RESUMEN

DS-2969b is a novel GyrB inhibitor in development for the treatment of Clostridium difficile infection. The aim of this study was to assess the safety, tolerability, pharmacokinetics, and effects on normal gastrointestinal microbiota groups of single daily oral ascending doses of DS-2969b in healthy subjects. The study enrolled 6 sequential ascending dose cohorts (6 mg, 20 mg, 60 mg, 200 mg, 400 mg, and 600 mg). In each cohort, 6 subjects were administered DS-2969b and 2 subjects were administered matching placebo. DS-2969b was safe and well tolerated at all dose levels examined. All adverse events related to DS-2969b were mild to moderate in severity and predominantly related to the gastrointestinal tract. DS-2969a (free form of DS-2969b) plasma concentrations increased with increasing doses; however, both the maximum serum concentration and area under the plasma concentration-time curve generally increased less than dose proportionally. DS-2969a was predominantly eliminated in the urine, with feces as a minor route of elimination. While the overall proportion of DS-2969a eliminated in the feces was low, target fecal levels sufficient for C. difficile eradication were achieved within 24 hours of administration with doses of 60 mg or higher. In exploratory analyses, DS-2969b appeared to reduce bacterial counts in 8 of the 25 groups of normal intestinal microbiota examined, suggesting that DS-2969b has only a mild effect on intestinal microbiota. Data from this study support and encourage further development of DS-2969b as a novel treatment for C. difficile infection.

Asunto(s)

Imidazoles/efectos adversos , Imidazoles/farmacocinética , Piperidinas/efectos adversos , Piperidinas/farmacocinética , Tiadiazoles/efectos adversos , Tiadiazoles/farmacocinética , Inhibidores de Topoisomerasa II/efectos adversos , Inhibidores de Topoisomerasa II/farmacocinética , Adolescente , Adulto , Área Bajo la Curva , Bacterias/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Semivida , Humanos , Imidazoles/administración & dosificación , Imidazoles/sangre , Masculino , Persona de Mediana Edad , Estructura Molecular , Piperidinas/administración & dosificación , Piperidinas/sangre , Tiadiazoles/administración & dosificación , Tiadiazoles/sangre , Inhibidores de Topoisomerasa II/administración & dosificación , Inhibidores de Topoisomerasa II/sangre , Adulto Joven

RESUMEN

Background Vosaroxin is a first-in-class anticancer quinolone derivative that is being investigated for patients with relapsed or refractory acute myeloid leukemia (AML). The primary objective of this study was to quantitatively determine the pharmacokinetics of vosaroxin and its metabolites in patients with advanced solid tumors. Methods This mass balance study investigated the pharmacokinetics (distribution, metabolism, and excretion) of vosaroxin in cancer patients after a single dose of 60 mg/m2 14C-vosaroxin, administered as short intravenous injection. Blood, urine and feces were collected over 168 h after injection or until recovered radioactivity over 24 h was less than 1% of the administered dose (whichever was earlier). Total radioactivity (TRA), vosaroxin and metabolites were studied in all matrices. Results Unchanged vosaroxin was the major species identified in plasma, urine, and feces. N-desmethylvosaroxin was the only circulating metabolite detected in plasma, accounting for <3% of the administered dose. However, in plasma, the combined vosaroxin + N-desmethylvosaroxin AUC0-∞ was 21% lower than the TRA AUC0-∞ , suggesting the possible formation of protein bound metabolites after 48 h when the concentration-time profiles diverged. The mean recovery of TRA in excreta was 81.3% of the total administered dose; 53.1% was excreted through feces and 28.2% through urine. Conclusions Unchanged vosaroxin was the major compound found in the excreta, although 10 minor metabolites were detected. The biotransformation reactions were demethylation, hydrogenation, decarboxylation and phase II conjugation including glucuronidation.

Asunto(s)

Naftiridinas/farmacocinética , Neoplasias/metabolismo , Tiazoles/farmacocinética , Inhibidores de Topoisomerasa II/farmacocinética , Adulto , Anciano , Biotransformación , Radioisótopos de Carbono , Heces/química , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Naftiridinas/efectos adversos , Naftiridinas/sangre , Naftiridinas/orina , Neoplasias/sangre , Neoplasias/orina , Tiazoles/efectos adversos , Tiazoles/sangre , Tiazoles/orina , Inhibidores de Topoisomerasa II/efectos adversos , Inhibidores de Topoisomerasa II/sangre , Inhibidores de Topoisomerasa II/orina

RESUMEN

The long-acting muscarinic antagonist umeclidinium (UMEC) is approved as a once-daily monotherapy and in combination with the long-acting ß2 agonist vilanterol (VI) for chronic obstructive pulmonary disease. The objective of this analysis was to assess the relationship between observed plasma UMEC and/or VI concentrations and QT interval corrected using Fridericia's correction (QTcF). 103 subjects were enrolled and 86 (83 %) completed the study. Subjects were randomized to 4 of 5 repeat-dose treatments (days 1-10: n = 77 subjects received placebo, n = 76 UMEC 500 µg, n = 78 UMEC/VI 125/25 µg, or n = 76 UMEC/VI 500/100 µg; day 10: n = 74 oral tablet moxifloxacin 400 mg [positive control]). The concentration-QTcF interval relationship was examined using nonlinear mixed-effects methods. For UMEC, predicted QTcF interval prolongation (at observed geometric mean of maximum plasma concentrations) was -2.38 ms (90 % prediction interval [PI] -3.82, -0.85) with UMEC 500 µg and -0.50 ms (90 % PI -0.80, -0.18) and -2.01 ms (90 % PI -3.22, -0.72) with UMEC/VI 125/25 µg and 500/100 µg, respectively. For VI, estimates were 5.89 ms (90 % PI 4.89, 6.91) and 7.23 ms (90 % PI 5.88, 8.55) with UMEC/VI 125/25 µg and 500/100 µg, respectively. Combined additive mean effects were estimated for UMEC/VI 125/25 µg (5.39 ms [90 % PI 4.40, 6.47]) and 500/100 µg (5.22 ms [90 % PI 3.72, 6.80]). The model-predicted decrease with UMEC and increase with UMEC/VI combination in QTcF interval suggest that the QT effect is likely attributable to VI. These model-predicted results support those of previously-published traditional statistical analyses.

