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AIM: To evaluate the impact of the sodium glucose co-transporter 2 inhibitor canagliflozin on intrahepatic triglyceride (IHTG) accumulation and its relationship to changes in body weight and glucose metabolism. MATERIALS AND METHODS: In this double-blind, parallel-group, placebo-controlled, 24-week trial subjects with inadequately controlled type 2 diabetes mellitus (T2DM; HbA1c = 7.7% ± 0.7%) from two centres were randomly assigned (1:1) to canagliflozin 300 mg or placebo. We measured IHTG by proton-magnetic resonance spectroscopy (primary outcome), hepatic/muscle/adipose tissue insulin sensitivity during a 2-step euglycaemic insulin clamp, and beta-cell function during a mixed meal tolerance test. Analyses were per protocol. RESULTS: Between 8 September 2014-13 June 2016, 56 patients were enrolled. Canagliflozin reduced HbA1c (placebo-subtracted change: -0.71% [-1.08; -0.33]) and body weight (-3.4% [-5.4; -1.4]; both P ≤ 0.001). A numerically larger absolute decrease in IHTG occurred with canagliflozin (-4.6% [-6.4; -2.7]) versus placebo (-2.4% [-4.2; -0.6]; P = 0.09). In patients with non-alcoholic fatty liver disease (n = 37), the decrease in IHTG was -6.9% (-9.5; -4.2) versus -3.8% (-6.3; -1.3; P = 0.05), and strongly correlated with the magnitude of weight loss (r = 0.69, P < 0.001). Body weight loss ≥5% with a ≥30% relative reduction in IHTG occurred more often with canagliflozin (38% vs. 7%, P = 0.009). Hepatic insulin sensitivity improved with canagliflozin (P < 0.01), but not muscle or adipose tissue insulin sensitivity. Beta-cell glucose sensitivity, insulin clearance, and disposition index improved more with canagliflozin (P < 0.05). CONCLUSIONS: Canagliflozin improves hepatic insulin sensitivity and insulin secretion and clearance in patients with T2DM. IHTG decreases in proportion to the magnitude of body weight loss, which tended to be greater and occur more often with canagliflozin.
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Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Resistência à Insulina , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Fígado/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Triglicerídeos/metabolismo , Idoso , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Feminino , Técnica Clamp de Glucose , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Espectroscopia de Prótons por Ressonância Magnética , Resultado do Tratamento , Redução de PesoRESUMO
A key aspect of research into the prevention and treatment of type 2 diabetes is the availability of reproducible clinical research methodology to assess ß-cell function. One commonly used method employs nonglycemic secretagogues like arginine (arg) or glucagon (glgn). This study was designed to quantify the insulin response to arg and glgn and determine test repeatability and tolerability. Obese overnight-fasted subjects with normal glucose tolerance were studied on 4 separate days: twice using arg (5 g iv) and twice with glgn (1 mg iv). Pre- and postinfusion samples for plasma glucose, insulin, and C-peptide were acquired. Arg and glgn challenges were repeated in the last 10 min of a 60-min glucose (900 mg/min) infusion. Insulin and C-peptide secretory responses were estimated under baseline fasting glucose conditions (AIRarg and AIRglgn) and hyperglycemic (AIRargMAX AIRglgnMAX) states. Relative repeatability was estimated by intraclass correlation coefficient (ICC). Twenty-three (12 men and 11 women) subjects were studied (age: 42.4 ± 8.3 yr; BMI: 31.4 ± 2.8 kg/m²). Geometric means (95% CI) for baseline-adjusted values AIRarg and AIRglgn were 84 (75-95) and 102 (90-115) µU/ml, respectively. After the glucose infusion, AIRargMAX and AIRglgnMAX were 395 (335-466) and 483 (355-658) µU/ml, respectively. ICC values were >0.90 for AIRarg andAIRargMAX. Glucagon ICCs were 0.83, 0.34, and 0.36, respectively, although the exclusion of one outlier increased the latter two values (to 0.84 and 0.86). Both glgn and arg induced mild adverse events that were transient. Glucagon, but not arginine, induced moderate adverse events due to nausea. Taken together, arginine is preferred to glucagon for assessment of ß-cell function.
