RESUMEN
BACKGROUND: In the phase 3 STELLAR trial, sotatercept, an investigational first-in-class activin signalling inhibitor, demonstrated beneficial effects on 6-min walk distance and additional efficacy endpoints in pre-treated participants with pulmonary arterial hypertension (PAH). METHODS: This post hoc analysis evaluated data from right heart catheterisation (RHC) and echocardiography (ECHO) obtained from the STELLAR trial. Changes from baseline in RHC and ECHO parameters were assessed at 24â weeks. An analysis of covariance (ANCOVA) model was used to estimate differences in least squares means with treatment and randomisation stratification (mono/double versus triple therapy; World Health Organization functional class II versus III) as fixed factors, and baseline value as covariate. RESULTS: Relative to placebo, treatment with sotatercept led to significant (all p<0.0001 except where noted) improvements from baseline in mean pulmonary artery (PA) pressure (-13.9â mmHg), pulmonary vascular resistance (-254.8 dyn·s·cm-5), mean right atrial pressure (-2.7â mmHg), mixed venous oxygen saturation (3.84%), PA elastance (-0.42â mmHg·mL-1·beat-1), PA compliance (0.58â mL·mmHg-1), cardiac efficiency (0.48â mL·beat-1·mmHg-1), right ventricular (RV) work (-0.85â g·m) and RV power (-32.70â mmHg·L·min-1). ECHO showed improvements in tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure ratio (0.12â mm·mmHg-1), end-systolic and end-diastolic RV areas (-4.39â cm2 and -5.31â cm2, respectively), tricuspid regurgitation and RV fractional area change (2.04% p<0.050). No significant between-group changes from baseline were seen for TAPSE, heart rate, cardiac output, stroke volume or their indices. CONCLUSION: In pre-treated patients with PAH, sotatercept demonstrated substantial improvements in PA pressures, PA compliance, PA-RV coupling and right heart function.
Asunto(s)
Corazón , Hemodinámica , Humanos , Proteínas Recombinantes de Fusión/uso terapéutico , Cateterismo Cardíaco , Hipertensión Pulmonar Primaria FamiliarRESUMEN
OBJECTIVE: Lp(a) [lipoprotein (a)] is composed of apoB (apolipoprotein B) and apo(a) [apolipoprotein (a)] and is an independent risk factor for cardiovascular disease and aortic stenosis. In clinical trials, anacetrapib, a CETP (cholesteryl ester transfer protein) inhibitor, causes significant reductions in plasma Lp(a) levels. We conducted an exploratory study to examine the mechanism for Lp(a) lowering by anacetrapib. APPROACH AND RESULTS: We enrolled 39 participants in a fixed-sequence, double-blind study of the effects of anacetrapib on the metabolism of apoB and high-density lipoproteins. Twenty-nine patients were randomized to atorvastatin 20 mg/d, plus placebo for 4 weeks, and then atorvastatin plus anacetrapib (100 mg/d) for 8 weeks. The other 10 subjects were randomized to double placebo for 4 weeks followed by placebo plus anacetrapib for 8 weeks. We examined the mechanisms of Lp(a) lowering in a subset of 12 subjects having both Lp(a) levels >20 nmol/L and more than a 15% reduction in Lp(a) by the end of anacetrapib treatment. We performed stable isotope kinetic studies using 2H3-leucine at the end of each treatment to measure apo(a) fractional catabolic rate and production rate. Median baseline Lp(a) levels were 21.5 nmol/L (interquartile range, 9.9-108.1 nmol/L) in the complete cohort (39 subjects) and 52.9 nmol/L (interquartile range, 38.4-121.3 nmol/L) in the subset selected for kinetic studies. Anacetrapib treatment lowered Lp(a) by 34.1% (P≤0.001) and 39.6% in the complete and subset cohort, respectively. The decreases in Lp(a) levels were because of a 41% reduction in the apo(a) production rate, with no effects on apo(a) fractional catabolic rate. CONCLUSIONS: Anacetrapib reduces Lp(a) levels by decreasing its production. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00990808.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Hipercolesterolemia/tratamiento farmacológico , Lipoproteína(a)/sangre , Oxazolidinonas/uso terapéutico , Adulto , Anciano , Anticolesterolemiantes/efectos adversos , Biomarcadores/sangre , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Cromatografía Liquida , Método Doble Ciego , Regulación hacia Abajo , Femenino , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/diagnóstico , Masculino , Persona de Mediana Edad , Ciudad de Nueva York , Oxazolidinonas/efectos adversos , Pennsylvania , Índice de Severidad de la Enfermedad , Espectrometría de Masas en Tándem , Factores de Tiempo , Resultado del TratamientoRESUMEN
This phase 3, multiregional, randomized, double-blind, placebo-controlled study assessed the efficacy/safety profile of anacetrapib added to ongoing therapy with statin ± other lipid-modifying therapies in patients with hypercholesterolemia who were not at their low-density lipoprotein (LDL-C) goal (as per the National Cholesterol Education Program Adult Treatment Panel III guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of statin ± other lipid-modifying therapies and with LDL-C ≥70 to <115, ≥100 to <145, ≥130, or ≥160 mg/dl for very high, high, moderate, or low CHD risk or at LDL-C goal (per CHD risk category) with HDL-C ≤40 mg/dl were randomized in a ratio of 1:1 to anacetrapib 100 mg (n = 290) or placebo (n = 293) for 24 weeks, followed by a 12-week off-drug phase. The co-primary end points were % change from baseline in LDL-C and HDL-C and the safety profile of anacetrapib. Treatment with anacetrapib reduced LDL-C (BQ) by 37% (95% confidence interval -42.5, -31.0) and increased HDL-C by 118% (95% confidence interval 110.6, 125.7) relative to placebo (p <0.001 for both). Anacetrapib also reduced non-HDL-C, apolipoprotein B, and lipoprotein a and increased apolipoprotein AI versus placebo (p <0.001 for all). There were no clinically meaningful differences between the anacetrapib and placebo groups in the % patients who discontinued drug due to an adverse event or in abnormalities in liver enzymes, creatine kinase, blood pressure, electrolytes, or adjudicated cardiovascular events. Treatment with anacetrapib substantially reduced LDL-C and also increased HDL-C and was well tolerated over 24 weeks in statin-treated patients with hypercholesterolemia or low HDL-C.
