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1.
Cell Host Microbe ; 32(3): 382-395.e10, 2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38309259

RESUMEN

Methionine is an essential proteinogenic amino acid, but its excess can lead to deleterious effects. Inborn errors of methionine metabolism resulting from loss of function in cystathionine ß-synthase (CBS) cause classic homocystinuria (HCU), which is managed by a methionine-restricted diet. Synthetic biotics are gastrointestinal tract-targeted live biotherapeutics that can be engineered to replicate the benefits of dietary restriction. In this study, we assess whether SYNB1353, an E. coli Nissle 1917 derivative, impacts circulating methionine and homocysteine levels in animals and healthy volunteers. In both mice and nonhuman primates (NHPs), SYNB1353 blunts the appearance of plasma methionine and plasma homocysteine in response to an oral methionine load. A phase 1 clinical study conducted in healthy volunteers subjected to an oral methionine challenge demonstrates that SYNB1353 is well tolerated and blunts plasma methionine by 26%. Overall, SYNB1353 represents a promising approach for methionine reduction with potential utility for the treatment of HCU.


Asunto(s)
Homocistinuria , Metionina , Humanos , Ratones , Animales , Metionina/metabolismo , Metionina/uso terapéutico , Voluntarios Sanos , Escherichia coli/genética , Escherichia coli/metabolismo , Modelos Animales de Enfermedad , Homocistinuria/tratamiento farmacológico , Homocistinuria/metabolismo , Racemetionina , Homocisteína/uso terapéutico
2.
Front Neurosci ; 18: 1302714, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38362023

RESUMEN

Introduction: Nipocalimab is a high-affinity, fully human, aglycosylated, effectorless, immunoglobulin G (IgG) 1 monoclonal antibody that targets the neonatal Fc receptor (FcRn), decreases systemic IgG including autoantibodies, and is under development in several IgG autoantibody- and alloantibody-mediated diseases, including generalized myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, maternal-fetal medicine, and multiple other therapeutic areas. An initial phase 1 study with single and multiple ascending doses of nipocalimab infused intravenously (IV) over 2 h demonstrated dose-dependent serum pharmacokinetics and IgG reductions, with an adverse event (AE) profile comparable to placebo. Methods: The current investigation evaluates the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of nipocalimab across various IV infusion rates in a randomized, double-blind, placebo-controlled, sequential-dose study. Forty participants were randomized to receive nipocalimab 30 mg/kg over 60, 30, 15 or 7.5 min (0.5, 1, 2, or 4 mg/kg/min); nipocalimab 60 mg/kg over 15 min (4 mg/kg/min); or matching placebo. Results: At doses up to 60 mg/kg and infusion rates up to 4 mg/kg/min (maximum clinically feasible rate), single doses of nipocalimab were tolerable, with 12 (40%) participants experiencing AEs across nipocalimab cohorts compared with 1 (10%) participant in the placebo cohort. AEs deemed treatment related occurred in 6 (20%) participants receiving nipocalimab and 1 (10%) participant receiving placebo. None of the AEs were severe, and no participants discontinued treatment due to AEs. Nipocalimab provided consistent, dose-dependent serum pharmacokinetics and IgG reductions, regardless of infusion rate. Discussion: This study supports the use of shortened durations of nipocalimab infusion for future studies.

3.
Nat Metab ; 5(10): 1685-1690, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37770764

RESUMEN

Despite available treatment options, many patients with phenylketonuria (PKU) cannot achieve target plasma phenylalanine (Phe) levels1. We previously modified Escherichia coli Nissle 1917 to metabolize Phe in the gut after oral administration (SYNB1618) and designed a second strain (SYNB1934) with enhanced activity of phenylalanine ammonia lyase2,3. In a 14-day open-label dose-escalation study (Synpheny-1, NCT04534842 ), we test a primary endpoint of change from baseline in labeled Phe (D5-Phe AUC0-24; D5-Phe area under the curve (AUC) over 24 hours after D5-Phe administration) in plasma after D5-Phe challenge in adult participants with screening Phe of greater than 600 µM. Secondary endpoints were the change from baseline in fasting plasma Phe and the incidence of treatment-emergent adverse events. A total of 20 participants (ten male and ten female) were enrolled and 15 completed the study treatment. Here, we show that both strains lower Phe levels in participants with PKU: D5-Phe AUC0-24 was reduced by 43% from baseline with SYNB1934 and by 34% from baseline with SYNB1618. SYNB1934 led to a decrease in fasting plasma Phe of 40% (95% CI, -52, -24). There were no serious adverse events or infections. Four participants discontinued because of adverse events, and one withdrew during the baseline period. We show that synthetic biotics can metabolize Phe in the gut, lower post-prandial plasma Phe levels and lower fasting plasma Phe in patients with PKU.


