 6 weeks, followed by investigation of the dose schedules 0·3 mg/kg and 0·4 mg/kg every 6 weeks and 0·2 mg/kg every 3 weeks. Primary objectives were to assess the safety of rovalpituzumab tesirine, including the maximum tolerated dose and dose-limiting toxic effects. The primary activity endpoint was objective response by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT01901653. The study is closed to enrolment; this report focuses on the cohort with small-cell lung cancer. FINDINGS: Between July 22, 2013, and Aug 10, 2015, 82 patients were enrolled, including 74 patients with small-cell lung cancer and eight with large-cell neuroendocrine carcinoma, all of whom received at least one dose of rovalpituzumab tesirine. Dose-limiting toxic effects of rovalpituzumab tesirine occurred at a dose of 0·8 mg/kg every 3 weeks, including grade 4 thrombocytopenia (in two of two patients at that dose level) and grade 4 liver function test abnormalities (in one patient). The most frequent grade 3 or worse treatment-related adverse events in 74 patients with small-cell lung cancer were thrombocytopenia (eight [11%]), pleural effusion (six [8%]), and increased lipase (five [7%]). Drug-related serious adverse events occurred in 28 (38%) of 74 patients. The maximum tolerated dose of rovalpituzumab tesirine was 0·4 mg/kg every 3 weeks; the recommended phase 2 dose and schedule is 0·3 mg/kg every 6 weeks. At active doses of rovalpituzumab tesirine (0·2 mg/kg or 0·4 mg/kg every 3 weeks or 0·3 mg/kg or 0·4 mg/kg every 6 weeks), 11 (18%) of 60 assessable patients had a confirmed objective response. 11 (18%) of 60 assessable patients had a confirmed objective response, including ten (38%) of 26 patients confirmed to have high DLL3 expression (expression in 50% or more of tumour cells). INTERPRETATION: Rovalpituzumab tesirine shows encouraging single-agent antitumour activity with a manageable safety profile. Further development of rovalpituzumab tesirine in DLL3-expressing malignant diseases is warranted. FUNDING: Stemcentrx Inc.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Benzodiazepinonas/uso terapéutico , Carcinoma de Células Grandes/tratamiento farmacológico , Carcinoma Neuroendocrino/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Péptidos y Proteínas de Señalización Intracelular/inmunología , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas de la Membrana/inmunología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Anciano , Carcinoma de Células Grandes/inmunología , Carcinoma de Células Grandes/patología , Carcinoma Neuroendocrino/inmunología , Carcinoma Neuroendocrino/patología , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Inmunoconjugados/farmacología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Carcinoma Pulmonar de Células Pequeñas/inmunología , Carcinoma Pulmonar de Células Pequeñas/patología , Tasa de SupervivenciaRESUMEN
AIMS: Brentuximab vedotin, an antibody-drug conjugate (ADC), selectively delivers the microtubule-disrupting agent monomethyl auristatin E (MMAE) into CD30-expressing cells. The pharmacokinetics of brentuximab vedotin have been characterized in patients with CD30-positive haematologic malignancies. The primary objective of this phase 1 open label evaluation was to assess the pharmacokinetics of brentuximab vedotin in patients with hepatic or renal impairment. METHODS: Systemic exposures were evaluated following intravenous administration of 1.2 mg kg(-1) brentuximab vedotin in patients with CD30-positive haematologic malignancies and hepatic (n = 7) or renal (n = 10) impairment and compared with those of unimpaired patients (n = 8) who received 1.2 mg kg(-1) brentuximab vedotin in another arm of the study. RESULTS: For any hepatic impairment, the ratios of geometric means (90% confidence interval) for AUC(0,∞) were 0.67 (0.48, 0.93) for ADC and 2.29 (1.27, 4.12) for MMAE. Mild or moderate renal impairment caused no apparent change in ADC or MMAE exposures. Severe renal impairment (creatinine clearance <30 ml min(-1) ; n = 3) decreased ADC exposures (0.71 [0.54, 0.94]) and increased MMAE exposures (1.90 [0.85, 4.21]). No consistent pattern of specific adverse events was evident, but analysis of the safety data was confounded by the patients' poor baseline conditions. Five patients died due to adverse events considered unrelated to brentuximab vedotin. All had substantial comorbidities and most had poor baseline performance status. CONCLUSIONS: Hepatic impairment and severe renal impairment may cause decreases in brentuximab vedotin ADC exposures and increases in MMAE exposures.