Asunto(s)
HDL-Colesterol/sangre , Tolerancia a Medicamentos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Hipercolesterolemia/tratamiento farmacológico , Oxazolidinonas/administración & dosificación , Anciano , Anticolesterolemiantes/administración & dosificación , HDL-Colesterol/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Hipercolesterolemia/sangre , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: We aimed to assess the effects of cholesteryl ester transfer protein inhibitor anacetrapib added to statin ± other lipid-modifying therapies (LMT) in Japanese patients with dyslipidemia who were not at their LDL-C goal. METHODS: Patients on a stable dose of statin ± other LMT with LDL-C ≥100 mg/dL to <145 mg/dL, ≥120 mg/dL to <165 mg/dL, ≥140 mg/dL or ≥160 mg/dL for patients with a history of coronary heart disease (CHD), high-, moderate- and low-risk patients respectively, were randomized 2:1, stratified by background therapy, to double-blind anacetrapib 100 mg (n = 204) or placebo (n = 103) for 24 weeks, followed by a 28-week open-label extension phase (anacetrapib 100 mg) and a 12-week off-drug safety follow-up phase. The primary endpoint was percent change from baseline in LDL-C (beta-quantification method), as well as the safety profile of anacetrapib at Week 24; HDL-C was a key secondary endpoint. RESULTS: Anacetrapib 100 mg further reduced LDL-C (38.0%), non-HDL-C (35.1%), ApoB (28.7%), and Lp(a) (48.3%) and increased HDL-C (148.9%) and ApoAI (50.7%) versus placebo (p < 0.001 for all). There were no meaningful differences between the groups in the proportion of patients with liver enzymes elevations (2.0% vs. 0%), creatine kinase elevations overall (0.5% vs. 0%) or with muscle symptoms (0.5% vs. 0%), blood pressure, electrolytes or adjudicated cardiovascular events (0.5% vs. 0%). In the open-label period, sustained effects on lipid parameters were observed with anacetrapib and the treatment was generally well tolerated. CONCLUSIONS: Long-term treatment with anacetrapib 100 mg substantially reduced LDL-C, increased HDL-C and was well tolerated in Japanese patients with dyslipidemia (ClinicalTrials.gov number NCT01760460).
Asunto(s)
Anticolesterolemiantes/uso terapéutico , LDL-Colesterol/sangre , Hipercolesterolemia/tratamiento farmacológico , Oxazolidinonas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticolesterolemiantes/efectos adversos , Apolipoproteína A-I/sangre , Apolipoproteína B-100/sangre , Biomarcadores/sangre , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Método Doble Ciego , Femenino , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/diagnóstico , Japón , Lipoproteína(a)/sangre , Masculino , Persona de Mediana Edad , Oxazolidinonas/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Purpose To evaluate MK-8242 in patients with wild-type TP53 advanced solid tumors. Patients and Methods MK-8242 was administered orally twice a day on days 1 to 7 in 21-day cycles. The recommended phase II dose (RP2D) was determined on the basis of safety, tolerability, pharmacokinetics (PK), and by mRNA expression of the p53 target gene pleckstrin homology-like domain, family A, member 3 ( PHLDA3). Other objectives were to characterize the PK/pharmacodynamic (PD) relationship, correlate biomarkers with response, and assess tumor response. Results Forty-seven patients received MK-8242 across eight doses that ranged from 60 to 500 mg. Initially, six patients developed dose-limiting toxicities (DLTs): grade (G) 2 nausea at 120 mg; G3 fatigue at 250 mg; G2 nausea and G4 thrombocytopenia at 350 mg; and G3 vomiting and G3 diarrhea at 500 mg. DLT criteria were revised to permit management of GI toxicities. Dosing was resumed at 400 mg, and four additional DLTs were observed: G4 neutropenia and G4 thrombocytopenia at 400 mg and G4 thrombocytopenia (two patients) at 500 mg. Other drug-related G3 and G4 events included anemia, leukopenia, pancytopenia, nausea, hyperbilirubinemia, hypophosphatemia, and anorexia. On the basis of safety, tolerability, PK, and PD, the RP2D was established at 400 mg (15 evaluable patients experienced two DLTs). PK for 400 mg (day 7) showed Cmax 3.07 µM, Tmax 3.0 hours, t1/2 (half-life) 6.6 hours, CL/F (apparent clearance) 28.9 L/h, and Vd/F (apparent volume) 274 L. Blood PHLDA3 mRNA expression correlated with drug exposure ( R2 = 0.68; P < .001). In 41 patients with postbaseline scans, three patients with liposarcoma achieved a partial response (at 250, 400, and 500 mg), 31 showed stable disease, and eight had progressive disease. In total, 27 patients with liposarcoma had a median progression-free survival of 237 days. Conclusion At the RP2D of 400 mg twice a day, MK-8242 activated the p53 pathway with an acceptable safety and tolerability profile. The observed clinical activity (partial response and prolonged progression-free survival) provides an impetus for further study of HDM2 inhibitors in liposarcoma.