Asunto(s)
Fenilalanina , Fenilcetonurias , Adulto , Humanos , Masculino , Femenino , Fenilalanina/uso terapéutico , Fenilcetonurias/tratamiento farmacológico , Fenilanina Amoníaco-Liasa/uso terapéutico , Administración Oral , Escherichia coli
5.
Commun Biol ; 4(1): 898, 2021 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-34294862

RESUMEN

The development of therapeutics depends on predictions of clinical activity from pre-clinical data. We have previously described SYNB1618, an engineered bacterial therapeutic (synthetic biotic) for the treatment of Phenylketonuria (PKU), a rare genetic disease that leads to accumulation of plasma phenylalanine (Phe) and severe neurological complications. SYNB1618 consumes Phe in preclinical models, healthy human volunteers, and PKU patients. However, it remains unclear to what extent Phe consumption by SYNB1618 in the gastrointestinal tract lowers plasma Phe levels in PKU patients. Here, we construct a mechanistic model that predicts SYNB1618 function in non-human primates and healthy subjects by combining in vitro simulations and prior knowledge of human physiology. In addition, we extend a model of plasma Phe kinetics in PKU patients, in order to estimate plasma Phe lowering by SYNB1618. This approach provides a framework that can be used more broadly to define the therapeutic potential of synthetic biotics.


Asunto(s)
Voluntarios Sanos , Fenilcetonurias/genética , Primates/fisiología , Animales , Humanos , Fenilcetonurias/metabolismo , Primates/genética
6.
Nat Metab ; 3(8): 1125-1132, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34294923

RESUMEN

Phenylketonuria (PKU) is a rare disease caused by biallelic mutations in the PAH gene that result in an inability to convert phenylalanine (Phe) to tyrosine, elevated blood Phe levels and severe neurological complications if untreated. Most patients are unable to adhere to the protein-restricted diet, and thus do not achieve target blood Phe levels. We engineered a strain of E. coli Nissle 1917, designated SYNB1618, through insertion of the genes encoding phenylalanine ammonia lyase and L-amino acid deaminase into the genome, which allow for bacterial consumption of Phe within the gastrointestinal tract. SYNB1618 was studied in a phase 1/2a randomized, placebo-controlled, double-blind, multi-centre, in-patient study ( NCT03516487 ) in adult healthy volunteers (n = 56) and patients with PKU and blood Phe level ≥600 mmol l-1 (n = 14). Participants were randomized to receive a single dose of SYNB1618 or placebo (part 1) or up to three times per day for up to 7 days (part 2). The primary outcome of this study was safety and tolerability, and the secondary outcome was microbial kinetics. A D5-Phe tracer (15 mg kg-1) was used to study exploratory pharmacodynamic effects. SYNB1618 was safe and well tolerated with a maximum tolerated dose of 2 × 1011 colony-forming units. Adverse events were mostly gastrointestinal and of mild to moderate severity. All participants cleared the bacteria within 4 days of the last dose. Dose-responsive increases in strain-specific Phe metabolites in plasma (trans-cinnamic acid) and urine (hippuric acid) were observed, providing a proof of mechanism for the potential to use engineered bacteria in the treatment of rare metabolic disorders.


Asunto(s)
Terapia Biológica/métodos , Escherichia coli , Fenilcetonurias/terapia , Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Terapia Biológica/efectos adversos , Escherichia coli/enzimología , Escherichia coli/genética , Ingeniería Genética , Humanos , Fenilanina Amoníaco-Liasa/genética , Fenilanina Amoníaco-Liasa/metabolismo , Fenilcetonurias/sangre , Fenilcetonurias/genética , Resultado del Tratamiento
7.
J Vet Pharmacol Ther ; 44(4): 533-543, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33576078

