RESUMEN
AIMS: To assess the pharmacokinetic and pharmacodynamic profile of a single dose of empagliflozin in young people with Type 2 diabetes to identify the appropriate doses for further paediatric development. METHODS: We conducted a single-dose, open-label, randomized, parallel-group study with empagliflozin 5 mg, 10 mg and 25 mg in young people with Type 2 diabetes aged 10-17 years. RESULTS: Of 39 participants screened, 27 were randomized and completed the study; their mean (± sd) age was 14.1±2.0 years and body weight was 96.7±23.5 kg. Compared with similar studies in adults with Type 2 diabetes, the maximum observed plasma concentrations were slightly lower with the 10-mg and 25-mg doses, and the area under the plasma concentration-time curve was slightly lower with the 10-mg but slightly higher with the 25-mg dose. The adjusted mean increases in urinary glucose excretion were 53 g/24 h (95% CI 32,74), 73 g/24 h (95% CI 52,94) and 87 g/24 h (95% CI 68,107), and the adjusted mean decreases in fasting plasma glucose were 0.9 mmol/l (95% CI -1.6,-0.1), 0.9 mmol/l (95% CI -1.7,-0.2) and 1.1 mmol/l (95% CI -1.8,-0.5) for the 5- 10- and 25-mg doses, respectively. There were no serious adverse events and one investigator-reported drug-related event (dehydration). CONCLUSIONS: After a single oral dose of empagliflozin, adults and young people with Type 2 diabetes had similar exposure-response relationships after adjusting for significant covariates. These data support testing 10-mg and/or 25-mg doses of empagliflozin in an upcoming paediatric phase III Type 2 diabetes trial. (ClinicalTrials.gov registration no.: NCT02121483).
Asunto(s)
Compuestos de Bencidrilo/farmacocinética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glucósidos/farmacocinética , Hipoglucemiantes/farmacocinética , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacocinética , Administración Oral , Adolescente , Compuestos de Bencidrilo/administración & dosificación , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Niño , Diabetes Mellitus Tipo 2/sangre , Relación Dosis-Respuesta a Droga , Femenino , Glucósidos/administración & dosificación , Humanos , Hipoglucemiantes/administración & dosificación , Masculino , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificaciónAsunto(s)
Antineoplásicos/uso terapéutico , Conducta Cooperativa , Diseño de Fármacos , Descubrimiento de Drogas/métodos , Piperazinas/uso terapéutico , Acrilamidas , Compuestos de Anilina , Antineoplásicos/química , Aprobación de Drogas/métodos , Descubrimiento de Drogas/tendencias , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Piperazinas/química , Factores de TiempoRESUMEN
BACKGROUND AND OBJECTIVES: A human recombinant monoclonal anti-RhD IgG may be useful to prevent RhD allo-immunization. Roledumab is such an antibody with a glycosylation pattern optimized for biological activity. The objective of the study was to assess the safety and pharmacokinetics of roledumab in healthy RhD-negative volunteers. MATERIALS AND METHODS: A total of 46 subjects received doses of 30-3000 µg i.v. of roledumab or placebo using a double-blind escalating single-dose design; 12 of these subjects also received 300 µg i.m. of roledumab. Subjects were followed for 6 months after administration. Serum roledumab concentrations were determined using flow cytometry. RESULTS: Fourteen treatment-emergent adverse events related to treatment were reported in nine subjects, with no apparent difference in their frequency or nature after placebo or roledumab administration. No anti-roledumab antibodies were detected. AUC(last) increased from 4·4 ng/ml.day at 30 µg i.v. to 2257 ng/ml.day at 3000 g i.v. The t(½) ranged from 18 to 22 days, and the absolute bioavailability after i.m. administration was between 73% and 80%. CONCLUSION: Roledumab is safe and well tolerated in healthy RhD-negative volunteers and shows a pharmacokinetic profile similar to that of polyclonal anti-RhD immunoglobulin.