Asunto(s)
Citarabina/administración & dosificación , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Citarabina/efectos adversos , Citarabina/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/genética , Neoplasias/metabolismo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
To assess the effects of anacetrapib added to statin ± other lipid-modifying therapies in patients with hypercholesterolemia and not at their low-density lipoprotein cholesterol (LDL-C) goal (as per National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III] guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of moderate/high-intensity statin ± other lipid-modifying therapies with LDL-C ≥70, ≥100, ≥130, or ≥160 mg/dl for very high, high, moderate, and low coronary heart disease risk, respectively, or at LDL-C goal with HDL-C ≤40 mg/dl, were randomized 1:1:1, stratified by background therapy use, to anacetrapib 100 mg (n = 153), anacetrapib 25 mg (n = 152), or placebo (n = 154) for 24 weeks, followed by a 12-week off-drug reversal phase. The primary end points were percent change from baseline in LDL-C (beta-quantification method) and HDL-C, as well as the safety profile of anacetrapib. Both doses of anacetrapib reduced LDL-C, non-HDL-C, apolipoprotein (Apo) B, and lipoprotein a and increased HDL-C and Apo AI versus placebo (p <0.001 for all). There were no meaningful differences between the anacetrapib 25 mg, 100 mg, and placebo groups in the proportions of discontinuations due to drug-related adverse events (0.7%, 1.3% vs 1.3%) or in abnormalities in liver enzymes (0%, 0% vs 0.7%), creatine kinase elevations overall (0%, 0.7% vs 0%) or with muscle symptoms (none seen), blood pressure, electrolytes, or adjudicated cardiovascular events (0.7%, 0.7% vs 1.3%). In conclusion, treatment with anacetrapib resulted in substantial reductions in LDL-C and increases in HDL-C and was generally well tolerated.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Oxazolidinonas/uso terapéutico , Anciano , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Método Doble Ciego , Quimioterapia Combinada , Dislipidemias/sangre , Dislipidemias/tratamiento farmacológico , Ezetimiba/uso terapéutico , Femenino , Ácidos Fíbricos/uso terapéutico , Humanos , Hipercolesterolemia/sangre , Masculino , Persona de Mediana Edad , Niacina/uso terapéutico , Resultado del TratamientoRESUMEN
Omarigliptin is a dipeptidyl peptidase-4 inhibitor being developed as a once-weekly treatment for type 2 diabetes. This double-blind, double-dummy, randomized, 3-period balanced crossover study definitively evaluated the effects of a supratherapeutic omarigliptin dose on QTc interval. Population-specific correction of QT interval (QTcP) was used for the primary analysis. Healthy subjects (n = 60) were enrolled and received treatments separated by a ≥4-week washout: (1) single-dose 25 mg omarigliptin (day 1), single-dose 175 mg omarigliptin (day 2); (2) placebo (day 1) followed by single-dose 400 mg moxifloxacin (day 2); (3) placebo (days 1 and 2). Day 2 QTcP intervals were analyzed. The primary hypothesis was supported if the 90%CIs for the least-squares mean differences between omarigliptin 175 mg and placebo in QTcP interval change from baseline were all < 10 milliseconds at every postdose point on day 2. The upper bounds of the 90%CIs for the differences (omarigliptin-placebo) in QTcP change from baseline for omarigliptin 175 mg were < 10 milliseconds at all postdose times on day 2. In conclusion, a supratherapeutic dose of omarigliptin does not prolong the QTcP interval to a clinically meaningful degree relative to placebo, confirming the results of the earlier concentration-QTc analysis.