RESUMEN

An ideal dexmedetomidine protocol has yet to be determined for standing sedation in horses. It was hypothesized that an IV bolus followed by CRI dexmedetomidine would have a quicker increase in plasma concentrations compared with repeated IM injections. In a crossover design, eight adult, female horses were randomly placed into two groups: the CRI group (IV bolus dexmedetomidine at 0.005 mg/kg followed by a CRI at 0.01 mg/kg/h for 15 min then 0.005 mg/kg/h for 60 min) and the IM group (dexmedetomidine at 0.01 mg/kg, followed by 0.005 mg/kg in 30-min intervals for 60 min). Clearance and elimination half-life were 134 ± 67.4 ml/kg/min and 44.3 ± 26.3 min, respectively, in the CRI group, and apparent clearance and half-life were 412 ± 306 ml/kg/min (Cl/F) and 38.9 ± 18.6 min, respectively, in the IM group. Analgesia was evaluated using mechanical pressure threshold. Intravenous dexmedetomidine produced faster onset of sedation and increased pressure threshold compared with IM administration. Individual horses had a large variability in dexmedetomidine plasma concentrations between CRI and IM administration. The odds of a decreased GI motility following IV administration was 12.34 times greater compared with IM administration.


Asunto(s)
Dexmedetomidina , Administración Intravenosa/veterinaria , Animales , Estudios Cruzados , Femenino , Caballos , Infusiones Intravenosas/veterinaria , Inyecciones Intravenosas/veterinaria
8.
Cell Rep Med ; 1(4): 100057, 2020 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-33205064

RESUMEN

Experimental fibroblast growth factor 21 (FGF21) analogs can improve lipid profiles in patients with metabolic diseases. However, their effects on markers of insulin sensitivity appear to be minimal, potentially because of insufficient exposure. Systemic drug levels vary from sub-pharmacological to demonstrating pharmacodynamic effects but with dose-limiting adverse events. Here we report results from a phase 1 multiple ascending dose study of AKR-001, an Fc-FGF21 fusion protein engineered for sustained systemic pharmacologic exposure, in individuals with type 2 diabetes. With a half-life of 3-3.5 days, the peak-to-trough ratio under steady-state conditions is approximately 2 following QW dosing. AKR-001 appears to demonstrate pharmacodynamic effects on serum markers of insulin sensitivity and acceptable tolerability up to and including 70 mg QW. Positive trends in lipoprotein profile, including triglycerides, non-high-density lipoprotein (non-HDL) cholesterol, HDL-C, and apolipoproteins B and C3 are consistent with other FGF21 analogs. AKR-001's clinical profile supports further evaluation as a treatment for metabolic diseases.


Asunto(s)
Diabetes Mellitus Tipo 2 , Factores de Crecimiento de Fibroblastos , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Método Doble Ciego , Factores de Crecimiento de Fibroblastos/farmacocinética , Factores de Crecimiento de Fibroblastos/farmacología , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/sangre , Obesidad/tratamiento farmacológico , Efecto Placebo , Triglicéridos/sangre , Estados Unidos
9.
Am J Gastroenterol ; 115(5): 783-785, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31449156

RESUMEN

INTRODUCTION: Ammonia levels are used to assess hepatic encephalopathy, but their levels are highly variable in clinical practice. METHODS: We studied factors associated with variation in ammonia values in cirrhotic patients without previous hepatic encephalopathy and healthy volunteers (HVs). RESULTS: Ammonia increased by 12% and 18% at 1 and 2 hour, respectively, after a protein meal in 64 cirrhotic patients (P < 0.001). In 237 HVs, ammonia levels varied significantly between sites (P < 0.0001). New site-specific ammonia upper limits based on HV levels using a strict analysis protocol differed from routinely used values. Correlation between paired fresh samples was high (r = 0.83) but modest between fresh and frozen samples (r = 0.62). DISCUSSION: Sample handling, processing, and protein intake impact ammonia levels across sites.


Asunto(s)
Amoníaco/sangre , Ensayos Clínicos como Asunto , Encefalopatía Hepática/sangre , Cirrosis Hepática/sangre , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Progresión de la Enfermedad , Femenino , Voluntarios Sanos , Encefalopatía Hepática/diagnóstico , Encefalopatía Hepática/etiología , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto Joven
10.
Eur J Pain ; 23(6): 1129-1140, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30793411