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Anticuerpos Monoclonales/farmacocinética , Fragmentos Fc de Inmunoglobulinas/inmunología , Receptores de IgG/inmunología , Sistema del Grupo Sanguíneo Rh-Hr/inmunología , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/metabolismo , Masculino , Persona de Mediana Edad , Receptores de IgG/genética , Receptores de IgG/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacocinética , Adulto JovenRESUMEN
Vandetanib is a small-molecule inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and RET tyrosine kinases that has demonstrated clinical benefits in patients with medullary thyroid cancer (MTC). By identifying patients who are in greatest need of therapy, the risks of vandetanib can be balanced against the potential benefits in patients for whom there had been no effective therapy until now. This review discusses the development of vandetanib in patients with MTC and the benefits and risks in this patient population.
Asunto(s)
Antineoplásicos/uso terapéutico , Piperidinas/uso terapéutico , Quinazolinas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Animales , Ensayos Clínicos como Asunto/métodos , Receptores ErbB/antagonistas & inhibidores , Humanos , Neoplasias de la Tiroides/inmunología , Resultado del TratamientoRESUMEN
PURPOSE: High-dose pegylated interferon α-2b (peginterferon α-2b) significantly decreased disease recurrence in patients with resected stage III melanoma in a clinical study. We investigated the pharmacokinetics (PK) and safety of high-dose peginterferon α-2b in patients with high-risk melanoma. METHODS: For PK analysis, 32 patients received peginterferon α-2b 6 µg/(kg week) subcutaneously for 8 weeks (induction) then 3 µg/(kg week) for 4 weeks (maintenance). PK profiles were determined at weeks 1, 8, and 12. Exposure-response relationships between peginterferon α-2b and absolute neutrophil count (ANC) and alanine aminotransferase (ALT) level were also studied. RESULTS: Peginterferon α-2b was well-absorbed following SC administration, with a median T (max) of 24 h. Mean half-life estimates ranged from 43 to 51 h. The accumulation factor was 1.69 after induction therapy. PK parameters showed moderate interpatient variability. PK profiles were described by a one-compartmental model with first-order absorption and first-order elimination. Toxicity was profiled and was acceptable; observed side effects were similar to those previously described. Dose reduction produced proportional decreases in exposure and predictable effects on ANC in an Imax model; however, a PK/pharmacodynamic (PK/PD) relationship between peginterferon α-2b and ALT could not be established with high precision. CONCLUSIONS: Peginterferon α-2b was well-absorbed and sustained exposure to peginterferon α-2b was achieved with the doses tested. These data confirm and extend previous PK observations of peginterferon α-2b in melanoma and solid tumors. Our PK/PD model of exposure and ANC effect provides useful information for prediction of peginterferon α-2b-related hematologic toxicity.
Asunto(s)
Interferón-alfa/farmacología , Melanoma/tratamiento farmacológico , Modelos Biológicos , Polietilenglicoles/farmacología , Adulto , Anciano , Quimioterapia Adyuvante/métodos , Terapia Combinada , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Inyecciones Subcutáneas , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/farmacocinética , Masculino , Melanoma/patología , Melanoma/cirugía , Persona de Mediana Edad , Estadificación de Neoplasias , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacocinética , Estudios Prospectivos , Proteínas Recombinantes , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
In vitro studies indicate that lenograstim (glycosylated G-CSF) is more potent than filgrastim (nonglycosylated G-CSF) on a weight for weight basis. However, such a difference has not yet been shown in vivo. The primary objective of this trial was to compare the efficacy of equivalent doses (microgram) of lenograstim and filgrastim in mobilizing CD34+ cells. Thirty-two healthy male volunteers, median age 27 yr (19-44 yr), were randomized to receive either lenograstim 10 micrograms/kg followed by filgrastim 10 micrograms/kg or vice versa with a washout period of a minimum 4 wk. Both drugs were administered as s.c. injections once daily for 5 d (d 1-5). CD34+ cells were mobilized with a similar kinetics, peaking at median d 6 (5-6) for both drugs. A significant difference in favour of lenograstim was shown for peak number of CD34+ cells/microliter blood (104 +/- 38 vs. 82 +/- 35, mean +/- 1 SD, p < 0.0001, paired t-test, n = 30) and number of CFU-GM/microliter blood at d 6 (14.6 +/- 8.4 vs. 10.2 +/- 4.6, p < 0.0001), respectively. There was no difference in the d 6 number of CD3+ cells. Both drugs were generally well tolerated and did not differ with respect to number of adverse events. In conclusion, lenograstim 10 micrograms/kg/d mobilizes PBPC more efficiently than the identical dose of filgrastim, indicating a difference in in vivo potency between the two G-CSFs.