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Neoplasias Hematológicas/tratamiento farmacológico , Inmunoconjugados/farmacocinética , Antígeno Ki-1/inmunología , Administración Intravenosa , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Brentuximab Vedotina , Femenino , Neoplasias Hematológicas/inmunología , Insuficiencia Hepática/sangre , Insuficiencia Hepática/tratamiento farmacológico , Humanos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/sangre , Masculino , Persona de Mediana Edad , Insuficiencia Renal/sangre , Insuficiencia Renal/tratamiento farmacológico , Adulto JovenRESUMEN
AIMS: Calcitonin gene related peptide (CGRP) receptor antagonists are effective acute migraine treatments. A capsaicin-induced dermal vasodilatation (CIDV) model has been developed to provide target-engagement information in healthy volunteers. In the model, CGRP release is provoked after dermal capsaicin application, by activating transient receptor potential vanilloid-type-1 (TRPV1) receptors at peripheral sensory nerves. Laser Doppler imaging is used to quantify CIDV and subsequent inhibition by CGRP receptor antagonists. We sought to evaluate a CGRP receptor antagonist, MK-3207, in the biomarker model and to assess the predictability of the CIDV response to migraine clinical efficacy. METHODS: An integrated population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the exposure-response relationship for CIDV inhibition by CGRP and TRPV1 receptor antagonists. MK-3207 dose-response predictions were made based on estimated potency from the PK/PD model and mean plasma concentrations observed at the doses investigated. RESULTS: The results suggested that a 20 mg dose of MK-3207 (EC50 of 1.59 nm) would be required to attain the peripheral CIDV response at a target level that was shown previously to correlate with 2 h clinical efficacy based on phase 3 telcagepant clinical data, and that a plateau of the dose-response would be reached around 40-100 mg. These predictions provided a quantitative rationale for dose selection in a phase 2 clinical trial of MK-3207 and helped with interpretation of the efficacy results from the trial. CONCLUSIONS: The integrated CIDV PK/PD model provides a useful platform for characterization of PK/PD relationships and predictions of dose-response relationships to aid in future development of CGRP and TRPV1 receptor antagonists.
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Compuestos Bicíclicos Heterocíclicos con Puentes , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Capsaicina/farmacología , Modelos Biológicos , Piel/irrigación sanguínea , Compuestos de Espiro , Vasodilatación/efectos de los fármacos , Administración Oral , Adolescente , Adulto , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , Humanos , Masculino , Valor Predictivo de las Pruebas , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Adulto JovenRESUMEN
Antibody-drug conjugates (ADCs) are a class of therapeutics that are designed to deliver potent small-molecule drugs selectively to cells that express a specific target antigen while limiting systemic exposure to the drug. This is accomplished by conjugating a potent drug onto an antibody-based therapeutic with a linker that is exquisitely stable in plasma. The development of an effective ADC requires optimizing a number of design elements and an extensive understanding of absorption, distribution, metabolism/catabolism, and elimination (ADME) processes for the ADC construct. Furthermore, as ADCs are a combination of an antibody and small-molecule drug, understanding key aspects of the ADME of each individual component is needed. This review aims to provide considerations for the development of ADCs from an ADME point of view.