RESUMEN

BACKGROUND: Although reproducibility is considered essential for any method used in scientific research, it is investigated only rarely; thus, strikingly little has been published regarding the reproducibility of evoked pain models involving human subjects. Here, we studied the reproducibility of a battery of evoked pain models for demonstrating the analgesic effects of two analgesic compounds. METHODS: A total of 81 healthy subjects participated in four studies involving a battery of evoked pain tests in which mechanical, thermal and electrical stimuli were used to measure pain detection and tolerance thresholds. Pharmacodynamic outcome variables were analysed using a mixed model analysis of variance, and a coefficient of variation was calculated by dividing the standard deviation by the least squares means. RESULTS: A total of 76 subjects completed the studies. After being administered pregabalin, the subjects' pain tolerance thresholds in the cold pressor and pressure stimulation tests were significantly increased compared to the placebo group. Moreover, the heat pain detection threshold in UVB-irradiated skin was significantly increased in subjects who were administered ibuprofen compared to the placebo group. Variation among all evoked pain tests ranged from 2.2% to 30.6%. CONCLUSIONS: Four studies using a similar design showed reproducibility with respect to the included evoked pain models. The relatively high consistency and reproducibility of two analgesics at doses known to be effective in treating clinically relevant pain supports the validity of using this pain test battery to investigate the analgesic activity and determine the active dosage of putative analgesic compounds in early clinical development. SIGNIFICANCE: The consistency and reproducibility of measuring the profile of an analgesic at clinically relevant doses illustrates that this pain test battery is a valid tool for demonstrating the analgesic activity of a test compound and for determining the optimal active dose in early clinical drug development.


Asunto(s)
Analgésicos/uso terapéutico , Dimensión del Dolor/métodos , Dolor/tratamiento farmacológico , Adulto , Estudios Cruzados , Método Doble Ciego , Tolerancia a Medicamentos , Femenino , Voluntarios Sanos , Humanos , Ibuprofeno/farmacología , Masculino , Persona de Mediana Edad , Umbral del Dolor/efectos de los fármacos , Pregabalina/farmacología , Reproducibilidad de los Resultados , Piel/efectos de los fármacos , Piel/efectos de la radiación
11.
Sci Transl Med ; 11(475)2019 01 16.
Artículo en Inglés | MEDLINE | ID: mdl-30651324

RESUMEN

The intestine is a major source of systemic ammonia (NH3); thus, capturing part of gut NH3 may mitigate disease symptoms in conditions of hyperammonemia such as urea cycle disorders and hepatic encephalopathy. As an approach to the lowering of blood ammonia arising from the intestine, we engineered the orally delivered probiotic Escherichia coli Nissle 1917 to create strain SYNB1020 that converts NH3 to l-arginine (l-arg). We up-regulated arginine biosynthesis in SYNB1020 by deleting a negative regulator of l-arg biosynthesis and inserting a feedback-resistant l-arg biosynthetic enzyme. SYNB1020 produced l-arg and consumed NH3 in an in vitro system. SYNB1020 reduced systemic hyperammonemia, improved survival in ornithine transcarbamylase-deficient spfash mice, and decreased hyperammonemia in the thioacetamide-induced liver injury mouse model. A phase 1 clinical study was conducted including 52 male and female healthy adult volunteers. SYNB1020 was well tolerated at daily doses of up to 1.5 × 1012 colony-forming units administered for up to 14 days. A statistically significant dose-dependent increase in urinary nitrate, plasma 15N-nitrate (highest dose versus placebo, P = 0.0015), and urinary 15N-nitrate was demonstrated, indicating in vivo SYNB1020 activity. SYNB1020 concentrations reached steady state by the second day of dosing, and excreted cells were alive and metabolically active as evidenced by fecal arginine production in response to added ammonium chloride. SYNB1020 was no longer detectable in feces 2 weeks after the last dose. These results support further clinical development of SYNB1020 for hyperammonemia disorders including urea cycle disorders and hepatic encephalopathy.


Asunto(s)
Escherichia coli/genética , Ingeniería Genética , Voluntarios Sanos , Hiperamonemia/terapia , Amoníaco/sangre , Amoníaco/metabolismo , Animales , Arginina/metabolismo , Vías Biosintéticas , Modelos Animales de Enfermedad , Heces/química , Femenino , Humanos , Hiperamonemia/sangre , Hiperamonemia/orina , Macaca fascicularis , Masculino , Ratones , Nitratos/sangre , Nitratos/orina , Estrés Fisiológico/genética , Análisis de Supervivencia
12.
Clin Transl Sci ; 11(2): 200-207, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29194983

RESUMEN

Understanding the pharmacology of microbiome-based therapeutics is required to support the development of new medicines. Strains of E. coli Nissle (EcN) were genetically modified and administered to cynomolgus monkeys at doses of 1 × 109 and 1 × 1012 colony-forming units (CFU)/day for 28 days. A clinical study to evaluate the exposure and clearance of EcN in healthy volunteers was also performed. Healthy subjects received oral doses of EcN, 2.5 to 25 × 109 CFU 3 times daily for 28 days or a single day. In cynomolgus monkeys, replicating strains yielded higher fecal concentrations than nonreplicating strains and persisted for longer following cessation of dosing. In the clinical study, all subjects cleared EcN following cessation of dosing with median clearance of 1 week. Quantitative methodology can be applied to microbiome-based therapeutics, and similar kinetics and clearance were observed for EcN in cynomolgus monkeys and humans.


