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1.
Adv Ther ; 35(11): 1859-1872, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30374808

RESUMO

INTRODUCTION: Daratumumab, a human IgG monoclonal antibody targeting CD38, has demonstrated activity as monotherapy and in combination with standard-of-care regimens in multiple myeloma. Population pharmacokinetic analyses were conducted to determine the pharmacokinetics of intravenous daratumumab in combination therapy versus monotherapy, evaluate the effect of patient- and disease-related covariates on drug disposition, and examine the relationships between daratumumab exposure and efficacy/safety outcomes. METHODS: Four clinical studies of daratumumab in combination with lenalidomide/dexamethasone (POLLUX and GEN503); bortezomib/dexamethasone (CASTOR); pomalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone, and bortezomib/melphalan/prednisone (EQUULEUS) were included in the analysis. Using various dosing schedules, the majority of patients (684/694) received daratumumab at a dose of 16 mg/kg. In GEN503, daratumumab was administered at a dose of 2 mg/kg (n = 3), 4 mg/kg (n = 3), 8 mg/kg (n = 4), and 16 mg/kg (n = 34). A total of 650 patients in EQUULEUS (n = 128), POLLUX (n = 282), and CASTOR (n = 240) received daratumumab 16 mg/kg. The exposure-efficacy and exposure-safety relationships examined progression-free survival (PFS) and selected adverse events (infusion-related reactions; thrombocytopenia, anemia, neutropenia, lymphopenia, and infections), respectively. RESULTS: Pharmacokinetic profiles of daratumumab were similar between monotherapy and combination therapy. Covariate analysis identified no clinically important effects on daratumumab exposure, and no dose adjustments were recommended on the basis of these factors. Maximal clinical benefit on PFS was achieved for the majority of patients (approximately 75%) at the 16 mg/kg dose. No apparent relationship was observed between daratumumab exposure and selected adverse events. CONCLUSION: These data support the recommended 16 mg/kg dose of daratumumab and the respective dosing schedules in the POLLUX and CASTOR pivotal studies. FUNDING: Janssen Research & Development.


Assuntos
Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Relação Dose-Resposta a Droga , Mieloma Múltiplo/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Feminino , Finlândia , Humanos , Lenalidomida/uso terapêutico , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Intervalo Livre de Progressão , Talidomida/uso terapêutico , Resultado do Tratamento
2.
Clin Pharmacokinet ; 57(4): 529-538, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28983805

RESUMO

OBJECTIVE: The aim of this study was to understand the influence of disease and patient characteristics on exposure to daratumumab, an immunoglobulin Gκ (IgGκ) monoclonal antibody, and clinical outcomes in relapsed or refractory multiple myeloma (MM). PATIENTS AND METHODS: Baseline myeloma type, albumin levels, renal/hepatic function, age, sex, race, weight, Eastern Cooperative Oncology Group (ECOG) status, refractory status, and number of prior therapies were evaluated using data from two clinical studies-GEN501 (N = 104) and SIRIUS (N = 124). RESULTS: Daratumumab clearance was approximately 110% higher in IgG myeloma patients than non-IgG myeloma patients, leading to significantly lower exposure in IgG myeloma patients based on maximum trough serum concentrations (p < 0.0001). However, the overall response rate was similar for IgG and non-IgG myeloma patients (odds ratio 1.08, 95% confidence interval 0.54-2.17, p = 0.82). For a given exposure, the drug effect was significantly higher (approximately two times) in IgG versus non-IgG patients (p = 0.03). The influence of other patient and disease characteristics on daratumumab exposure was minimal and no significant effect on efficacy was observed (p ≥ 0.1). The incidences of infections and overall grade 3 or higher adverse events in subpopulations were generally consistent with that of the overall population. CONCLUSION: Due to competition with the MM-produced IgG M-protein for neonatal Fc receptor protection from clearance, IgG-based monoclonal antibodies in general may have significantly higher clearance and lower concentrations in IgG MM patients compared with non-IgG MM patients. Careful evaluation of the impact of exposure and patient and disease characteristics on safety and efficacy is warranted for all IgG-based monoclonal antibodies used in MM.