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Arginina , Glucagon , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Adulto , Idoso , Arginina/administração & dosagem , Arginina/efeitos adversos , Glicemia/análise , Índice de Massa Corporal , Peptídeo C/sangue , Peptídeo C/metabolismo , Feminino , Glucagon/administração & dosagem , Glucagon/efeitos adversos , Glucagon/sangue , Humanos , Hiperglicemia/complicações , Infusões Intravenosas , Insulina/sangue , Secreção de Insulina , Cinética , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/metabolismo , Náusea/induzido quimicamente , Obesidade/sangue , Obesidade/complicações , Obesidade/fisiopatologia , Parestesia/induzido quimicamente , Reprodutibilidade dos TestesRESUMO
As a selective and potent inhibitor targeting the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib obtained approval from the US Food and Drug Administration (FDA) in 2017 for adult patients with acute myeloid leukemia (AML) with an IDH2 mutation. In vitro investigations demonstrated that enasidenib affects various drug metabolic enzymes and transporters. This current investigation aimed to assess enasidenib on the pharmacokinetics (PKs) of CYP substrates, including dextromethorphan (CYP2D6 probe drug), flurbiprofen (CYP2C9 probe drug), midazolam (CYP3A4 probe drug), omeprazole (CYP2C19 probe drug), and pioglitazone (CYP2C8 probe drug), in patients with AML or myelodysplastic syndrome. Results showed that following the co-administration of enasidenib (100 mg, once daily) for 28 days, the PK parameters AUC(0-∞) and Cmax of dextromethorphan increased by 1.37 (90% confidence interval (CI): 0.96, 1.96) and 1.24 (90% CI: 0.94, 1.65)-fold, respectively, compared to dextromethorphan alone. For flurbiprofen, these parameters increased by 1.14 (90%CI: 1.01, 1.29) and 0.97 (90% CI 0.86, 1.08)-fold, respectively, when compared to flurbiprofen alone. Conversely, midazolam exhibited decreases to 0.57 (90% CI 0.34, 0.97) and 0.77 (90% CI 0.39, 1.53)-fold, respectively, in comparison to midazolam alone. The parameters for omeprazole increased by 1.86 (90% CI: 1.33, 2.60) and 1.47 (0.93, 2.31)-fold, respectively, compared to omeprazole alone, while those for pioglitazone decreased to 0.80 (90% CI: 0.62, 1.03) and 0.87 (90% CI: 0.65, 1.16)-fold, respectively, in comparison to pioglitazone alone. These findings provide valuable insights into dose recommendations concerning drugs acting as substrates of CYP2D6, CYP2C9, CYP3A4, CYP2C19, and CYP2C8 when administered concurrently with enasidenib.
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Dextrometorfano , Interações Medicamentosas , Leucemia Mieloide Aguda , Midazolam , Síndromes Mielodisplásicas , Pioglitazona , Piridinas , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia Mieloide Aguda/tratamento farmacológico , Feminino , Idoso , Síndromes Mielodisplásicas/tratamento farmacológico , Midazolam/farmacocinética , Pioglitazona/farmacocinética , Pioglitazona/farmacologia , Dextrometorfano/farmacocinética , Dextrometorfano/administração & dosagem , Piridinas/farmacocinética , Piridinas/administração & dosagem , Flurbiprofeno/farmacocinética , Flurbiprofeno/administração & dosagem , Flurbiprofeno/análogos & derivados , Triazinas/farmacocinética , Triazinas/uso terapêutico , Triazinas/administração & dosagem , Adulto , Omeprazol/farmacocinética , Omeprazol/administração & dosagem , Sistema Enzimático do Citocromo P-450/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Recidiva , Idoso de 80 Anos ou mais , AminopiridinasRESUMO
Introduction: Iberdomide, a novel cereblon modulator (CELMoD®), is currently under clinical investigation for hematology indications. To evaluate the influence of hepatic impairment on the pharmacokinetics (PK) of iberdomide and its major active metabolite M12, a phase 1, multicenter, open-label study was conducted in healthy subjects and subjects with mild, moderate, and severe hepatic impairment. Methods: Forty subjects were enrolled in the study and divided into five groups based on hepatic function. 1 mg iberdomide was administered and plasma samples were collected to evaluate the pharmacokinetics of iberdomide and M12. Results: After a single dose of iberdomide (1 mg), mean iberdomide Cmax (maximum observed concentration) and AUC (area under the concentration-time curve) exposure were generally comparable between hepatic impairment (HI) subjects (severe, moderate and mild) and their respective matched normal controls. Mean Cmax and AUC exposure of the metabolite M12 were generally comparable between mild HI and matched normal subjects. However, mean Cmax of the M12 was 30% and 65% lower and AUC was 57% and 63% lower in moderate and severe HI subjects as compared to their respective matched normal controls. However, given the relatively low M12 exposure as compared to its parent drug, the observed differences were not considered clinically meaningful. Conclusion: In summary, 1 mg single oral dose of iberdomide was generally well-tolerated. HI (mild, moderate or severe) had no clinically relevant impact on iberdomide PK and therefore, no dose adjustment is warranted.
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OBJECTIVE: To assess and validate the application of a non-radioactive assay for cholesteryl ester transfer protein (CETP) activity in clinical samples. DESIGN AND METHODS: In this Phase 0 study, CETP activity was measured following addition of the CETP inhibitor JNJ-28545595 to plasma samples from normolipidemic and three subgroups of dyslipidemic subjects with differing lipid profiles. RESULTS: CETP activity was elevated in plasma samples from dyslipidemic subjects compared to normolipidemic subjects. Increased triglyceride levels correlated with decreased CETP inhibition. The assay was found to have good analytical precision and high throughput potential as required for clinical trial sample analysis. CONCLUSIONS: The results demonstrate that pharmacological inhibition of CETP is affected by the dyslipidemic nature of plasma samples. In addition, since the optimal degree of CETP inhibition for maximal cardiovascular benefit in patients is not known, this assay may be used to help define optimal dosing of CETP inhibitors.