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Inmunoconjugados/farmacocinética , Animales , Estabilidad de Medicamentos , Humanos , Inmunoconjugados/uso terapéutico , Distribución TisularRESUMEN
Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E (MMAE) into CD30-expressing cells. This study evaluated the CYP3A-mediated drug-drug interaction potential of brentuximab vedotin and the excretion of MMAE. Two 21-day cycles of brentuximab vedotin (1.2 or 1.8 mg/kg intravenously) were administered to 56 patients with CD30-positive hematologic malignancies. Each patient also received either a sensitive CYP3A substrate (midazolam), an effective inducer (rifampin), or a strong inhibitor (ketoconazole). Brentuximab vedotin did not affect midazolam exposures. ADC exposures were unaffected by concomitant rifampin or ketoconazole; however, MMAE exposures were lower with rifampin and higher with ketoconazole. The short-term safety profile of brentuximab vedotin in this study was generally consistent with historic clinical observations. The most common adverse events were nausea, fatigue, diarrhea, headache, pyrexia, and neutropenia. Over a 1-week period, â¼23.5% of intact MMAE was recovered after administration of brentuximab vedotin; all other species were below the limit of quantitation. The primary excretion route is via feces (median 72% of the recovered MMAE). These results suggest that brentuximab vedotin (1.8 mg/kg) and MMAE are neither inhibitors nor inducers of CYP3A; however, MMAE is a substrate of CYP3A.
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Antineoplásicos/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Neoplasias Hematológicas/metabolismo , Inmunoconjugados/farmacocinética , Antígeno Ki-1/inmunología , Oligopéptidos/metabolismo , Adolescente , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Brentuximab Vedotina , Estudios Cruzados , Inhibidores del Citocromo P-450 CYP3A , Interacciones Farmacológicas , Heces/química , Femenino , Humanos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Cetoconazol/administración & dosificación , Cetoconazol/efectos adversos , Masculino , Midazolam/administración & dosificación , Midazolam/efectos adversos , Midazolam/farmacocinética , Persona de Mediana Edad , Rifampin/administración & dosificación , Rifampin/efectos adversos , Adulto JovenRESUMEN
OBJECTIVE: To evaluate the pharmacokinetic profile and tolerability of single doses of rizatriptan oral disintegrating tablets (ODTs) in pediatric migraineurs. BACKGROUND: Acute migraine treatment options for children are limited despite a rising migraine prevalence. No triptans are approved in those under 12, and only sumatriptan nasal spray (European Union) and almotriptan tablets (USA) are approved for those aged 12-17. Appropriate dose selection based on body weight may be a factor in establishing treatment efficacy in this population. METHODS: Randomized, double-blind, placebo-controlled, parallel group, single-dose study in 6- to 17-year-old migraineurs. The study was performed between acute migraine attacks. Subjects were allocated to 1 of 2 groups based on body weight: (1) those weighing <40kg received rizatriptan ODT 5mg or placebo; (2) those weighing ≥40kg received rizatriptan 10mg ODT or placebo. Pharmacokinetic data were compared with historical data on rizatriptan ODT 10mg in healthy adults. RESULTS: The geometric mean area under the plasma concentration-time curve from time 0 to infinity (AUC((0-∞)) ) (hours·ng/mL) and maximum peak plasma concentration (C(max) ) (ng/mL) were 56.68 (95% confidence interval [CI]: 48.60, 66.09) and 22.39 (95% CI: 17.90, 28.02), respectively, for the <40kg group and 78.49 (95% CI: 68.93, 89.38) and 22.27 (95% CI: 18.43, 26.92), respectively, for the ≥40kg group. For the comparison of children vs adults, the geometric mean ratios for rizatriptan AUC((0-∞)) and C(max) were 0.85 (90% CI: 0.73, 0.98) and 1.07 (90% CI: 0.86, 1.34), respectively, for the <40kg group vs historical adult data and 1.17 (90% CI: 1.02, 1.34) and 1.06 (90% CI: 0.87, 1.30), respectively, for the ≥40kg group vs historical adult data. There were no serious adverse events, and rizatriptan was generally well tolerated. CONCLUSIONS: In pediatric migraineurs, a weight-based dosing scheme generated plasma rizatriptan AUC((0-∞)) and C(max) values that were generally similar to those historically observed in adults administered a 10-mg dose of rizatriptan ODT (a proven effective dose). The data support further evaluation of the safety, tolerability, and efficacy of this rizatriptan dosing scheme in larger scale clinical trials in the pediatric migraineur population.