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Fluoroquinolonas/administración & dosificación , Compuestos Heterocíclicos con 2 Anillos/administración & dosificación , Hipoglucemiantes/administración & dosificación , Piranos/administración & dosificación , Adolescente , Adulto , Estudios Cruzados , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Electrocardiografía , Femenino , Fluoroquinolonas/efectos adversos , Compuestos Heterocíclicos con 2 Anillos/efectos adversos , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacocinética , Síndrome de QT Prolongado/inducido químicamente , Masculino , Persona de Mediana Edad , Modelos Biológicos , Moxifloxacino , Piranos/efectos adversos , Piranos/farmacocinética , Adulto JovenRESUMEN
OBJECTIVE: Evaluate safety/tolerability/efficacy of MK-8242 in subjects with refractory/recurrent AML. METHODS: MK-8242 was dosed p.o. QD (30-250mg) or BID (120-250mg) for 7on/7off in 28-day cycle. Dosing was modified to 7on/14off, in 21-day cycle (210 or 300mg BID). RESULTS: 26 subjects enrolled (24 evaluable for response); 5/26 discontinued due to AEs. There were 7 deaths; 1 (fungal pneumonia due to marrow aplasia) possibly drug-related. With the 7on/7off regimen, 2 subjects had DLTs in the 250mg BID group (both bone marrow failure and prolonged cytopenia). With the 7on/14off, no DLTs were observed in 210mg BID or 300mg BID (doses>300mg not tested). Best responses were: 1/24 PR (11 weeks;120mg QD, 7on/7off); 1/24 CRi (2 weeks;210mg BID, 7on/14off); 1/24 morphologic leukemia-free state (4 weeks; 250mg BID, 7on/7off). PK on Day7 at 210mg BID revealed AUC0-12h 8.7µM·h,Cmax 1.5µM (n=5,Tmax, 2-6h),T1/2 7.9h, CLss/F 28.8L/h, and Vss/F 317L. CONCLUSIONS: The 7on/14off regimen showed a more favorable safety profile; no MTD was established. Efficacy was seen using both regimens providing impetus for further study of HDM2 inhibitors in subjects with AML.
Asunto(s)
Citarabina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Citarabina/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Terapia Recuperativa , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: LDL-C, non-HDL-C and ApoB levels are inter-correlated and all predict risk of atherosclerotic cardiovascular disease (ASCVD) in patients with type 2 diabetes mellitus (T2DM) and/or high TG. These levels are lowered by extended-release niacin (ERN), and changes in the ratios of these levels may affect ASCVD risk. This analysis examined the effects of extended-release niacin/laropiprant (ERN/LRPT) on the relationships between apoB:LDL-C and apoB:non-HDL-C in patients with T2DM. METHODS: T2DM patients (n = 796) had LDL-C ≥1.55 and <2.97 mmol/L and TG <5.65 mmol/L following a 4-week, lipid-modifying run-in (~78 % taking statins). ApoB:LDL-C and apoB:non-HDL-C correlations were assessed after randomized (4:3), double-blind ERN/LRPT or placebo for 12 weeks. Pearson correlation coefficients between apoB:LDL-C and apoB:non-HDL-C were computed and simple linear regression models were fitted for apoB:LDL-C and apoB:non-HDL-C at baseline and Week 12, and the correlations between measured apoB and measured vs predicted values of LDL-C and non-HDL-C were studied. RESULTS: LDL-C and especially non-HDL-C were well correlated with apoB at baseline, and treatment with ERN/LRPT increased these correlations, especially between LDL-C and apoB. Despite the tighter correlations, many patients who achieved non-HDL-C goal, and especially LDL-C goal, remained above apoB goal. There was a trend towards greater increases in these correlations in the higher TG subgroup, non-significant possibly due to the small number of subjects. CONCLUSIONS: ERN/LRPT treatment increased association of apoB with LDL-C and non-HDL-C in patients with T2DM. Lowering LDL-C, non-HDL-C and apoB with niacin has the potential to reduce coronary risk in patients with T2DM.