Asunto(s)
Terapia Biológica/métodos , Escherichia coli/metabolismo , Microbiota/fisiología , Microorganismos Modificados Genéticamente/metabolismo , Probióticos/farmacología , Administración Oral , Adulto , Animales , Arginina/metabolismo , Escherichia coli/genética , Escherichia coli/aislamiento & purificación , Heces/microbiología , Femenino , Voluntarios Sanos , Interacciones Microbiota-Huesped/genética , Interacciones Microbiota-Huesped/fisiología , Humanos , Masculino , Redes y Vías Metabólicas/genética , Errores Innatos del Metabolismo/terapia , Microbiota/genética , Microorganismos Modificados Genéticamente/genética , Microorganismos Modificados Genéticamente/aislamiento & purificación , Persona de Mediana Edad , Modelos Animales , Primates , Estudios Prospectivos , Adulto Joven
13.
Br J Clin Pharmacol ; 83(2): 326-338, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27621150

RESUMEN

AIM: To evaluate safety, tolerability and pharmacokinetics of oral PF-05190457, an oral ghrelin receptor inverse agonist, in healthy adults. METHODS: Single (SAD) and multiple ascending dose (MAD) studies were randomised, placebo-controlled, double-blind studies. Thirty-five healthy men (age 38.2 ± 10.4 years; body mass index 24.8 ± 3.1 kg m-2 [mean ± standard deviation]) received ≥1 dose (2, 10, 40 [divided], 50, 100, 150, and 300 [single or divided] mg) of PF-05190457 and/or placebo in the SAD. In the MAD study, 35 healthy men (age 39.7 ± 10.1 years; body mass index 25.9 ± 3.3 kg m-2 ) received ≥1 dose (2, 10, 40 and 100 mg twice daily) of PF-05190457 and/or placebo daily for 2 weeks. RESULTS: PF-05190457 absorption was rapid with a Tmax of 0.5-3 hours and a half-life between 8.2-9.8 hours. PF-05190457 dose-dependently blocked ghrelin (1 pmol kg-1  min-1 )-induced growth hormone (GH) release with (mean [90% confidence interval]) 77% [63-85%] inhibition at 100 mg. PF-05190457 (150 mg) delayed gastric emptying lag time by 30% [7-58%] and half emptying time by 20% [7-35%] with a corresponding decrease in postprandial glucose by 9 mg dL-1 . The most frequent adverse event reported by 30 subjects at doses ≥50 mg was somnolence. PF-05190457 plasma concentrations also increased heart rate up to 13.4 [4.8-58.2] beats min-1 and, similar to the effect on glucose and ghrelin-induced GH, was lost within 2 weeks. CONCLUSIONS: PF-05190457 is a well-tolerated first-in-class ghrelin receptor inverse agonist with acceptable pharmacokinetics for oral daily dosing. Blocking ghrelin receptors inhibits ghrelin-induced GH, and increases heart rate, effects that underwent tachyphylaxis with chronic dosing. PF-051940457 has the potential to treat centrally-acting disorders such as insomnia.


Asunto(s)
Azetidinas/administración & dosificación , Agonismo Inverso de Drogas , Receptores de Ghrelina/agonistas , Compuestos de Espiro/administración & dosificación , Administración Oral , Adulto , Azetidinas/farmacocinética , Azetidinas/farmacología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Semivida , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología
14.
Clin Pharmacol Drug Dev ; 5(6): 517-527, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27870481