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Bioensaio/métodos , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Dislipidemias/sangue , Lipídeos/sangue , Adulto , Idoso , Proteínas de Transferência de Ésteres de Colesterol/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Técnicas In Vitro , Concentração Inibidora 50 , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal interstitial lung disease (ILD); other ILDs have a progressive, fibrotic phenotype (PF-ILD). Antifibrotic agents can slow but not stop disease progression in patients with IPF or PF-ILD. c-Jun N-terminal kinases (JNKs) are stress-activated protein kinases implicated in the underlying mechanisms of fibrosis, including epithelial cell death, inflammation and polarisation of profibrotic macrophages, fibroblast activation and collagen production. CC-90001, an orally administered (PO), one time per day, JNK inhibitor, is being evaluated in IPF and PF-ILD. METHODS AND ANALYSIS: This is a phase 2, randomised, double-blind, placebo-controlled study evaluating efficacy and safety of CC-90001 in patients with IPF (main study) and patients with PF-ILD (substudy). Both include an 8-week screening period, a 24-week treatment period, up to an 80-week active-treatment extension and a 4-week post-treatment follow-up. Patients with IPF (n=165) will be randomised 1:1:1 to receive 200 mg or 400 mg CC-90001 or placebo administered PO one time per day; up to 25 patients/arm will be permitted concomitant pirfenidone use. Forty-five patients in the PF-ILD substudy will be randomised 2:1 to receive 400 mg CC-90001 or placebo. The primary endpoint is change in per cent predicted forced vital capacity from baseline to Week 24 in patients with IPF. ETHICS AND DISSEMINATION: This study will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles and local ethical and legal requirements. Results will be reported in a peer-reviewed publication. TRIAL REGISTRATION NUMBER: NCT03142191.
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Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Inibidores de Proteínas Quinases , Ensaios Clínicos Fase II como Assunto , Fibrose , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Capacidade VitalRESUMO
CC-90001 selectively inhibits c-Jun N-terminal kinase (JNK), a stress-activated protein implicated in fibrosis. In 3 phase 1 trials evaluating CC-90001 pharmacokinetics, pharmacodynamics, and safety, healthy adults (N = 184) received oral CC-90001 in a single dose (10-720 mg) or multiple doses (30-480 mg once daily for 7-18 days) or placebo. CC-90001 was rapidly absorbed (median time to maximum concentration, 1-4 hours) and eliminated with a mean terminal elimination half-life of 12-28 hours. Steady state was reached on day 5, with a mean accumulation ratio of 1.5- to 2-fold following daily dosing. Exposure was similar in fed versus fasted participants and in Japanese versus non-Japanese participants. CC-90001 demonstrated dose- and exposure-dependent inhibition of JNK as determined by histopathological analysis of c-Jun phosphorylation in ultraviolet-irradiated skin. The most common treatment-emergent adverse events were nausea and headache; all were mild or moderate in intensity. Based on exposure-response analysis using high-quality electrocardiogram data, no clinically relevant QT prolongation liability for CC-90001 was observed. Overall, single- and multiple-dose CC-90001 were generally safe and well tolerated at the tested doses and demonstrated JNK pathway engagement. These results support further clinical evaluation of CC-90001.
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Proteínas Quinases JNK Ativadas por Mitógeno , Adulto , Humanos , Voluntários Saudáveis , Meia-Vida , Relação Dose-Resposta a Droga , Método Duplo-CegoRESUMO
INTRODUCTION: The aims of this study were to characterize the single-dose pharmacokinetics (PK) of the major active metabolites of ozanimod, CC112273 and CC1084037, and to evaluate the effect of gemfibrozil (a strong inhibitor of cytochrome P450 [CYP] 2C8), itraconazole (a strong inhibitor of CYP3A and P-glycoprotein [P-gp]), and rifampin (a strong inducer of CYP3A/P-gp and moderate inducer of CYP2C8) on the single-dose PK of ozanimod and its major active metabolites in healthy subjects. METHODS: This was a phase 1, randomized, parallel-group, open-label study with two parts. In part 1, 40 subjects were randomized to receive a single oral dose of ozanimod 0.46 mg (group A, n = 20) or oral doses of gemfibrozil 600 mg twice daily for 17 days with a single oral dose of ozanimod 0.46 mg on day 4 (group B, n = 20). In part 2, 60 subjects were randomized to receive a single oral dose of ozanimod 0.92 mg (group C, n = 20), oral doses of itraconazole 200 mg once daily for 17 days with a single oral dose of ozanimod 0.92 mg on day 4 (group D, n = 20), or oral doses of rifampin 600 mg once daily for 21 days with a single oral dose of ozanimod 0.92 mg on day 8 (group E, n = 20). Plasma PK parameters for ozanimod, CC112273, and CC1084037 were estimated using noncompartmental methods. RESULTS: Dose-proportional increases in maximum observed concentration (Cmax) and area under the concentration-time curve (AUC) were observed for ozanimod, CC112273, and CC1084037. The mean terminal elimination half-life (t1/2) for ozanimod was approximately 20-22 h while the mean t1/2 for CC112273 and CC1084037 were approximately 10 days. CC112273 and CC1084037 exposures were highly correlated with or without interacting drugs. Itraconazole increased ozanimod AUC by approximately 13% while rifampin reduced ozanimod AUC by approximately 24%, suggesting a minor role of CYP3A and P-gp in the overall disposition of ozanimod. Gemfibrozil increased the AUC for CC112273 and CC1084037 by approximately 47% and 69%, respectively. Rifampin reduced the AUC for CC112273 and CC1084037, primarily via CYP2C8 induction, by approximately 60% and 55%, respectively. CONCLUSIONS: Ozanimod's major active metabolites, CC112273 and CC1084037, exhibited similar single-dose PK properties and their exposures were highly correlated. CYP2C8 is one of the important enzymes in the overall disposition of CC112273 and subsequently its direct metabolite CC1084037. TRIAL REGISTRATION: Clinical trial: NCT03624959.