Asunto(s)
Apolipoproteína B-100/sangre , LDL-Colesterol/sangre , Preparaciones de Acción Retardada/uso terapéutico , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Indoles/uso terapéutico , Niacina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Glucemia/metabolismo , HDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Método Doble Ciego , Ayuno , Femenino , Humanos , Hiperlipidemias/sangre , Hiperlipidemias/fisiopatología , Hipoglucemiantes/uso terapéutico , Insulina/sangre , Masculino , Persona de Mediana Edad , Triglicéridos/sangreRESUMEN
BACKGROUND AND AIMS: This multicenter, randomized, double-blind, placebo-controlled study assessed the lipid-modifying efficacy/safety profile of anacetrapib 100 mg added to ongoing statin ± other lipid-modifying therapies (LMT) in Japanese patients with heterozygous familial hypercholesterolemia (HeFH). METHODS: Patients 18-80 years with a genotype-confirmed/clinical diagnosis of HeFH who were on a stable dose of statin ± other LMT for ≥6 weeks and with an LDL-C concentration ≥100 mg/dL were randomized to anacetrapib 100 mg (n = 34) or placebo (n = 34) for 12 weeks, followed by a 12-week off-drug reversal phase. The primary endpoints were percent change from baseline in LDL-C (beta-quantification method [BQ]) and safety/tolerability. RESULTS: At Week 12, treatment with anacetrapib reduced LDL-C (BQ) compared to placebo and resulting in a between-group difference of 29.8% (95% CI: -38.6 to -21.0; p < 0.001) favoring anacetrapib. Anacetrapib also reduced non-HDL-C (23. 6%; p < 0.001), ApoB (14.1%; p < 0.001) and Lp(a) (48.7%; p < 0.001), and increased HDL-C (110.0%; p < 0.001) and ApoA1 (48.2%; p < 0.001) versus placebo. Anacetrapib 100 mg added to ongoing therapy with statin ± other LMT for 12 weeks was generally well-tolerated. There were no differences between the groups in the proportion of patients who discontinued drug due to an adverse event or abnormalities in liver enzymes, creatinine kinase, blood pressure, electrolytes or adjudicated cardiovascular events. CONCLUSIONS: In Japanese patients with HeFH, treatment with anacetrapib 100 mg for 12 weeks resulted in substantial reductions in LDL-C and increases in HDL-C and was well tolerated. (ClinicalTrials.govNCT01824238).
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Oxazolidinonas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Método Doble Ciego , Femenino , Homocigoto , Humanos , Japón , Masculino , Persona de Mediana Edad , Seguridad del Paciente , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
The pharmacokinetics (PK) and pharmacodynamics (PD) of omarigliptin, a novel once-weekly DPP-4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid, and food did not influence single-dose PK. Accumulation was minimal, and steady state was reached after 2 to 3 weeks. Weekly (area under the curve) AUC and Cmax displayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was â¼2 L/h. DPP-4 inhibition ranged from â¼77% to 89% at 168 hours following the last of 3 once-weekly doses over the dose range studied. Omarigliptin resulted in â¼2-fold increases in weighted average postprandial active GLP-1. Omarigliptin acts by stabilizing active GLP-1, which is consistent with its mechanism of action as a DPP-4 inhibitor. Administration of omarigliptin was generally well tolerated in healthy subjects, and both the PK and PD profiles support once-weekly dosing. A model-based assessment of QTc interval risk from the single ascending dose study predicted a low risk of QTc prolongation within the likely clinical dose range, a finding later confirmed in a thorough QT trial.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Compuestos Heterocíclicos con 2 Anillos/administración & dosificación , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Piranos/administración & dosificación , Piranos/farmacocinética , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: Anacetrapib (ANA), an inhibitor of cholesteryl ester transfer protein (CETP) activity, increases plasma concentrations of high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I (apoA)-I, apoA-II, and CETP. The mechanisms responsible for these treatment-related increases in apolipoproteins and plasma CETP are unknown. We performed a randomized, placebo (PBO)-controlled, double-blind, fixed-sequence study to examine the effects of ANA on the metabolism of HDL apoA-I and apoA-II and plasma CETP. APPROACH AND RESULTS: Twenty-nine participants received atorvastatin (ATV) 20 mg/d plus PBO for 4 weeks, followed by ATV plus ANA 100 mg/d for 8 weeks (ATV-ANA). Ten participants received double PBO for 4 weeks followed by PBO plus ANA for 8 weeks (PBO-ANA). At the end of each treatment, we examined the kinetics of HDL apoA-I, HDL apoA-II, and plasma CETP after D3-leucine administration as well as 2D gel analysis of HDL subspecies. In the combined ATV-ANA and PBO-ANA groups, ANA treatment increased plasma HDL-C (63.0%; P<0.001) and apoA-I levels (29.5%; P<0.001). These increases were associated with reductions in HDL apoA-I fractional clearance rate (18.2%; P=0.002) without changes in production rate. Although the apoA-II levels increased by 12.6% (P<0.001), we could not discern significant changes in either apoA-II fractional clearance rate or production rate. CETP levels increased 102% (P<0.001) on ANA because of a significant reduction in the fractional clearance rate of CETP (57.6%, P<0.001) with no change in CETP production rate. CONCLUSIONS: ANA treatment increases HDL apoA-I and CETP levels by decreasing the fractional clearance rate of each protein.