RESUMEN

Glucokinase enhances glucose conversion to glucose-6-phosphate, causing glucose-stimulated insulin secretion from pancreatic ß cells and increased hepatic glucose uptake. PF-04937319 is a partial glucokinase activator designed to maintain efficacy with reduced hypoglycemia risk. In this randomized, double-blind, double-dummy, 3-period crossover phase 1b study, patients aged 18-70 years with type 2 diabetes mellitus and on metformin received once-daily PF-04937319 (300 mg), split-dose PF-04937319 (150+100 mg; breakfast+lunch), or sitagliptin (100 mg once daily). The primary end point was day 14 weighted mean daily glucose (WMDG) change from period-specific baseline. Secondary end points included change from baseline in fasting plasma glucose, premeal C-peptide and insulin, and safety, including hypoglycemia frequency. Mean decrease from baseline in observed WMDG (mg/dL) was greater for PF-04937319 (split-dose, -31.24; once daily, -31.33) versus sitagliptin (-19.24). Using the integrated glucose red-cell HbA1c model, the observed WMDG effect with both PF-04937319 dosing regimens was projected to yield a clinically superior effect on mean glycated hemoglobin (HbA1c ; split-dose, -0.88%; once daily, -0.94%) compared with sitagliptin (-0.63%). There was no difference in premeal C-peptide or insulin levels, and although the effect on WMDG with both PF-04937319 regimens was similar, the split-dose regimen appeared to offer some advantage in safety and tolerability.


Asunto(s)
Benzofuranos/uso terapéutico , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Activadores de Enzimas/uso terapéutico , Glucoquinasa/metabolismo , Hipoglucemiantes/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Anciano , Benzofuranos/efectos adversos , Benzofuranos/farmacocinética , Estudios Cruzados , Diabetes Mellitus Tipo 2/sangre , Método Doble Ciego , Determinación de Punto Final , Activadores de Enzimas/efectos adversos , Activadores de Enzimas/farmacocinética , Femenino , Glucoquinasa/efectos de los fármacos , Hemoglobina Glucada , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacocinética , Insulina/sangre , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Fosfato de Sitagliptina/uso terapéutico
15.
Br J Clin Pharmacol ; 79(5): 831-7, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25377933

RESUMEN

AIMS: Calcitonin gene related peptide (CGRP) receptor antagonists are effective acute migraine treatments. A capsaicin-induced dermal vasodilatation (CIDV) model has been developed to provide target-engagement information in healthy volunteers. In the model, CGRP release is provoked after dermal capsaicin application, by activating transient receptor potential vanilloid-type-1 (TRPV1) receptors at peripheral sensory nerves. Laser Doppler imaging is used to quantify CIDV and subsequent inhibition by CGRP receptor antagonists. We sought to evaluate a CGRP receptor antagonist, MK-3207, in the biomarker model and to assess the predictability of the CIDV response to migraine clinical efficacy. METHODS: An integrated population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the exposure-response relationship for CIDV inhibition by CGRP and TRPV1 receptor antagonists. MK-3207 dose-response predictions were made based on estimated potency from the PK/PD model and mean plasma concentrations observed at the doses investigated. RESULTS: The results suggested that a 20 mg dose of MK-3207 (EC50 of 1.59 nm) would be required to attain the peripheral CIDV response at a target level that was shown previously to correlate with 2 h clinical efficacy based on phase 3 telcagepant clinical data, and that a plateau of the dose-response would be reached around 40-100 mg. These predictions provided a quantitative rationale for dose selection in a phase 2 clinical trial of MK-3207 and helped with interpretation of the efficacy results from the trial. CONCLUSIONS: The integrated CIDV PK/PD model provides a useful platform for characterization of PK/PD relationships and predictions of dose-response relationships to aid in future development of CGRP and TRPV1 receptor antagonists.


Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Capsaicina/farmacología , Modelos Biológicos , Piel/irrigación sanguínea , Compuestos de Espiro , Vasodilatación/efectos de los fármacos , Administración Oral , Adolescente , Adulto , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , Humanos , Masculino , Valor Predictivo de las Pruebas , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Adulto Joven
16.
Drug Metab Dispos ; 42(11): 1926-39, 2014 11.
Artículo en Inglés | MEDLINE | ID: mdl-25142735