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Genfibrozila , Itraconazol , Área Sob a Curva , Estudos Cross-Over , Interações Medicamentosas , Voluntários Saudáveis , Humanos , Indanos , Oxidiazóis , RifampinaRESUMO
INTRODUCTION: The aims of this study were to characterize the multiple-dose pharmacokinetics (PK) of ozanimod's major active metabolites (CC112273 and CC1084037) and to evaluate the pharmacodynamic and PK interactions with pseudoephedrine (PSE). METHODS: In this phase 1, single-center, randomized, double-blind, placebo-controlled study, 56 healthy adult subjects were randomized to receive either placebo or ozanimod once daily for 30 days (0.23 mg on days 1-4, 0.46 mg on days 5-7, 0.92 mg on days 8-10, and 1.84 mg on days 11-30). On day 30, a single oral dose of PSE 60 mg was co-administered with placebo or ozanimod. Maximum time-matched change in systolic blood pressure (SBP) from baseline (day 29) following PSE administration on day 30 was calculated. Plasma PK parameters for ozanimod, CC112273, CC1084037, and PSE were estimated using noncompartmental methods. RESULTS: Fifty-two subjects (92.9%) completed the study. Following multiple dosing, approximately 94% of circulating total active drug exposure was represented by ozanimod (6%), CC112273 (73%), and CC1084037 (15%). Exposures of CC112273 and CC1084037 were highly correlated. Mean maximum time-matched change from baseline for SBP was not significantly different between ozanimod + PSE and placebo + PSE. Ozanimod also had no effect on the PK of PSE. Co-administration of ozanimod with a single dose of PSE in healthy subjects was generally well tolerated. While CC112273 and CC1084037 selectively inhibited monoamine oxidase (MAO)-B in vitro, both active metabolites do not inhibit platelet MAO-B activity in vivo. CONCLUSION: Concomitant administration of ozanimod with PSE, a sympathomimetic agent, did not potentiate the effects on blood pressure. TRIAL REGISTRATION: NCT03644576.
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Indanos/farmacocinética , Oxidiazóis/farmacocinética , Pseudoefedrina/metabolismo , Simpatomiméticos/metabolismo , Administração Oral , Adulto , Pressão Sanguínea/efeitos dos fármacos , Preparações de Ação Retardada , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Indanos/metabolismo , Masculino , Pessoa de Meia-Idade , Oxidiazóis/metabolismo , Equivalência Terapêutica , Adulto JovemRESUMO
AIMS: JNJ-64179375 (hereafter JNJ-9375) is a first-in-class, highly specific, large molecule, exosite 1 thrombin inhibitor. In preclinical studies, JNJ-9375 demonstrated robust antithrombotic protection with a wider therapeutic index when compared to apixaban. The purpose of the present study was to examine for the first time the antiplatelet, anticoagulant and antithrombotic effects of JNJ-9375 in a translational model of ex vivo human thrombosis. METHODS AND RESULTS: Fifteen healthy volunteers participated in a double-blind randomized crossover study of JNJ-9375 (2.5, 25, and 250 µg/mL), bivalirudin (6 µg/mL; positive control), and matched placebo. Coagulation, platelet activation, and thrombus formation were determined using coagulation assays, flow cytometry, and an ex vivo perfusion chamber, respectively.JNJ-9375 caused concentration-dependent prolongation of all measures of blood coagulation (prothrombin time, activated partial thromboplastin time, and thrombin time; P < 0.001 for all) and agonist selective inhibition of thrombin (0.1 U/mL) stimulated platelet p-selectin expression (P < 0.001) and platelet-monocyte aggregates (P = 0.002). Compared to placebo, JNJ-9375 (250 µg/mL) reduced mean total thrombus area by 41.1% (95% confidence intervals 22.3 to 55.3%; P < 0.001) at low shear and 32.3% (4.9 to 51.8%; P = 0.025) at high shear. Under both shear conditions, there was a dose-dependent decrease in fibrin-rich thrombus (P < 0.001 for both) but not platelet-rich thrombus (P = ns for both). CONCLUSION: Exosite 1 inhibition with JNJ-9375 caused prolongation of blood coagulation, selective inhibition of thrombin-mediated platelet activation, and reductions in ex vivo thrombosis driven by a decrease in fibrin-rich thrombus formation. JNJ-9375 represents a novel class of anticoagulant with potential therapeutic applications.
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Antitrombinas/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Ativação Plaquetária/efeitos dos fármacos , Trombose/prevenção & controle , Adulto , Antitrombinas/efeitos adversos , Biomarcadores/sangue , Testes de Coagulação Sanguínea , Plaquetas/metabolismo , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Fibrina/metabolismo , Voluntários Saudáveis , Hirudinas/administração & dosagem , Humanos , Masculino , Selectina-P/sangue , Fragmentos de Peptídeos/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Escócia , Trombose/sangue , Trombose/diagnóstico , Adulto JovemRESUMO
BACKGROUND: The aims of this study were to 1. define the responses of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, and peptide YY (PYY) to an oral meal and to intravenous L-arginine; and 2. examine correlation of enteroendocrine hormones with insulin secretion. We hypothesized a relationship between circulating incretin concentrations and insulin secretion. METHODS: Subjects with normal glucose tolerance (NGT, n = 23), prediabetes (PDM, n = 17), or with type 2 diabetes (T2DM, n = 22) were studied twice, following a mixed test meal (470 kCal) (mixed meal tolerance test [MMTT]) or intravenous L-arginine (arginine maximal stimulation test [AST], 5 g). GLP-1 (total and active), PYY, GIP, glucagon, and ß cell function were measured before and following each stimulus. RESULTS: Baseline enteroendocrine hormones differed across the glucose tolerance (GT) spectrum, T2DM generally >NGT and PDM. In response to MMTT, total and active GLP-1, GIP, glucagon, and PYY increased in all populations. The incremental area-under-the-curve (0-120 min) of analytes like total GLP-1 were often higher in T2DM compared with NGT and PDM (35-51%; P < 0.05). At baseline glucose, L-arginine increased total and active GLP-1 and glucagon concentrations in all GT populations (all P < 0.05). As expected, the MMTT and AST provoked differential glucose, insulin, and C-peptide responses across GT populations. Baseline or stimulated enteroendocrine hormone concentrations did not consistently correlate with either measure of ß cell function. CONCLUSIONS/INTERPRETATION: Both MMTT and AST resulted in insulin and enteroendocrine hormone responses across GT populations without consistent correlation between release of incretins and insulin, which is in line with other published research. If a defect is in the enteroendocrine/ß cell axis, it is probably reduced response to rather than diminished secretion of enteroendocrine hormones.