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Apolipoproteína A-I/sangre , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Dislipidemias/tratamiento farmacológico , Lipoproteínas HDL/sangre , Oxazolidinonas/uso terapéutico , Adulto , Anciano , Anticolesterolemiantes/efectos adversos , Apolipoproteína A-II/sangre , Biomarcadores/sangre , Proteínas de Transferencia de Ésteres de Colesterol/sangre , Método Doble Ciego , Dislipidemias/sangre , Dislipidemias/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxazolidinonas/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: Omarigliptin (MK-3102) is a potent, oral, long-acting dipeptidyl peptidase (DPP)-4 inhibitor approved in Japan and in global development as a once-weekly treatment for type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of omarigliptin in obese participants with and without T2DM. METHODS: This was a Phase I, randomized, double-blind, placebo-controlled, multiple-dose study of 50-mg omarigliptin administered once weekly for 4 weeks. Participants included 24 obese but otherwise healthy subjects (panel A; omarigliptin, n = 18; placebo, n = 6) and 8 obese patients with T2DM (treatment naive, hemoglobin A1c ≥ 6.5% and ≤ 10.0% [panel B]; omarigliptin, n = 6; placebo, n = 2). Participants were 45 to 65 years of age with a body mass index of ≥ 30 and ≤ 40 kg/m(2). Blood sampling occurred at select time points, depending on the study panel, to evaluate the PK properties of omarigliptin, DPP-4 activity, active glucagon-like peptide 1 levels, and plasma glucose concentrations. Body weight was an exploratory end point. Due to sparse sampling in panel A, a thorough PK analysis was performed in obese patients with T2DM (panel B) only. PD analyses were performed in the overall study population (pooled panels A and B). FINDINGS: PK profiles in obese participants with and without T2DM were similar to those observed in nonobese reference subjects (historical data). Steady state was achieved after 1 or 2 weekly doses in obese participants with and without T2DM. In obese patients with T2DM, omarigliptin was rapidly absorbed, with a median Tmax of 1 to 2.5 hours (days 1 and 22). Compared with those in reference subjects, the geometric mean ratios (95% CI) (Obese T2DM/reference) for steady-state plasma AUC0-168h, Cmax, and C168h were 0.80 (0.65-0.98), 0.86 (0.53-1.41), and 1.08 (0.88-1.33), respectively. Trough DPP-4 activity was inhibited by ~90%; postprandial (PP) 4-hour weighted mean active GLP-1 concentrations were increased ~2-fold; and PP glucose was significantly reduced with omarigliptin versus placebo in the pooled population. Omarigliptin was generally well-tolerated in the pooled population, and there were no hypoglycemic events. Consistent with other DPP-4 inhibitors, omarigliptin had no effect on body weight in this short-duration study. IMPLICATIONS: The administration of omarigliptin was generally well-tolerated in obese participants with and without T2DM, and the favorable PK and PD profiles support once-weekly dosing. Omarigliptin may provide an important once-weekly treatment option for patients with T2DM. ClinicalTrials.gov identifier: NCT01088711.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Compuestos Heterocíclicos con 2 Anillos/farmacología , Hipoglucemiantes/farmacología , Obesidad/sangre , Piranos/farmacología , Administración Oral , Anciano , Área Bajo la Curva , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Péptido 1 Similar al Glucagón/sangre , Péptido 1 Similar al Glucagón/efectos de los fármacos , Hemoglobina Glucada/efectos de los fármacos , Hemoglobina Glucada/metabolismo , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Compuestos Heterocíclicos con 2 Anillos/uso terapéutico , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Piranos/farmacocinética , Piranos/uso terapéuticoRESUMEN
Exposure-response analyses of sugammadex on activated partial thromboplastin time (APTT) and prothrombin time international normalized ratio (PT(INR)) were performed using data from two clinical trials in which subjects were co-treated with anti-coagulants, providing a framework to predict these responses in surgical patients on thromboprophylactic doses of low molecular weight or unfractionated heparin. Sugammadex-mediated increases in APTT and PT(INR) were described with a direct effect model, and this relationship was similar in the presence or absence of anti-coagulant therapy in either healthy volunteers or surgical patients. In surgical patients on thromboprophylactic therapy, model-based predictions showed 13.1% and 22.3% increases in respectively APTT and PT(INR) within 30min after administration of 16mg/kg sugammadex. These increases remain below thresholds seen following treatment with standard anti-coagulant therapy and were predicted to be short-lived paralleling the rapid decline in sugammadex plasma concentrations.
Asunto(s)
Anticoagulantes/farmacología , Coagulación Sanguínea/efectos de los fármacos , Heparina/farmacología , Modelos Biológicos , gamma-Ciclodextrinas/farmacología , gamma-Ciclodextrinas/farmacocinética , Adolescente , Adulto , Anciano , Anticoagulantes/uso terapéutico , Estudios Cruzados , Método Doble Ciego , Interacciones Farmacológicas , Femenino , Heparina/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Tiempo de Tromboplastina Parcial , Tiempo de Protrombina , Sugammadex , Trombosis/prevención & control , Adulto Joven , gamma-Ciclodextrinas/sangreRESUMEN
BACKGROUND: There has been a longstanding question as to whether testosterone therapy could precipitate or worsen urinary symptoms in aging men. We investigated the effects of 1-year oral testosterone undecanoate (TU) therapy on urinary symptoms in aging, hypogonadal men. METHODS: A total of 322 men ≥50 years with symptomatic testosterone deficiency participated in a 1-year, randomized, multicenter, double-blind trial. Patients received placebo or oral TU 80 mg/day, 160 mg/day, or 240 mg/day. RESULTS AND LIMITATIONS: Compared with placebo, treatment with oral TU at doses of 80 mg/day and 160 mg/day resulted in no significant change in IPSS urinary symptoms or quality of life (QoL) scores. Treatment with oral TU 240 mg/day led to a statistically significant, but clinically insignificant, improvement in IPSS total score and a significant improvement in IPSS QoL score. None of the TU doses tested had a significant effect on PSA or PV. CONCLUSIONS: Long-term oral TU therapy had no deleterious effects on IPSS total score and did not change PV and PSA in aging, hypogonadal men. Oral TU therapy at a dose of 240 mg/day may even improve IPSS QoL score.