RESUMEN

The present article summarizes Metabolites in Safety Testing (MIST) studies on a glucokinase activator, N,N-dimethyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide (PF-04937319), which is under development for the treatment of type 2 diametes mellitus. Metabolic profiling in rat, dog, and human hepatocytes revealed that PF-04937319 is metabolized via oxidative (major) and hydrolytic pathways (minor). N-Demethylation to metabolite M1 [N-methyl-5-((2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yl)oxy)pyrimidine-2-carboxamide] was the major metabolic fate of PF-04937319 in human (but not rat or dog) hepatocytes, and was catalyzed by CYP3A and CYP2C isoforms. Qualitative examination of circulating metabolites in humans at the 100- and 300-mg doses from a 14-day multiple dose study revealed unchanged parent drug and M1 as principal components. Because M1 accounted for 65% of the drug-related material at steady state, an authentic standard was synthesized and used for comparison of steady-state exposures in humans and the 3-month safety studies in rats and dogs at the no-observed-adverse-effect level. Although circulating levels of M1 were very low in beagle dogs and female rats, adequate coverage was obtained in terms of total maximal plasma concentration (∼7.7× and 1.8×) and area under the plasma concentration-time curve (AUC; 3.6× and 0.8× AUC) relative to the 100- and 300-mg doses, respectively, in male rats. Examination of primary pharmacology revealed M1 was less potent as a glucokinase activator than the parent drug (compound PF-04937319: EC50 = 0.17 µM; M1: EC50 = 4.69 µM). Furthermore, M1 did not inhibit major human P450 enzymes (IC50 > 30 µM), and was negative in the Salmonella Ames assay, with minimal off-target pharmacology, based on CEREP broad ligand profiling. Insights gained from this analysis should lead to a more efficient and focused development plan for fulfilling MIST requirements with PF-04937319.


Asunto(s)
Benzofuranos/farmacocinética , Activadores de Enzimas/farmacocinética , Glucoquinasa/metabolismo , Pirimidinas/farmacocinética , Animales , Área Bajo la Curva , Benzofuranos/sangre , Perros , Activadores de Enzimas/sangre , Femenino , Humanos , Pirimidinas/sangre , Ratas
17.
AAPS J ; 16(6): 1259-70, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25160589

RESUMEN

A potent novel compound (MK-3577) was developed for the treatment of type 2 diabetes mellitus (T2DM) through blocking the glucagon receptor. A semi-mechanistic model was developed to describe the drug effect on glucagon and the interaction between glucagon, insulin, and glucose in healthy subjects (N = 36) during a glucagon challenge study in which glucagon, octreotide (Sandostatin), and basal insulin were infused for 2 h starting from 3, 12, or 24 h postdose of a single 0-900 mg MK-3577 administration. The drug effect was modeled by using an inhibitory E max model (I max = 0.96 and IC50 = 13.9 nM) to reduce the ability of glucagon to increase the glucose production rate (GPROD). In addition, an E max model (E max = 0.79 and EC50 = 575 nM) to increase glucagon secretion by the drug was used to account for the increased glucagon concentrations prechallenge (via compensatory feedback). The model adequately captured the observed profiles of glucagon, glucose, and insulin pre- and postchallenge. The model was then adapted for the T2DM patient population. A linear model to correlate fasting plasma glucose (FPG) to weighted mean glucose (WMG) was developed and provided robust predictions to assist with the dose adjustment for the interim analysis of a phase IIa study.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucagón/sangre , Glucosa/metabolismo , Hipoglucemiantes/uso terapéutico , Insulina/sangre , Modelos Biológicos , Receptores de Glucagón/antagonistas & inhibidores , Adulto , Glucemia/análisis , Estudios Cruzados , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Método Doble Ciego , Esquema de Medicación , Interacciones Farmacológicas , Femenino , Glucagón/administración & dosificación , Glucagón/farmacología , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/farmacocinética , Insulina/administración & dosificación , Insulina/farmacología , Masculino , Persona de Mediana Edad
18.
J Pharmacokinet Pharmacodyn ; 41(6): 581-98, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25168488

RESUMEN

Our objective was to expand our understanding of the predictors of Alzheimer's disease (AD) progression to help design a clinical trial on a novel AD medication. We utilized the Coalition Against Major Diseases AD dataset consisting of control-arm data (both placebo and stable background AD medication) from 15 randomized double-blind clinical trials in mild-to-moderate AD patients (4,495 patients; July 2013). Our ADAS-cog longitudinal model incorporates a beta-regression with between-study, -subject, and -residual variability in NONMEM; it suggests that faster AD progression is associated with younger age and higher number of apolipoprotein E type 4 alleles (APOE*4), after accounting for baseline disease severity. APOE*4, in particular, seems to be implicated in the AD pathogenesis. In addition, patients who are already on stable background AD medications appear to have a faster progression relative to those who are not receiving AD medication. The current knowledge does not support a causality relationship between use of background AD medications and higher rate of disease progression, and the correlation is potentially due to confounding covariates. Although causality has not necessarily been demonstrated, this model can inform inclusion criteria and stratification, sample size, and trial duration.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Anciano , Alelos , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Humanos , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto
19.
J Clin Pharmacol ; 52(9): 1306-16, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22162541