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Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/metabolismo , Triazoles/efectos adversos , Triazoles/farmacocinética , Triptaminas/efectos adversos , Triptaminas/farmacocinética , Adolescente , Niño , Método Doble Ciego , Femenino , Cefalea/inducido químicamente , Cefalea/metabolismo , Humanos , MasculinoRESUMEN
PURPOSE: The antibody-drug conjugate (ADC) brentuximab vedotin comprises a CD30-directed antibody covalently attached to the potent antimicrotubule agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. This study explored the safety, maximum-tolerated dose (MTD), and activity of weekly dosing of brentuximab vedotin in patients with relapsed or refractory CD30-positive hematologic malignancies. EXPERIMENTAL DESIGN: In this phase I dose-escalation study, brentuximab vedotin was administered intravenously on Days 1, 8, and 15, of each 28-day cycle at doses ranging from 0.4 to 1.4 mg/kg. Forty-four patients were enrolled: 38 with Hodgkin lymphoma, five with systemic anaplastic large cell lymphoma, and one with peripheral T-cell lymphoma not otherwise specified. Doses were escalated in increments of 0.2 mg/kg until dose-limiting toxicity (DLT) was observed. Patients were monitored for antitherapeutic antibodies and pharmacokinetic parameters. Antitumor assessments were carried out every two cycles. RESULTS: The MTD was 1.2 mg/kg. The most common adverse events were peripheral sensory neuropathy, fatigue, nausea, diarrhea, arthralgia, and pyrexia; and the majority of events were mild to moderate in severity. Tumor regression occurred in 85% of patients and the overall objective response rate was 59% (n = 24), with 34% (n = 14) complete remissions. The median duration of response was not reached at a median follow-up of 45 weeks on study. CONCLUSIONS: Weekly administration of brentuximab vedotin resulted in tumor regression and durable remissions in patients with CD30-positive malignancies. This ADC was associated with manageable toxicity, including peripheral neuropathy. Further study in CD30-positive malignancies is warranted.
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Neoplasias Hematológicas/tratamiento farmacológico , Inmunoconjugados/uso terapéutico , Antígeno Ki-1/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Brentuximab Vedotina , Niño , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Neoplasias Hematológicas/mortalidad , Humanos , Inmunoconjugados/farmacocinética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Distribución Tisular , Adulto JovenRESUMEN
AIM: This study aimed to evaluate the safety, pharmacokinetics and treatment effects of an alpha(nu)beta(3) integrin inhibitor on bone turnover and disease activity in men with hormone-refractory prostate cancer (HRPC) and bone metastases. METHODS: A total of 21 patients with bone metastases and HRPC were randomized to receive MK-0429 200 mg b.i.d. or 1600 mg b.i.d. for 4 weeks. Toxicity, pharmacokinetics and markers of bone turnover and tumor activity were examined. RESULTS: Nausea was the most common adverse event: one (200-mg group) and 11 (1600-mg group) patients. At 4 weeks, mean AUC(0-12 h) was 210 mmol*h (200-mg group) and 673 mmol*h (1600-mg group); mean C(max) values were 42 mmol/L (200-mg group) and 154 mmol/L (1600-mg group). Urinary cross-linked N-telopeptides of type I collagen to creatinine ratio (uNTx), a bone turnover biomarker, showed a change from baseline of -43.4 percent (200-mg group) and -34.1 percent (1600-mg group). There was an increase in serum prostate specific antigen (PSA), a marker for disease activity, of 54.1 percent (200-mg group) and 44.5 percent (1600-mg group). CONCLUSION: MK-0429 was generally well tolerated, with the most common side-effect being nausea. There was some evidence of an early reduction of bone turnover, indicating a potential for clinical use in the treatment of MBD although serum PSA was unexpectedly increased during the study.
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Conservadores de la Densidad Ósea/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Huesos/efectos de los fármacos , Integrinas/antagonistas & inhibidores , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Conservadores de la Densidad Ósea/farmacocinética , Neoplasias Óseas/sangre , Neoplasias Óseas/secundario , Método Doble Ciego , Humanos , Masculino , Persona de Mediana Edad , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Resultado del TratamientoRESUMEN
Telcagepant is a novel, orally active, and selective calcitonin gene-related peptide receptor antagonist being developed for acute treatment of migraine with and without aura. Three separate clinical studies were conducted to evaluate the pharmacokinetics and tolerability of telcagepant following single oral doses in healthy young and elderly men and women and multiple oral doses in men. Telcagepant was rapidly absorbed with a time to maximum concentration of approximately 1.5 hours. The terminal half-life was approximately 6 hours. A greater than dose-proportional increase was observed in the area under the plasma concentration versus time curve from zero to infinity. Following twice-daily dosing, with each dose separated by 2 hours, steady state was achieved in approximately 3 to 4 days with an accumulation ratio of approximately 2. There were no clinically meaningful pharmacokinetic differences when compared across age and gender. Telcagepant was generally well tolerated up to single doses of 1200 mg and multiple doses of 400 mg twice daily.