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Arginina/administração & dosagem , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Ingestão de Alimentos , Células Enteroendócrinas/efeitos dos fármacos , Hormônios Gastrointestinais/sangue , Células Secretoras de Insulina/efeitos dos fármacos , Estado Pré-Diabético/sangue , Administração Intravenosa , Biomarcadores/sangue , Estudos Transversais , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Células Enteroendócrinas/metabolismo , Polipeptídeo Inibidor Gástrico/sangue , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Insulina/sangue , Células Secretoras de Insulina/metabolismo , Peptídeo YY/sangue , Período Pós-Prandial , Estado Pré-Diabético/diagnóstico , Estado Pré-Diabético/fisiopatologia , Fatores de Tempo , Estados UnidosRESUMO
Standard practice to minimize variability in beta cell function (BCF) measurement is to test in inpatient (IP) settings. IP testing strains trial subjects, investigators, and budgets. Outpatient (OP) testing may be a solution although there are few reports on OP BCF testing variability. We compared variability metrics between OP and IP from a standardized mixed meal tolerance test (MMTT) and arginine stimulation test (AST) in two separate type 2 diabetes (T2DM) cohorts (OP, n = 20; IP n = 22) in test-retest design. MMTT variables included: insulin sensitivity (Si); beta cell responsivity (Φtot); and disposition index (DItot = Si* Φtot) following 470 kCal meal. AST variables included: acute insulin response to arginine (AIRarg) and during hyperglycemia (AIRargMAX). RESULTS: Baseline characteristics were well-matched. Between and within subject variance for each parameter across cohorts, and intraclass correlation coefficients (ICC-a measure of reproducibility) across parameters were generally comparable for OP to IP. Table summarizes the ICC results for each key parameter and cohort. [Table: see text] In conclusion, the variability (reproducibility) of BCF measures from standardized MMTT and AST is comparable between OP and IP settings. These observations have significant implications for complexity and cost of metabolic studies.
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PURPOSE: The objectives of these population pharmacokinetic analyses were to (1) assess the overall disposition of pemetrexed, (2) characterize between-patient and within-patient variability and identify influential covariates with respect to pemetrexed pharmacokinetics; and, (3) provide individual empirical Bayesian estimates of pharmacokinetic parameters for use in a subsequent pharmacokinetic/pharmacodynamic evaluation of neutropenia following pemetrexed administration. PATIENTS AND METHODS: Data from 287 patients who received 441 cycles without folic acid or vitamin B12 supplementation during participation in one of ten phase II cancer trials were evaluated by population pharmacokinetic analysis using NONMEM. Starting doses were 500 or 600 mg pemetrexed per m2 body surface area, administered as 10-min intravenous infusions every 21 days (1 cycle). The model was developed using data from eight of the ten studies. Predictive performance was evaluated using data from the other two studies. RESULTS: The population pharmacokinetics of pemetrexed administered as a 10-min intravenous infusion are well characterized by a two-compartment model. Typical values of total systemic clearance, central volume of distribution, distributional clearance, and peripheral volume of distribution were 91.6 ml/min, 12.9 l, 14.4 ml/min, and 3.38 l, respectively. Based on these parameter estimates, the terminal elimination half-life of pemetrexed was approximately 3.5 h. Renal function was identified as a covariate with respect to total systemic clearance, and body surface area as a covariate with respect to the central volume of distribution. CONCLUSION: Total systemic exposure (AUC) for a given dose of pemetrexed increases as renal function decreases. Since pharmacodynamic analyses have shown that AUC and not C (max) is the primary determinant of neutropenic response to pemetrexed, this suggests that dose adjustments based on renal function, rather than body surface area, might be considered for pemetrexed.