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Adyuvantes Inmunológicos/farmacología , Factor Estimulante de Colonias de Granulocitos/farmacología , Movilización de Célula Madre Hematopoyética/métodos , Células Madre Hematopoyéticas/efectos de los fármacos , Leucaféresis/métodos , Adyuvantes Inmunológicos/efectos adversos , Adulto , Antígenos CD34/análisis , Estudios Cruzados , Filgrastim , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Lenograstim , Recuento de Leucocitos/efectos de los fármacos , Masculino , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/farmacología , Método Simple Ciego , Subgrupos de Linfocitos T/efectos de los fármacos , Linfocitos T/química , Linfocitos T/efectos de los fármacosRESUMEN
The purpose of this study was to, assess the efficacy of glycosylated recombinant human granulocyte colony-stimulating factor (lenograstim) in the prevention of neutropenia and infection in patients receiving dose-intensive chemotherapy for non-Hodgkin's lymphoma (NHL). A second objective was to determine clinical predicators of delay to cytotoxic chemotherapy administration. One hundred-sixty two patients with intermediate- or high-grade NHL and at least one poor prognostic factor received a total of 4 cycles of the LNH-84-regimen every 2 weeks, with an open randomization to treatment with anthracyclines. Patients were randomized to receive subcutaneous lenograstim 5 micrograms/kg/day (n = 82) or placebo (n = 80) from day 6 to day 13 of each cycle. The incidence of severe neutropenia (absolute neutrophil count (ANC) < 0.5 x 10(9)/L) was reduced in the lenograstim group compared with placebo (52% vs 75%). A significant reduction (p < 0.001) in the median duration of ANC < 0.5 x 10(9)/L was also observed in patients treated with lenograstim during each cycle of chemotherapy (0-1 day vs 2-4 days in placebo recipients). Fever occurred in 66 patients in each treatment group. Thirty-four percent of placebo recipients had documented infections during ANC < 1.0 x 10(9)/L compared with 18.5% of lenograstim-treated patients (p < 0.05). Infections of > or = 2 severity were significantly less frequent (p = 0.001) among lenograstim recipients compared with placebo (25 vs 49). The most common adverse events among lenograstim recipients were headache, mild bone pain and injection site reactions. Although lenograstim significantly increased (p = 0.0001) relative dose intensity compared with placebo (93% vs 80%), no difference in CR rate (67% vs 71%) or 3-year survival (63% vs 55%) was observed. The results of this study suggest that patients treated with a chemotherapy regimen that induces severe neutropenia can benefit from treatment with lenograstim. Furthermore, lenograstim permits treatment to be delivered at full dose intensity at 2 week intervals, even in patients with bone marrow involvement, and may permit further dose escalation of the chemotherapeutic regimen used.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Neutropenia/tratamiento farmacológico , Adolescente , Adulto , Bleomicina/uso terapéutico , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Fiebre/complicaciones , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Infecciones , Lenograstim , Linfoma no Hodgkin/complicaciones , Linfoma no Hodgkin/mortalidad , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Placebos , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Tasa de Supervivencia , Resultado del Tratamiento , Vindesina/uso terapéuticoRESUMEN
A multicentre Phase II clinical trial was recently undertaken to document the value of treatment with recombinant human granulocyte colony-stimulating factor (rG-CSF) in children with congenital agranulocytosis. To assess the impact of such therapy on health-related quality of life (HRQOL), we developed a questionnaire that was administered to the parents of study patients, twice prior to the initiation of treatment, and then monthly thereafter for six months. The questionnaire focused on several aspects of HRQOL that we thought were important in this patient population, including functional status, general health perceptions, activity limitation, disease symptoms, and discomfort associated with therapy. In this paper, we describe the questionnaire that we developed and the process by which it was translated into several languages. We also report on the impact of rG-CSF therapy on HRQOL. A total of 130 questionnaires were administered to the parents of 19 study patients between the ages of four and one-half months and 18 years in 11 study centres in four countries. Although our sample size is small, our findings suggest that treatment with rG-CSF may result in significant improvements in general health perceptions, limitations of daily activities, and symptoms of the disease.
