RESUMEN
Exposure-response analysis of QT interval in clinical studies has been proposed as a thorough QT study alternative. Many exposure-response model structures have been proposed for cardiovascular (CV) safety markers, but few studies have compared models across multiple drugs. To recommend preferred drug-effect exposure-response models on vital signs and electrocardiogram (ECG) intervals, an individual-level model-based meta-analysis (39 studies and 1,291 subjects) compared 90 model structures. Models were selected to describe the data and cross-validate studies on the same drug. The most commonly selected baseline model was an unstructured model (estimation of a value at each study nominal time) for all measures but blood pressure. The unstructured model estimated a better cross-validated drug-effect when considering all markers. A linear model was the most commonly selected to characterize drug-effect on all markers. We propose these models as a starting point assisting with CV safety exposure-response assessment in nondedicated small studies with healthy subjects.
Asunto(s)
Enfermedades Cardiovasculares/inducido químicamente , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Modelos Teóricos , Biomarcadores/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Ensayos Clínicos como Asunto/métodos , Electrocardiografía , Humanos , Modelos Lineales , Síndrome de QT Prolongado/inducido químicamenteRESUMEN
AIM: To assess the efficacy and safety of a range of doses of a systemic, partial, glucokinase activator, PF-04937319, as add-on therapy to metformin, in patients with type 2 diabetes mellitus (T2DM). METHODS: Patients were randomized to once-daily PF-04937319 doses of 10, 50, 100 mg, or matching placebo (Study B1621002); or PF-04937319 doses of 3, 20, 50, 100 mg, or matching placebo (Study B1621007). Titrated glimepiride (Study B1621002) or sitagliptin (Study B1621007) were included in a double-dummy manner. The primary measure was change from baseline in glycated haemoglobin (HbA1c) at week 12. Key secondary measures included other glycaemic variables and safety and tolerability. RESULTS: In the 639 patients randomized, the minimally efficacious PF-04937319 dose was identified as 50 mg once daily. At the highest PF-04937319 dose tested (100 mg), on average, a clinically significant reduction in HbA1c [-4.94 or -5.11 mmol/mol (-0.45 or -0.47%), placebo-adjusted], which was similar to that achieved with sitagliptin [-4.69 mmol/mol (-0.43%)] but lower than that achieved with titrated glimepiride [-9.07 mmol/mol (-0.83%)], was observed. At this dose, the effect on fasting plasma glucose was not consistent between the two studies (Study B1621002 vs Study B1621007: placebo-adjusted mean change of -0.83 vs +0.50 mmol/l). PF-04937319 was well tolerated at doses up to 100 mg. Hypoglycaemia was reported in 2.5% of patients (on placebo), 5.1% of patients (on PF-04937319 100 mg), 1.8% of patients (on sitagliptin) and 34.4% of patients (on titrated glimepiride). CONCLUSIONS: In patients on metformin monotherapy, the addition of a 100-mg dose of PF-04937319 improved glycaemic control and was well tolerated.
Asunto(s)
Benzofuranos/administración & dosificación , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Metformina/administración & dosificación , Pirimidinas/administración & dosificación , Anciano , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada/métodos , Ayuno/sangre , Femenino , Glucoquinasa , Hemoglobina Glucada/efectos de los fármacos , Humanos , Hipoglucemia/inducido químicamente , Masculino , Persona de Mediana Edad , Fosfato de Sitagliptina/administración & dosificación , Compuestos de Sulfonilurea/administración & dosificaciónRESUMEN
1. Ten compounds from the Merck Research Laboratories pipeline were selected to evaluate the utility of using intrinsic clearance derived from recombinantly expressed cytochromes P450 (CYP) and physiologically based pharmacokinetic modelling to predict Phase I pharmacokinetics using simCYP. The compounds selected were anticipated to be eliminated predominantly by P450 metabolism. 2. There was a reasonable agreement between the predicted and actual clinical exposure with 80% of the predicted exposures being within three-fold of the observed values. Furthermore, prediction of C(t) (plasma concentration at a specified time point) and T(max) were acceptable with greater than or equal to 70% of the predicted data being within three-fold of the observed values. However, prediction of C(max) was unreliable and may have been due to error in predicting the time-dependent change in volume of distribution and/or error in estimating absorption rate. 3. Although it is acknowledged that research is needed to improve predictive performance, the data presented are supportive of using recombinant P450 intrinsic clearance and physiologically based pharmacokinetic modelling to predict Phase I pharmacokinetics for compounds eliminated by P450 metabolism.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Preparaciones Farmacéuticas/sangre , Administración Oral , Células CACO-2 , Cromatografía Liquida , Simulación por Computador , Método Doble Ciego , Evaluación Preclínica de Medicamentos , Humanos , Tasa de Depuración Metabólica , Modelos Biológicos , Proteínas Recombinantes/metabolismo , Espectrometría de Masas en TándemRESUMEN
Visualization of flowing neutrophils colliding with adherent 1-mum-diameter beads presenting P-selectin allowed the simultaneous measurement of collision efficiency (epsilon), membrane tethering fraction (f), membrane tether growth dynamics, and PSGL-1/P-selectin binding lifetime. For 1391 collisions analyzed over venous wall shear rates from 25 to 200 s(-1), epsilon decreased from 0.17 to 0.004, whereas f increased from 0.15 to 0.70, and the average projected membrane tether length, L(tether)(m), increased from 0.35 mum to approximately 2.0 mum over this shear range. At all shear rates tested, adhesive collisions lacking membrane tethers had average bond lifetimes less than those observed for collisions with tethers. For adhesive collisions that failed to form membrane tethers, the regressed Bell parameters (consistent with single bond Monte Carlo simulation) were zero-stress off-rate, k(off)(0) = 0.56 s(-1) and reactive compliance, r = 0.10 nm, similar to published atomic force microscopy (AFM) measurements. For all adhesion events (+/- tethers), the bond lifetime distributions were more similar to those obtained by rolling assay and best simulated by Monte Carlo with the above Bell parameters and an average of 1.48 bonds (n = 1 bond (67%), n = 2 (22%), and n = 3-5 (11%)). For collisions at 100 s(-1), pretreatment of neutrophils with actin depolymerizing agents, latrunculin or cytochalasin D, had no effect on epsilon, but increased L(tether)(m) by 1.74- or 2.65-fold and prolonged the average tether lifetime by 1.41- or 1.65-fold, respectively. Jasplakinolide, an actin polymerizing agent known to cause blebbing, yielded results similar to the depolymerizing agents. Conversely, cholesterol-depletion with methyl-beta-cyclodextrin or formaldehyde fixation had no effect on epsilon, but reduced L(tether)(m) by 66% or 97% and reduced the average tether lifetime by 30% or 42%, respectively. The neutrophil-bead collision assay combines advantages of atomic force microscopy (small contact zone), aggregometry (discrete interactions), micropipette manipulation (tether visualization), and rolling assays (physiologic flow loading). Membrane tether growth can be enhanced or reduced pharmacologically with consequent effects on PSGL-1/P-selectin lifetimes.