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Antimetabólitos Antineoplásicos/farmacocinética , Glutamatos/farmacocinética , Guanina/análogos & derivados , Neoplasias/metabolismo , Adolescente , Adulto , Idoso , Análise de Variância , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Teorema de Bayes , Superfície Corporal , Ensaios Clínicos Fase II como Assunto , Feminino , Glutamatos/efeitos adversos , Glutamatos/uso terapêutico , Guanina/efeitos adversos , Guanina/farmacocinética , Guanina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamente , Pemetrexede , População , Reprodutibilidade dos TestesRESUMO
PURPOSE: The objectives of these analyses were to (1) develop a semimechanistic-physiologic population pharmacokinetic/pharmacodynamic (PK/PD) model to describe neutropenic response to pemetrexed and to (2) identify influential covariates with respect to pharmacodynamic response. PATIENTS AND METHODS: Data from 279 patients who received 1,136 treatment cycles without folic acid or vitamin B12 supplementation during participation in one of eight phase II cancer trials were available for analysis. Starting doses were 500 or 600 mg pemetrexed per m2 body surface area (BSA), administered as 10-min intravenous infusions every 21 days (1 cycle). The primary analyses included 105 patients (279 cycles) for which selected covariates-including vitamin deficiency marker data (i.e., homocysteine, cystathionine, methylmalonic acid, and methylcitrate [I, II, and total] plasma concentrations)-were available. Classical statistical multivariate regression analyses and a semimechanistic-physiologic population PK/PD model were used to evaluate neutropenic response to single-agent pemetrexed administration. RESULTS: The timecourse of neutropenia following single-agent pemetrexed administration was adequately described by a semimechanistic-physiologic model. Population estimates for system-based model parameters (i.e., baseline neutrophil count, mean transit time, and the feedback parameter), which mathematically represent current understanding of the process and physiology of hematopoiesis, were consistent with previously reported values. The population PK/PD model included homocysteine, cystathionine, albumin, total protein, and BSA as covariates relative to neutropenic response. CONCLUSION: These results support the programmatic decision to introduce folic acid and vitamin B12 supplementation during pemetrexed clinical development as a means of normalizing patient homocysteine levels, thereby managing the risk of severe neutropenia secondary to pemetrexed administration. The current results also suggest that the addition of vitamin B6 supplementation to normalize patient cystathionine levels may further decrease the incidence of grade 4 neutropenia following pemetrexed administration. The results also suggest the use of folic acid as a means of lessening hematologic toxicity following administration of cytotoxic agents other than antifolates.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Glutamatos/efeitos adversos , Glutamatos/farmacocinética , Guanina/análogos & derivados , Neutropenia/induzido quimicamente , Adulto , Idoso , Algoritmos , Análise de Variância , Antimetabólitos Antineoplásicos/administração & dosagem , Área Sob a Curva , Deficiência de Vitaminas/metabolismo , Contagem de Células Sanguíneas , Superfície Corporal , Ensaios Clínicos Fase II como Assunto , Interpretação Estatística de Dados , Feminino , Ácido Fólico/uso terapêutico , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/farmacocinética , Humanos , Infusões Intravenosas , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Neutropenia/epidemiologia , Neutropenia/prevenção & controle , Neutrófilos/fisiologia , Pemetrexede , População , Vitamina B 12/uso terapêutico , Vitamina B 6/uso terapêutico , Vitaminas/uso terapêuticoRESUMO
PURPOSE: The objective of these analyses was to examine the effect of variations in the explanatory factors of neutropenic response, identified by semimechanistic-physiologic population pharmacokinetic/pharmacodynamic (PK/PD) modeling, on clinically important features of the absolute neutrophil count (ANC)-time profile (e.g, the nadir of the ANC [NANC], its timing [T (Nadir)], and the timecourse of recovery [T (Rec)]). METHODS: Correlation analyses were used to evaluate the relationship of NANC, T (Nadir), and T (Rec) as a function of overall systemic exposure (AUC) and each of the covariates contained in the population PK/PD model. Simulations using the final PK/PD model were used to generate complete ANC-time profiles. Frequency counts of NANCs from the simulated profiles were used to quantitatively explore differences in the incidence and severity of neutropenia associated with a variety of scenarios (500 mg/m2 versus 600 mg/m2, normal vitamin deficiency markers versus elevated vitamin deficiency markers, and body surface area-based versus renal function-based dosing) and to evaluate the effect of individual explanatory factors with respect to neutropenic response. RESULTS: Information obtained from correlation analysis and simulations was helpful in quantitatively exploring the impact of dose, exposure, and/or patient characteristics on neutropenic response. The information gained from these simulations provided supportive evidence for the decision to routinely include vitamin supplementation during pemetrexed treatment as a means of managing the risk of severe neutropenia secondary to pemetrexed administration. These techniques also provided information regarding the specific T (Nadir) and T( Rec) for inclusion in product labeling and suggested that a 14-day treatment cycle might be feasible for pemetrexed. CONCLUSION: For population PK/PD models, to provide useful information for the practicing clinician or the clinical development team, it is not sufficient to look only at influences of covariates on model parameters. Rather, the modeling results need to be carefully investigated in terms of clinically relevant measures.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Glutamatos/efeitos adversos , Glutamatos/farmacocinética , Guanina/análogos & derivados , Neutropenia/induzido quimicamente , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Área Sob a Curva , Deficiência de Vitaminas/sangue , Biomarcadores , Ensaios Clínicos Fase II como Assunto , Relação Dose-Resposta a Droga , Feminino , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/farmacocinética , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Neutropenia/epidemiologia , Neutropenia/prevenção & controle , Neutrófilos , Pemetrexede , PopulaçãoRESUMO
INTRODUCTION: This randomized, double-blind, placebo-controlled, single and multiple ascending-dose study evaluated the pharmacodynamic effects and safety/tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes. METHODS: Patients (N = 116) discontinued their antihyperglycemic medications 2 weeks before randomization. Patients received canagliflozin 30, 100, 200, or 400 mg once daily or 300 mg twice daily, or placebo at 2 study centers in the United States and Germany, or canagliflozin 30 mg once daily or placebo at 1 study center in Korea, while maintaining an isocaloric diet for 2 weeks. On Days -1, 1, and 16, urinary glucose excretion (UGE), plasma glucose (PG), fasting PG (FPG), and insulin were measured. The renal threshold for glucose (RTG) was calculated from UGE, PG, and estimated glomerular filtration rate. Safety was evaluated based on adverse event (AE) reports, vital signs, electrocardiograms, clinical laboratory tests, and physical examinations. RESULTS: Canagliflozin increased UGE dose-dependently (,80-120 g/day with canagliflozin $100 mg), with increases maintained over the 14-day dosing period with each dose. Canagliflozin dose-dependently decreased RTG, with maximal reductions to ,4-5 mM (72-90 mg/dL). Canagliflozin also reduced FPG and 24-hour mean PG; glucose reductions were seen on Day 1 and maintained over 2 weeks. Plasma insulin reductions with canagliflozin were consistent with observed PG reductions. Canagliflozin also reduced body weight. AEs were transient, mild to moderate in intensity, and balanced across groups; 1 canagliflozin-treated female reported an episode of vaginal candidiasis. Canagliflozin did not cause hypoglycemia, consistent with the RTG values remaining above the hypoglycemia threshold. At Day 16, there were no clinically meaningful changes in urine volume, urine electrolyte excretion, renal function, or routine laboratory test values. CONCLUSIONS: Canagliflozin increased UGE and decreased RTG, leading to reductions in PG, insulin, and body weight, and was generally well tolerated in patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00963768.