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Agranulocitosis/psicología , Agranulocitosis/terapia , Factores Estimulantes de Colonias/uso terapéutico , Calidad de Vida , Actividades Cotidianas , Adolescente , Agranulocitosis/congénito , Niño , Preescolar , Estado de Salud , Humanos , Lactante , Encuestas y Cuestionarios/normas , TraducciónRESUMEN
The aim of this work was to study the evolution of neutrophil functions in non-neutropenic cancer patients. Thirty non-neutropenic patients, median age 35 years (range 19-52), with solid tumors (n = 21) or lymphomas (n = 9) entered a phase I study of five days of s.c. (n = 24) or i.v. bolus (n = 6) lenograstim, recombinant human glycosylated granulocyte colony-stimulating factor (rHuG-CSF Chugai-Rhône-Poulenc), with dose escalation from 1 to 40 micrograms/kg/day. Neutrophil functions were studied before lenograstim (D1) and 24 h after the last dose (D6). Granulocyte count rose in a significant way, and enzyme release, phagocytosis and bacterial killing were stimulated. All patients had improvement of at least one neutrophil function. Directed migration was depressed, although it was still in the normal range. These findings confirm that lenograstim is a potent activator of neutrophil functions in non-neutropenic cancer patients and may be useful as an adjunct to conventional antimicrobial therapy.
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Factor Estimulante de Colonias de Granulocitos/toxicidad , Linfoma/terapia , Neoplasias/terapia , Neutrófilos/fisiología , Adulto , Adhesión Celular/efectos de los fármacos , Quimiotaxis de Leucocito/efectos de los fármacos , Femenino , Factor Estimulante de Colonias de Granulocitos/farmacología , Granulocitos/efectos de los fármacos , Enfermedad de Hodgkin/sangre , Enfermedad de Hodgkin/terapia , Humanos , Técnicas In Vitro , Lenograstim , Recuento de Leucocitos/efectos de los fármacos , Elastasa de Leucocito , Linfoma/sangre , Linfoma no Hodgkin/sangre , Linfoma no Hodgkin/terapia , Masculino , Persona de Mediana Edad , Muramidasa/sangre , N-Formilmetionina Leucil-Fenilalanina/farmacología , Neoplasias/sangre , Neutrófilos/efectos de los fármacos , Elastasa Pancreática/sangre , Fagocitosis/efectos de los fármacos , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/toxicidadRESUMEN
Colony stimulating factors and especially rHuG-GSF, the first available neutrophil growth factor, have led to considerable interest in the field of stem cell transplantation because of their ability to induce stem cell peripheralization either alone or in association with high-dose chemotherapy. Few data exist, however, on the impact of rHuG-CSF on large scale bone marrow collection and autologous bone marrow transplantation (ABMT). This phase I, non-randomized, dose escalation study of rHu-G-CSF (lenograstim) administered to 30 patients at doses ranging from 1 to 40 micrograms/kg/day for 5 days before bone marrow harvesting showed that priming with rHu-G-CSF in vivo increased the number of bone marrow cells and D14 myeloid restricted progenitors (CFU-GM) and led to a better neutrophil recovery after ABMT compared with a contemporary unprimed control population. Otherwise, this study established that 5 days of rHuG-CSF therapy, as a sole stimulus, induced a tenfold increase in the circulating CFU-GM amongst which immature progenitors, estimated by the Delta assay (secondary CFU-GM grown after 7 days of liquid culture/primary CFU-GM), are detected. These conclusions were valid for doses as low as 2 micrograms/kg/day which induced only mild neutrophilia up to the highest dose (40 micrograms/kg/day) and suggest that a short course of rHuG-CSF is beneficial in increasing the stem cell collection.