Assuntos
Anticorpos Monoclonais/farmacocinética , Antineoplásicos Imunológicos/farmacocinética , Mieloma Múltiplo/tratamento farmacológico , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/sangue , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/sangue , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/diagnóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Resultado do Tratamento
4.
Clin Pharmacokinet ; 56(8): 915-924, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-27896689

RESUMO

Daratumumab is a CD38 monoclonal antibody recently approved for the treatment of multiple myeloma (MM). We report daratumumab pharmacokinetic data from GEN501, a phase I/II dose-escalation (0.005-24 mg/kg) and dose-expansion (8 or 16 mg/kg) study, and SIRIUS, a phase II study (8 or 16 mg/kg), in relapsed or refractory MM. Noncompartmental analysis was conducted to characterize daratumumab pharmacokinetics, and, in both studies, daratumumab exhibited nonlinear pharmacokinetic characteristics. Decreasing daratumumab clearance with increasing dose suggests saturation of target-mediated clearance at higher dose levels, whereas decreasing clearance over time with repeated dosing may be due to tumor burden reductions as CD38-positive cells are eliminated. These and other pharmacokinetic data analyses support the use of the recommended dose regimen of daratumumab (16 mg/kg weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks thereafter) to rapidly saturate target-mediated clearance during weekly dosing and maintain saturation when dosing every 2 or 4 weeks.


Assuntos
ADP-Ribosil Ciclase 1/farmacocinética , Anticorpos Monoclonais/farmacocinética , Antineoplásicos/farmacocinética , Glicoproteínas de Membrana/farmacocinética , Mieloma Múltiplo/tratamento farmacológico , ADP-Ribosil Ciclase 1/administração & dosagem , ADP-Ribosil Ciclase 1/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Humanos , Fatores Imunológicos/uso terapêutico , Infusões Intravenosas , Glicoproteínas de Membrana/administração & dosagem , Glicoproteínas de Membrana/efeitos adversos , Avaliação de Resultados em Cuidados de Saúde , Inibidores de Proteassoma/uso terapêutico , Resultado do Tratamento
5.
J Econ Entomol ; 95(2): 414-24, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12020022

RESUMO

Susceptibility to tebufenozide and methoxyfenozide of beet armyworm [Spodoptera exigua (Hübner)] from the southern United States and Thailand was determined through exposure of first and third instars to dipped cotton leaves. Among the field populations evaluated, tebufenozide LC50 values for first and third instars, respectively, ranged from 0.377 to 4.41 and 4.37-46.6 microg (AI) /ml of solution. Methoxyfenozide LC50 values for first and third instars of field populations ranged from 0.058 to 0.487 and 0.601-3.83 microg (AI)/ml of solution. A Thailand field strain exhibiting reduced susceptibility to both compounds was subjected to intense laboratory selection for three nonconsecutive generations. At the LC50 and LC90, selected Thailand strains were 45-68 times and 150-1,500 times less susceptible to tebufenozide and 340-320 times and 120-67 times less susceptible to methoxyfenozide as first and third instars, respectively, when compared with the laboratory reference strain. Among the U.S. field populations evaluated, ones from Belle Glade, FL, and Florence, SC, were generally the most susceptible and ones from Maricopa and Parker, AZ, were the least susceptible. Selection of the Thailand field strain with tebufenozide reduced susceptibility to both compounds, and selection of Thailand strains previously pressured with either compound further reduced susceptibility to both, suggesting at least some commonality of resistance mechanism. Characterization of this resistance will provide information that will be helpful for pro-active management of resistance for this valuable group of insecticides.


Assuntos
Hidrazinas/farmacologia , Controle de Insetos , Inseticidas/farmacologia , Hormônios Juvenis/farmacologia , Spodoptera/efeitos dos fármacos , Animais , Bioensaio , Resistência a Inseticidas , Larva , Folhas de Planta
6.
J Econ Entomol ; 95(6): 1185-9, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12539830

RESUMO

The toxicity of a number of emamectin benzoate homologues and photodegradates to five species of Lepidoptera was investigated using diet and foliar bioassays. The emamectin benzoate homologues B1a and B1b were equally toxic in the diet and foliar assays to Spodoptera exigua (Hübner), Heliothis virescens (F.), Tricoplusia ni (Hübner), and Spodoptera frugiperda (J. E. Smith), within each of these species. Plutella xylostella (L.) was the most sensitive species to emamectin benzoate. The AB1a photodegradate of emamectin benzoate was as toxic as the parent compound in the diet assay. However, in the foliage assay AB1a was 4.4-fold less toxic to S. exigua than the parent compound. The MFB1a photodegradate of emamectin benzoate was as toxic as the parent compound to P. xylostella, and 3.1 to 6.2 times as toxic as the parent compound to the other species in the diet assay. The order of toxicity of the photodegradates were AB1a > MFB1a > FAB1a > 8,9-Z-MAB1a > PAB1a.


Assuntos
Inseticidas/química , Ivermectina/análogos & derivados , Ivermectina/química , Lepidópteros , Animais , Fotoquímica , Spodoptera
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