RESUMEN

MK-5046 is an orally active, potent, selective agonist of the orphan G protein-coupled receptor bombesin receptor subtype-3 (BRS-3) that is under evaluation for treatment of obesity. We report the safety, tolerability, pharmacokinetics, and pharmacodynamics of oral doses of MK-5046 (10-160 mg) in a double-blind, randomized, placebo-controlled study in healthy and obese male volunteers. MK-5046 exposure increased dose proportionally, and MK-5046 was eliminated with an apparent terminal half-life of 1.5 to 3.5 hours. Single doses transiently increased blood pressure. Patients reported adverse events (erections and feeling hot, cold, and/or jittery) that coincided with time of occurrence (T(max)) and increased with increasing dose. No changes were observed in body temperature, heart rate, plasma glucose levels, or feelings of hunger/satiety. The blood pressure and thermal experiences attenuated with a second dose 6 hours after the first. Additionally, the erections suggest a possible, unanticipated, role for BRS-3 in reproductive physiology. Oral administration of MK-5046 achieves plasma concentrations that are projected to activate BRS-3 and therefore should be suitable for exploring its biological role in humans.


Asunto(s)
Fármacos Antiobesidad/administración & dosificación , Imidazoles/administración & dosificación , Pirazoles/administración & dosificación , Receptores de Bombesina/agonistas , Fármacos Antiobesidad/sangre , Fármacos Antiobesidad/farmacocinética , Apetito/efectos de los fármacos , Área Bajo la Curva , Glucemia/análisis , Presión Sanguínea/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Método Doble Ciego , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Imidazoles/sangre , Imidazoles/farmacocinética , Insulina/sangre , Masculino , Pirazoles/sangre , Pirazoles/farmacocinética
20.
PLoS Comput Biol ; 6(9)2010 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-20941387

RESUMEN

Blood function defines bleeding and clotting risks and dictates approaches for clinical intervention. Independent of adding exogenous tissue factor (TF), human blood treated in vitro with corn trypsin inhibitor (CTI, to block Factor XIIa) will generate thrombin after an initiation time (T(i)) of 1 to 2 hours (depending on donor), while activation of platelets with the GPVI-activator convulxin reduces T(i) to ∼20 minutes. Since current kinetic models fail to generate thrombin in the absence of added TF, we implemented a Platelet-Plasma ODE model accounting for: the Hockin-Mann protease reaction network, thrombin-dependent display of platelet phosphatidylserine, VIIa function on activated platelets, XIIa and XIa generation and function, competitive thrombin substrates (fluorogenic detector and fibrinogen), and thrombin consumption during fibrin polymerization. The kinetic model consisting of 76 ordinary differential equations (76 species, 57 reactions, 105 kinetic parameters) predicted the clotting of resting and convulxin-activated human blood as well as predicted T(i) of human blood under 50 different initial conditions that titrated increasing levels of TF, Xa, Va, XIa, IXa, and VIIa. Experiments with combined anti-XI and anti-XII antibodies prevented thrombin production, demonstrating that a leak of XIIa past saturating amounts of CTI (and not "blood-borne TF" alone) was responsible for in vitro initiation without added TF. Clotting was not blocked by antibodies used individually against TF, VII/VIIa, P-selectin, GPIb, protein disulfide isomerase, cathepsin G, nor blocked by the ribosome inhibitor puromycin, the Clk1 kinase inhibitor Tg003, or inhibited VIIa (VIIai). This is the first model to predict the observed behavior of CTI-treated human blood, either resting or stimulated with platelet activators. CTI-treated human blood will clot in vitro due to the combined activity of XIIa and XIa, a process enhanced by platelet activators and which proceeds in the absence of any evidence for kinetically significant blood borne tissue factor.


Asunto(s)
Coagulación Sanguínea/fisiología , Redes y Vías Metabólicas/fisiología , Activación Plaquetaria/fisiología , Biología de Sistemas/métodos , Trombina/metabolismo , Coagulación Sanguínea/efectos de los fármacos , Factores de Coagulación Sanguínea/metabolismo , Simulación por Computador , Venenos de Crotálidos/farmacología , Factor XIIa/metabolismo , Fibrinolíticos/farmacología , Colorantes Fluorescentes , Ensayos Analíticos de Alto Rendimiento , Humanos , Inmunoensayo , Lectinas Tipo C , Redes y Vías Metabólicas/efectos de los fármacos , Proteínas de Plantas/farmacología , Activación Plaquetaria/efectos de los fármacos , Reproducibilidad de los Resultados , Tromboplastina/metabolismo
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