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Trasplante de Médula Ósea , Factor Estimulante de Colonias de Granulocitos/farmacología , Células Madre Hematopoyéticas/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Adolescente , Adulto , Separación Celular , Femenino , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Lenograstim , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/farmacología , Trasplante AutólogoRESUMEN
Seven patients with glycogen storage disease type Ib suffering from severe and/or recurrent bacterial infections were treated with glycosylated recombinant G-CSF (Lenograstim). Mean follow up was 20.8 months (range 9-30 months). In all cases a median dose of 5 micrograms/kg/day resulted in rapid clinical improvement, associated in 6/7 with an increase in absolute polymorphonuclear (PMN) count. In the remaining subject, a striking amelioration of infectious status contrasted with a persistently low PMN count. Liver transplantation in one patient resolved metabolic complications but did not improve PMN count or the infectious status, while neutropenia was corrected by G-CSF. Prevention of recurrent infections was achieved in all cases with intermittent therapy. Short term treatment was well tolerated, thrombocytopenia in two patients (WHO grade 0 and grade 3) recovering after decrease of G-CSF dosage.
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Infecciones Bacterianas/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo I/complicaciones , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Adolescente , Infecciones Bacterianas/sangre , Infecciones Bacterianas/complicaciones , Niño , Preescolar , Femenino , Estudios de Seguimiento , Enfermedad del Almacenamiento de Glucógeno Tipo I/sangre , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Pruebas Hematológicas , Humanos , Lenograstim , Masculino , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , RecurrenciaAsunto(s)
Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Hemoglobinas/metabolismo , Recuento de Leucocitos/efectos de los fármacos , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/tratamiento farmacológico , Recuento de Plaquetas/efectos de los fármacos , Adolescente , Transfusión de Componentes Sanguíneos , Estudios de Seguimiento , Humanos , Masculino , Síndromes Mielodisplásicos/terapia , Neutrófilos/efectos de los fármacos , Proteínas Recombinantes/uso terapéutico , Factores de TiempoRESUMEN
One hundred and twenty nine children with chronic lead poisoning were followed from August 1985 to July 1989. Old lead paint was recognized as the contaminant source at home. Pica of paint flakes was the main mode of intoxication. Children were classified according to the Center for Disease Control 1985 as follows: class IV (39 cases), class III (45 cases), class II (30 cases), class I (15 cases). Nineteen of those in class IV had blood lead levels above 700 micrograms/l and received BAL + EDTA followed by EDTA alone for a mean of 4.6 +/- 3.5 courses. With this treatment, blood lead level decreases were 50 +/- 17%. Nine of these class IV children had an evaluation at last 3 months after the last chelation course: 5 became class I or II, and 2 class III with a negative provocative test. The remaining 20 children in class IV were given a mean of 2.7 +/- 1.4 courses of EDTA. Blood lead levels decreased by 52 +/- 15%; 11 children were evaluable at least 3 months after the last chelation course: 4 became class I, and 7 class II. Thus overall 80% of class IV moved under treatment to class I or II. Among those 45 children in class II, 30 underwent a provocative test and 24 one to three courses of EDTA: 8 were further studied: 3 became class I and 5 class II. Combination of screening, medical treatment and sociocultural approach led to avoid acute effects of severe chronic childhood lead poisoning. The efficacy of such an approach in preventing chronic effects has still to be evaluated.
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Intoxicación por Plomo/clasificación , Quelantes/uso terapéutico , Niño , Dimercaprol/uso terapéutico , Ácido Edético/uso terapéutico , Femenino , Humanos , Intoxicación por Plomo/diagnóstico , Intoxicación por Plomo/tratamiento farmacológico , MasculinoRESUMEN
Treatment with GM-CSF or G-CSF is becoming widely used in patients with chronic neutropenia, or who are aplastic following chemotherapy or autologous or allogeneic bone marrow transplantation. Recently, some authors have described a phenomenon analogous to cyclic agranulocytosis following treatment with G-CSF in a patient with chronic neutropenia. We wish to describe the same phenomenon in a patient with chronic granulocytic leukemia who received GM-CSF (Sandoz) after T cell depletion in order to accelerate hematological reconstitution.