Assuntos
Canagliflozina/farmacocinética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose , Adulto , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Canagliflozina/administração & dosagem , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Jejum , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Glicosúria/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Transportador 2 de Glucose-Sódio/metabolismo , UrináliseRESUMO
INTRODUCTION: This randomized, double-blind, placebo-controlled, single and multiple ascending-dose study evaluated the pharmacodynamic effects and safety/tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes. METHODS: Patients (Nâ=â116) discontinued their antihyperglycemic medications 2 weeks before randomization. Patients received canagliflozin 30, 100, 200, or 400 mg once daily or 300 mg twice daily, or placebo at 2 study centers in the United States and Germany, or canagliflozin 30 mg once daily or placebo at 1 study center in Korea, while maintaining an isocaloric diet for 2 weeks. On Days -1, 1, and 16, urinary glucose excretion (UGE), plasma glucose (PG), fasting PG (FPG), and insulin were measured. The renal threshold for glucose (RTG) was calculated from UGE, PG, and estimated glomerular filtration rate. Safety was evaluated based on adverse event (AE) reports, vital signs, electrocardiograms, clinical laboratory tests, and physical examinations. RESULTS: Canagliflozin increased UGE dose-dependently (â¼80-120 g/day with canagliflozin ≥100 mg), with increases maintained over the 14-day dosing period with each dose. Canagliflozin dose-dependently decreased RTG, with maximal reductions to â¼4-5 mM (72-90 mg/dL). Canagliflozin also reduced FPG and 24-hour mean PG; glucose reductions were seen on Day 1 and maintained over 2 weeks. Plasma insulin reductions with canagliflozin were consistent with observed PG reductions. Canagliflozin also reduced body weight. AEs were transient, mild to moderate in intensity, and balanced across groups; 1 canagliflozin-treated female reported an episode of vaginal candidiasis. Canagliflozin did not cause hypoglycemia, consistent with the RTG values remaining above the hypoglycemia threshold. At Day 16, there were no clinically meaningful changes in urine volume, urine electrolyte excretion, renal function, or routine laboratory test values. CONCLUSIONS: Canagliflozin increased UGE and decreased RTG, leading to reductions in PG, insulin, and body weight, and was generally well tolerated in patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00963768.
Assuntos
Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/farmacologia , Hipoglicemiantes/farmacologia , Rim/efeitos dos fármacos , Tiofenos/farmacologia , Adulto , Idoso , Glicemia , Peso Corporal/fisiologia , Canagliflozina , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Glucosídeos/efeitos adversos , Glucosídeos/uso terapêutico , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Tiofenos/efeitos adversos , Tiofenos/uso terapêuticoRESUMO
CONTEXT: The stepwise hyperglycemic clamp procedure (SHCP) is the gold standard for measuring the renal threshold for glucose excretion (RT(G)), but its use is limited to small studies in specialized laboratories. OBJECTIVE: The objective of the study was to validate a new method for determining RT(G) using data obtained during a mixed-meal tolerance test (MMTT) in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus (T2DM). DESIGN: This was an open-label study with 2 sequential parts. SETTING: The study was performed at a single center in Germany. PATIENTS: Twenty-eight subjects with T2DM were studied. INTERVENTIONS: No treatment intervention was given in part 1. In part 2, subjects were treated with canagliflozin 100 mg/d for 8 days. In each part, subjects underwent an MMTT and a 5-step SHCP on consecutive days. MAIN OUTCOME MEASURES: For both methods, RT(G) was estimated using measured blood glucose (BG) and urinary glucose excretion (UGE); estimated glomerular filtration rates were also used to determine RT(G) during the MMTT. The methods were compared using the concordance correlation coefficient and geometric mean ratios. RESULTS: In untreated and canagliflozin-treated subjects, the relationship between UGE rate and BG was well described by a threshold relationship. Good agreement was obtained between the MMTT-based and SHCP-derived RT(G) values. The concordance correlation coefficient (for all subjects) was 0.94; geometric mean ratios (90% confidence intervals) for RT(G) values (MMTT/SHCP) were 0.93 (0.89-0.96) in untreated subjects and 1.03 (0.78-1.37) in canagliflozin-treated subjects. Study procedures and treatments were generally well tolerated in untreated and canagliflozin-treated subjects. CONCLUSIONS: In both untreated and canagliflozin-treated subjects with T2DM, RT(G) can be accurately estimated from measured BG, UGE, and estimated glomerular filtration rates using an MMTT-based method.