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Azepinas/farmacocinética , Azepinas/toxicidad , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Imidazoles/farmacocinética , Imidazoles/toxicidad , Adolescente , Adulto , Anciano , Envejecimiento , Azepinas/administración & dosificación , Azepinas/sangre , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Imidazoles/administración & dosificación , Imidazoles/sangre , Absorción Intestinal , Masculino , Persona de Mediana Edad , Trastornos Migrañosos/tratamiento farmacológico , Caracteres Sexuales , Adulto JovenRESUMEN
INTRODUCTION: Telcagepant (MK-0974) is a novel, orally active and selective CGRP receptor antagonist being investigated for acute treatment of migraine. Early clinical data suggested greater than dose proportional increases in exposure following oral administration. The aim of the present studies was to definitively characterize the oral and IV dose proportionality of telcagepant. METHODS: Healthy adult subjects were enrolled in two separate open-label randomized dose proportionality studies: 1) single oral dose crossover from 50 to 600 mg (N = 19); 2) single IV dose parallel group from 5 to 250 mg (N = 10 per dose). Blood samples were collected at time points from 0 to 48 hours postdose. RESULTS: Telcagepant was rapidly absorbed with a T(max) of approximately 1 to 2 hours after oral administration. The terminal half-life was approximately 8 to 9 hours after IV dosing and approximately 4 to 7 hours after oral dosing. Oral administration of telcagepant resulted in greater than dose proportional increases in exposure, while IV administration resulted in approximately dose proportional increases in exposure. CONCLUSIONS: Telcagepant was generally well tolerated. Oral telcagepant exhibits non-linear pharmacokinetics.
RESUMEN
Nitroxyl (HNO), the one-electron reduced and protonated congener of nitric oxide (NO), is a chemically unique species with potentially important biological activity. Although HNO-based pharmaceuticals are currently being considered for the treatment of chronic heart failure or stroke/transplant-derived ischemia, the chemical events leading to therapeutic responses are not established. The interaction of HNO with oxidants results in the well-documented conversion to NO, but HNO is expected to be readily reduced as well. Recent thermodynamic calculations predict that reduction of HNO is biologically accessible. Herein, kinetic analysis suggests that the reactions of HNO with several mechanistically distinct reductants are also biologically feasible. Product analysis verified that the reductants had in fact been oxidized and that in several instances HNO had been converted to hydroxylamine. Moreover, a theoretical analysis suggests that in the reaction of HNO with thiol reductants, the pathway producing sulfinamide is significantly more favorable than that leading to disulfide. Additionally, simultaneous production of HNO and NO yielded a biphasic oxidative capacity.