Asunto(s)
Andrógenos/administración & dosificación , Hipogonadismo/tratamiento farmacológico , Síntomas del Sistema Urinario Inferior/tratamiento farmacológico , Testosterona/análogos & derivados , Administración Oral , Anciano , Envejecimiento , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Hipogonadismo/fisiopatología , Síntomas del Sistema Urinario Inferior/etiología , Masculino , Persona de Mediana Edad , Hiperplasia Prostática/complicaciones , Testosterona/administración & dosificación , Testosterona/sangreRESUMEN
BACKGROUND: Individuals treated with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibit a reduction in both LDL cholesterol and apolipoprotein B (ApoB) in response to monotherapy or combination therapy with a statin. It is not clear how anacetrapib exerts these effects; therefore, the goal of this study was to determine the kinetic mechanism responsible for the reduction in LDL and ApoB in response to anacetrapib. METHODS: We performed a trial of the effects of anacetrapib on ApoB kinetics. Mildly hypercholesterolemic subjects were randomized to background treatment of either placebo (n = 10) or 20 mg atorvastatin (ATV) (n = 29) for 4 weeks. All subjects then added 100 mg anacetrapib to background treatment for 8 weeks. Following each study period, subjects underwent a metabolic study to determine the LDL-ApoB-100 and proprotein convertase subtilisin/kexin type 9 (PCSK9) production rate (PR) and fractional catabolic rate (FCR). RESULTS: Anacetrapib markedly reduced the LDL-ApoB-100 pool size (PS) in both the placebo and ATV groups. These changes in PS resulted from substantial increases in LDL-ApoB-100 FCRs in both groups. Anacetrapib had no effect on LDL-ApoB-100 PRs in either treatment group. Moreover, there were no changes in the PCSK9 PS, FCR, or PR in either group. Anacetrapib treatment was associated with considerable increases in the LDL triglyceride/cholesterol ratio and LDL size by NMR. CONCLUSION: These data indicate that anacetrapib, given alone or in combination with a statin, reduces LDL-ApoB-100 levels by increasing the rate of ApoB-100 fractional clearance. TRIAL REGISTRATION: ClinicalTrials.gov NCT00990808. FUNDING: Merck & Co. Inc., Kenilworth, New Jersey, USA. Additional support for instrumentation was obtained from the National Center for Advancing Translational Sciences (UL1TR000003 and UL1TR000040).
Asunto(s)
Anticolesterolemiantes/administración & dosificación , Apolipoproteína B-100/sangre , LDL-Colesterol/sangre , Hipercolesterolemia , Lipoproteínas LDL/sangre , Oxazolidinonas/administración & dosificación , Triglicéridos/sangre , Adulto , Anciano , Atorvastatina , Método Doble Ciego , Femenino , Ácidos Heptanoicos/administración & dosificación , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pirroles/administración & dosificación , Factores de TiempoRESUMEN
BACKGROUND: Present guidelines emphasise the importance of low concentrations of LDL cholesterol (LDL-C) in patients with familial hypercholesterolaemia. In most patients with the disease, however, these concentrations are not achieved with present treatments, so additional treatment is therefore warranted. Inhibition of cholesteryl ester transfer protein has been shown to reduce LDL-C concentrations in addition to regular statin treatment in patients with hypercholesterolaemia or at high risk of cardiovascular disease. We aimed to investigate the safety and efficacy of anacetrapib, a cholesteryl ester transfer protein inhibitor, in patients with heterozygous familial hypercholesterolaemia. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 3 study, patients aged 18-80 years with a genotype-confirmed or clinical diagnosis of heterozygous familial hypercholesterolaemia, on optimum lipid-lowering treatment for at least 6 weeks, and with an LDL-C concentration of 2·59 mmol/L or higher without cardiovascular disease or 1·81 mmol/L or higher with cardiovascular disease from 26 lipid clinics across nine countries were eligible. We randomly allocated participants with a computer-generated allocation schedule (2:1; block size of six; no stratification) to oral anacetrapib 100 mg or placebo for 52 weeks, with a 12 week post-treatment follow-up afterwards. We masked patients, care providers, and those assessing outcomes to treatment groups throughout the study. The primary outcome was percentage change from baseline in LDL-C concentration. We did analysis using a constrained longitudinal repeated measures model. This trial is registered with ClinicalTrials.gov, number NCT01524289. FINDINGS: Between Feb 10, 2012, and Feb 12, 2014, we randomly allocated 204 patients to anacetrapib and 102 to placebo. One patient in the anacetrapib group did not receive the drug. At week 52, anacetrapib reduced mean LDL-C concentration from 3·3 mmol/L (SD 0·8) to 2·1 mmol/L (0·8; percentage change 36·0% [95% CI -39·5 to -32·5] compared with an increase with placebo from 3·4 mmol/L (1·2) to 3·5 mmol/L (1·6; percentage change 3·7% [-1·2 to 8·6], with a difference in percentage change between anacetrapib and placebo of -39·7% (95% CI -45·7 to -33·7; p<0·0001). The number of cardiovascular events was increased in patients given anacetrapib compared with those given placebo (4 [2%] of 203 vs none [0%] of 102; p=0·1544), but the proportion with adverse events leading to discontinuation was similar (12 [6%] of 203 vs five [5%] of 102). INTERPRETATION: In patients with heterozygous familial hypercholesterolaemia, treatment with anacetrapib for 1 year was well tolerated and resulted in substantial reductions in LDL-C concentration. Whether this change leads to a reduction of cardiovascular events will be answered in an outcome study. FUNDING: Merck & Co, Inc.