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Glicosúria/prevenção & controle , Hipoglicemiantes/uso terapêutico , Rim/efeitos dos fármacos , Moduladores de Transporte de Membrana/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose , Tiofenos/uso terapêutico , Glicemia/análise , Índice de Massa Corporal , Canagliflozina , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/urina , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Glucosídeos/efeitos adversos , Glicosúria/etiologia , Humanos , Hiperglicemia/etiologia , Hiperglicemia/prevenção & controle , Hipoglicemiantes/efeitos adversos , Rim/metabolismo , Rim/fisiopatologia , Testes de Função Renal , Masculino , Moduladores de Transporte de Membrana/efeitos adversos , Pessoa de Meia-Idade , Sobrepeso/complicações , Período Pós-Prandial , Tiofenos/efeitos adversosRESUMO
OBJECTIVE: Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor, is also a low-potency SGLT1 inhibitor. This study tested the hypothesis that intestinal canagliflozin levels postdose are sufficiently high to transiently inhibit intestinal SGLT1, thereby delaying intestinal glucose absorption. RESEARCH DESIGN AND METHODS: This two-period, crossover study evaluated effects of canagliflozin on intestinal glucose absorption in 20 healthy subjects using a dual-tracer method. Placebo or canagliflozin 300 mg was given 20 min before a 600-kcal mixed-meal tolerance test. Plasma glucose, (3)H-glucose, (14)C-glucose, and insulin were measured frequently for 6 h to calculate rates of appearance of oral glucose (RaO) in plasma, endogenous glucose production, and glucose disposal. RESULTS: Compared with placebo, canagliflozin treatment reduced postprandial plasma glucose and insulin excursions (incremental 0- to 2-h area under the curve [AUC0-2h] reductions of 35% and 43%, respectively; P < 0.001 for both), increased 0- to 6-h urinary glucose excretion (UGE0-6h, 18.2 ± 5.6 vs. <0.2 g; P < 0.001), and delayed RaO. Canagliflozin reduced AUC RaO by 31% over 0 to 1 h (geometric means, 264 vs. 381 mg/kg; P < 0.001) and by 20% over 0 to 2 h (576 vs. 723 mg/kg; P = 0.002). Over 2 to 6 h, canagliflozin increased RaO such that total AUC RaO over 0 to 6 h was <6% lower versus placebo (960 vs. 1,018 mg/kg; P = 0.003). A modest (â¼10%) reduction in acetaminophen absorption was observed over the first 2 h, but this difference was not sufficient to explain the reduction in RaO. Total glucose disposal over 0 to 6 h was similar across groups. CONCLUSIONS: Canagliflozin reduces postprandial plasma glucose and insulin by increasing UGE (via renal SGLT2 inhibition) and delaying RaO, likely due to intestinal SGLT1 inhibition.
Assuntos
Glucose/metabolismo , Glucosídeos/uso terapêutico , Glicosúria/induzido quimicamente , Insulina/sangue , Absorção Intestinal/efeitos dos fármacos , Tiofenos/uso terapêutico , Acetaminofen/farmacocinética , Adolescente , Adulto , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Canagliflozina , Estudos Cross-Over , Depressão Química , Esvaziamento Gástrico/efeitos dos fármacos , Humanos , Insulina/metabolismo , Masculino , Placebos , Período Pós-Prandial , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio , Inibidores do Transportador 2 de Sódio-GlicoseRESUMO
AIMS: Human stresscopin is a corticotropin-releasing factor (CRF) type 2 receptor (CRFR2) selective agonist and a member of the CRF peptide family. Stimulation of CRFR2 improves cardiac output and left ventricular ejection fraction (LVEF) in patients with stable heart failure (HF) with reduced LVEF. We examined the safety, pharmacokinetics, and effects on haemodynamics and serum biomarkers of intravenous human stresscopin acetate (JNJ-39588146) in patients with stable HF with LVEF ≤ 35% and cardiac index (CI) ≤ 2.5 L/min/m(2). METHODS AND RESULTS: Sixty-two patients with HF and LVEF ≤ 35% were instrumented with a pulmonary artery catheter and randomly assigned (ratio 3:1) to receive an intravenous infusion of JNJ-39588146 or placebo. The main study was an ascending dose study of three doses (5, 15, and 30 ng/kg/min) of study drug or placebo administered in sequential 1 h intervals (3 h total). Statistically significant increases in CI and reduction in systemic vascular resistance (SVR) were observed with both the 15 ng/kg/min (2 h time point) and 30 ng/kg/min (3 h time point) doses of JNJ-39588146 without significant changes in heart rate (HR) or systolic blood pressure (SBP). No statistically significant reductions in pulmonary capillary wedge pressure (PCWP) were seen with any dose tested in the primary analysis, although a trend towards reduction was seen. CONCLUSION: In HF patients with reduced LVEF and CI, ascending doses of JNJ-39588146 were associated with progressive increases in CI and reductions in SVR without significant effects on PCWP, HR, or SBP. TRIAL REGISTRATION: NCT01120210.