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Óxido Nítrico/metabolismo , Óxidos de Nitrógeno/química , Sustancias Reductoras/farmacología , Compuestos de Sulfhidrilo/farmacología , Hidroxilamina/química , Hidroxilamina/metabolismo , Cinética , Modelos Teóricos , Óxidos de Nitrógeno/metabolismo , Oxidantes/farmacología , Oxidación-ReducciónRESUMEN
BACKGROUND: A single 115-mg dose of fosaprepitant, the IV prodrug of the NK(1) receptor antagonist aprepitant, is bioequivalent to a 125-mg dose of oral aprepitant. Thus far, fosaprepitant/aprepitant has not shown a meaningful effect on QTc intervals; in this study, we sought to confirm these findings. METHODS: This double-blind, active-controlled, randomized, three-treatment, three-period, crossover study in healthy young subjects evaluated the effect of a 200-mg dose of fosaprepitant on QTc prolongation. In each period, subjects received 400 mg moxifloxacin per os, 200 mg fosaprepitant IV, or placebo in randomized sequence. The effect of fosaprepitant on QTc interval was assessed by 12-lead electrocardiograms (ECGs). The baseline value for QTc interval for each subject during each period was defined as the average of five replicate baseline QTc intervals extracted from predose ECGs. ECGs were performed at predose, 2, 5, 10, 15, 20, 30, 45 min; and 1, 1.5, 2, 3, 4, 6, and 8 h postinfusion. Values for individual QTc change from baseline were evaluated in a repeated-measures mixed model appropriate for a crossover design. A two-sided 90% confidence interval (CI) for the true difference in QTc interval change from baseline at each timepoint was calculated for fosaprepitant versus placebo and for moxifloxacin versus placebo. RESULTS: After fosaprepitant 200-mg administration, the mean (95% CI) QTc interval change from baseline at T(max) was -1.45 (-4.67 to 1.77) ms, and the placebo-corrected mean (90% CI) QTc interval change from baseline was -1.37 (-4.78 to 2.05) ms. Neither was statistically significant at alpha = 0.05. After 400 mg moxifloxacin administration, the mean (95% CI) QTc interval change from baseline at 2 h was 9.71 (6.49-12.93) ms, and the placebo-corrected mean (90% CI) QTc interval change from baseline at moxifloxacin T(max) was 10.50 (7.09-13.92) ms. Both were statistically significant at alpha = 0.05. The maximum aprepitant concentration after fosaprepitant 200 mg administration was 6300 ng/mL (approximately twofold, fourfold, and ninefold higher than that observed historically with fosaprepitant 115 mg [3095 ng/mL], aprepitant 125 mg [1600 ng/mL], and aprepitant 40 mg [675 ng/mL]). CONCLUSIONS: In subjects receiving fosaprepitant 200 mg, no clinically meaningful increases in QTc were seen at any timepoint, whereas after moxifloxacin 400 mg, increases were observed at the approximate T(max) of moxifloxacin and additional timepoints. The lack of QTc increase at this high dose of fosaprepitant and resulting aprepitant plasma exposures support the expectation that clinical doses of fosaprepitant or aprepitant will not be associated with significant QTc prolongation.
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Antidepresivos/efectos adversos , Electrocardiografía/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Morfolinas/efectos adversos , Profármacos/efectos adversos , Adolescente , Adulto , Antiinfecciosos/farmacología , Antidepresivos/farmacocinética , Aprepitant , Compuestos Aza/farmacología , Estudios Cruzados , Método Doble Ciego , Electrocardiografía Ambulatoria , Femenino , Fluoroquinolonas , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Morfolinas/farmacocinética , Moxifloxacino , Profármacos/farmacocinética , Quinolinas/farmacología , Adulto JovenRESUMEN
Fosaprepitant is an intravenous formulation of aprepitant, an oral NK1 antagonist used to prevent chemotherapy-induced nausea and vomiting. This randomized study was designed to evaluate fosaprepitant in polysorbate 80 vehicle for tolerability and bioequivalency to aprepitant. Tolerability was assessed by physical and laboratory examinations and adverse events. Plasma collected for 72 hours was assayed for aprepitant and fosaprepitant. Analysis of variance models were applied to natural log-transformed aprepitant area under the curve (AUC) data. Fosaprepitant up to 150 mg (1 mg/mL) was generally well tolerated. Fosaprepitant 115 mg was AUC bioequivalent to aprepitant 125 mg; the 90% confidence interval for the geometric mean ratio of aprepitant AUC for fosaprepitant 115 mg/aprepitant 125 mg fell within prespecified equivalence bounds of 0.80 to 1.25.