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Oxazolidinonas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticolesterolemiantes/farmacología , Enfermedades Cardiovasculares/complicaciones , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , LDL-Colesterol/sangre , LDL-Colesterol/efectos de los fármacos , Método Doble Ciego , Femenino , Humanos , Hiperlipoproteinemia Tipo II/complicaciones , Hipolipemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Oxazolidinonas/farmacología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The degree of glycemic control in patients with type 2 diabetes mellitus (T2DM) may alter lipid levels and may alter the efficacy of lipid-modifying agents. OBJECTIVE: Evaluate the lipid-modifying efficacy of extended-release niacin/laropiprant (ERN/LRPT) in subgroups of patients with T2DM with better or poorer glycemic control. METHODS: Post hoc analysis of clinical trial data from patients with T2DM who were randomized 4:3 to double-blind ERN/LRPT or placebo (n=796), examining the lipid-modifying effects of ERN/LRPT in patients with glycosylated hemoglobin or fasting plasma glucose levels above and below median baseline levels. RESULTS: At Week 12 of treatment, ERN/LRPT significantly improved low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol, triglycerides, and lipoprotein (a), compared with placebo, with equal efficacy in patients above or below median baseline glycemic control. Compared with placebo, over 36 weeks of treatment more patients treated with ERN/LRPT had worsening of their diabetes and required intensification of antihyperglycemic medication, irrespective of baseline glycemic control. Incidences of other adverse experiences were generally low in all treatment groups. CONCLUSION: The lipid-modifying effects of ERN/LRPT are independent of the degree of baseline glycemic control in patients with T2DM (NCT00485758).
Asunto(s)
Biomarcadores/sangre , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dislipidemias/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Hipolipemiantes/uso terapéutico , Indoles/uso terapéutico , Lípidos/sangre , Niacina/uso terapéutico , Anciano , Glucemia/metabolismo , Preparaciones de Acción Retardada , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Método Doble Ciego , Combinación de Medicamentos , Interacciones Farmacológicas , Dislipidemias/sangre , Dislipidemias/diagnóstico , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/efectos adversos , Hipolipemiantes/efectos adversos , Indoles/efectos adversos , Masculino , Persona de Mediana Edad , Niacina/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVES: Our aim was to assess the effects of the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib and atorvastatin, both as monotherapy and in combination, on particle concentrations of low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), and intermediate-density lipoproteins in dyslipidemic patients. BACKGROUND: Although increases in high-density lipoproteins with CETP inhibition are well-documented, effects on atherogenic lipoprotein particle subclasses in dyslipidemic patients have not been extensively characterized. METHODS: Ion mobility was performed on stored plasma samples collected from patients before and after treatment with anacetrapib alone (150 and 300 mg/d) or in combination with atorvastatin (20 mg/d) in a previously conducted 8-week phase IIb study. RESULTS: Anacetrapib produced significant placebo-adjusted reductions of total LDL particles and all subfractions except for increases in very small LDL 4a and 4b. Atorvastatin reduced all LDL subfractions except LDL 4b. Results were generally additive for anacetrapib + atorvastatin. For patients treated with anacetrapib, the placebo-adjusted reduction in LDL 3a was attenuated and there was an increase in LDL 3b and 4a for those with low vs high triglyceride (TG) levels. For the atorvastatin alone vs placebo treatment comparison, there were small reductions in LDL 3a, 3b, and 4a for those with low vs high TG levels. CONCLUSIONS: Anacetrapib and atorvastatin produced similar reductions from baseline in total LDL particles, but did not have comparable effects on all LDL particle subfractions, and neither drug reduced the smallest LDL 4b particles. The clinical significance of these changes and the differential effects on very small LDL 4a in patients with higher vs lower TG remain to be determined (clinicaltrials.gov, NCT00325455).