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Antieméticos/efectos adversos , Morfolinas/efectos adversos , Antagonistas del Receptor de Neuroquinina-1 , Profármacos/efectos adversos , Administración Oral , Adulto , Análisis de Varianza , Antieméticos/administración & dosificación , Antieméticos/sangre , Antieméticos/farmacocinética , Aprepitant , Área Bajo la Curva , Estudios Cruzados , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Morfolinas/administración & dosificación , Morfolinas/sangre , Morfolinas/farmacocinética , Profármacos/administración & dosificación , Profármacos/farmacocinética , Equivalencia TerapéuticaRESUMEN
Endothelial-derived nitric oxide (NO) diffuses abluminally to regulate blood flow by activating soluble guanylate cyclase in medial smooth muscle. However, a significant fraction of NO diffuses luminally, where the extremely high reaction rate with red blood cell hemoglobin (Hb) effectively reduces luminal concentration to zero. The erythrocytosis of cyanotic congenital heart disease has potentially opposing effects, namely, a reduction in medial smooth muscle NO bioavailability because of the increase in luminal consumption of the molecule and, conversely, an increase in the elaboration of NO in response to the high endothelial shear stress of the erythrocytotic perfusate. NO metabolism in cyanotic congenital heart disease is unknown. Accordingly, this study aimed to establish the metabolic fate of NO and to determine the degree to which its levels are altered. Blood samples from 25 nonfasting patients with cyanotic congenital heart disease and 25 nonfasting normal controls were collected in Vacutainer tubes containing citrate dextrose and in separate Vacutainer tubes containing a solution that specifically preserves S-nitrosated Hb. Total NO species, plasma S-nitrosated proteins, iron nitrosyl Hb, and S-nitrosated Hb were quantified using chemiluminescence. In conclusion, a significant increase in plasma concentrations of NO metabolites and a modest increase in iron nitrosyl Hb levels were found, suggesting increased luminal consumption caused by erythrocytosis and further suggesting that hypoxemia might activate nonoxidative NO metabolic pathways and enhance tissue oxygen delivery.
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Cianosis/sangre , Cardiopatías Congénitas/sangre , Óxido Nítrico/metabolismo , Adulto , Estudios de Casos y Controles , Cianosis/etiología , Femenino , Hemoglobina Glucada , Cardiopatías Congénitas/complicaciones , Hemoglobinas/metabolismo , Humanos , Mediciones Luminiscentes , Masculino , Óxido Nítrico/sangreRESUMEN
Nitrogen oxides are endogenously produced signaling/effector molecules that have the potential to both cause and ameliorate oxidative stress. Whether nitrogen oxides behave as oxidants or antioxidants is dependent on many factors including the cellular environment, the concentration, and the presence of other reactive species. To date, the nitrogen oxide nitroxyl (HNO) has only been reported to possess prooxidant properties. However, some of its chemical properties would predict that it could also serve as an antioxidant. In this study, the possible antioxidant actions of HNO were examined using the yeast Saccharomyces cerevisiae model system. The effect of HNO on membrane lipid peroxidation was examined and HNO was determined to act solely as an antioxidant in this system. In the presence of glutathione, a thiol-containing peptide that scavenges HNO, the antioxidant action was decreased. In addition, the antioxidant properties of HNO were not due to the conversion of HNO to NO. These results were also confirmed with in vitro assays of oxidative stress. Thus, HNO has the potential to preserve lipid membrane integrity by its antioxidant actions.
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Antioxidantes/farmacología , Óxidos de Nitrógeno/farmacología , Ácidos Grasos Insaturados/administración & dosificación , Peroxidación de Lípido/efectos de los fármacos , Luminiscencia , Estrés Oxidativo , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/metabolismo , Ubiquinona/deficienciaRESUMEN
Encapsulation of hemoglobin (Hb) within red blood cells (RBCs) preserves nitric oxide (NO) bioactivity. With encapsulation, millimolar concentrations of Hb quench only a fraction of NO bioactivity, whereas mere micromolar concentrations of cell-free Hb completely quench NO bioactivity. A submembrane cytoskeletal barrier has been hypothesized to account for the lowered quenching of NO bioactivity. In order to substantiate this hypothesis, here, the underlying submembrane cytoskeletal barrier was physically reduced and the rate of NO entry into the modified RBC measured. The submembrane cytoskeletal barrier of normal and depleted RBCs was characterized using atomic force microscopy and the lipid to protein ratio measured. The reduction in the submembrane cytoskeletal barrier resulted in an increase in the rate of NO entry. We suggest that the underlying submembrane cytoskeleton may be a key component of RBC mediated regulation of NO bioavailability.