Asunto(s)

Alcoholes Bencílicos/administración & dosificación , Clorobencenos/administración & dosificación , Fluoroquinolonas/administración & dosificación , Antagonistas Muscarínicos/administración & dosificación , Quinuclidinas/administración & dosificación , Inhibidores de Topoisomerasa II/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 2/sangre , Adulto , Alcoholes Bencílicos/sangre , Clorobencenos/sangre , Estudios Cruzados , Combinación de Medicamentos , Femenino , Fluoroquinolonas/sangre , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Moxifloxacino , Antagonistas Muscarínicos/sangre , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Quinuclidinas/sangre , Comprimidos/administración & dosificación , Inhibidores de Topoisomerasa II/sangre , Adulto Joven

RESUMEN

Fluoroquinolones are broad-spectrum antibiotics with efficacy against a wide range of pathogenic microbes associated with respiratory and meningeal infections. The potential toxicity of this class of chemical agents is a source of major concern and is becoming a global issue. The aim of this study was to develop a method for the brain distribution and the pharmacokinetic profile of gatifloxacin in healthy Sprague-Dawley rats, via Multicenter matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) and quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS). We developed a sensitive LC-MS/MS method to quantify gatifloxacin in plasma, lung, and brain homogenates. A pharmacokinetic profile was observed where there is a double peak pattern; a sharp initial increase in the concentration soon after dosing followed by a steady decline until another increase in concentration after a longer period post dosing in all three biological samples was observed. The imaging results showed the drug gradually entering the brain via the blood brain barrier and into the cortical regions from 15 to 240 min post dose. As time elapses, the drug leaves the brain following the same path as it followed on its entry and finally concentrates at the cortex. Copyright © 2015 John Wiley & Sons, Ltd.

Asunto(s)

Antibacterianos/farmacocinética , Fluoroquinolonas/farmacocinética , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Espectrometría de Masas en Tándem/métodos , Inhibidores de Topoisomerasa II/farmacocinética , Animales , Antibacterianos/sangre , Encéfalo/metabolismo , Cromatografía Liquida/métodos , Femenino , Fluoroquinolonas/sangre , Gatifloxacina , Pulmón/metabolismo , Ratas Sprague-Dawley , Inhibidores de Topoisomerasa II/sangre

RESUMEN

A new and specific HPLC-DAD method for the direct determination of Prulifloxacin and its active metabolite, Ulifloxacin, in human plasma has been developed. Plasma samples were analysed after a simple solid phase extraction (SPE) clean-up using a new HILIC stationary phase based high-performance liquid chromatography (HPLC) column and an ammonium acetate buffer (5 mM, pH 5.8)/acetonitrile (both with 1% Et(3)N, v/v) mobile phase in isocratic elution mode, with Danofloxacin as the internal standard. Detection was performed using DAD from 200 to 500 nm and quantitative analyses were carried out at 278 nm. The LOQ of the method was 1 µg/mL of the cited analytes and the calibration curve showed a good linearity up to 25 µg/mL. For both analytes the precision (RSD%) and the trueness (bias%) of the method fulfil with International Guidelines. The method was applied for stability studies, at three QC concentration levels, in human plasma samples stored at different temperature of + 25, + 4 and -20 °C in order to evaluate plasma stability profiles.

Asunto(s)

Dioxolanos/sangre , Fluoroquinolonas/sangre , Piperazinas/sangre , Inhibidores de Topoisomerasa II/sangre , Cromatografía Líquida de Alta Presión , Estabilidad de Medicamentos , Humanos , Estructura Molecular , Extracción en Fase Sólida

RESUMEN

AIM: To investigate the QT/QTc effects of orally administered moxifloxacin in healthy Chinese volunteers. METHODS: This was a single-blinded, randomized, single-dose, placebo-controlled, two-period cross-over study. A total of 24 healthy Chinese volunteers were enrolled, randomly assigned to two groups: one group received moxifloxacin (400 mg, po) followed by placebo with a 7-d interval, another group received placebo followed by moxifloxacin with a 7-d interval. On the days of dosing, 12-lead 24 h Holter ECGs were recorded and evaluated by an ECG laboratory blind to the treatments. Blood samples were collected to determine plasma concentrations of moxifloxacin. RESULTS: The orally administered moxifloxacin significantly prolonged the mean QTc at all time points except 0.5 h post-dose. The largest time-matched difference in the QTcI was 8.35 ms (90% CI: 5.43, 11.27) at 4 h post-dose. The peak effect on QTcF was 9.35 ms (90% CI: 6.36, 12.34) at 3 h post-dose. A pharmacokinetic-QTc model suggested a 2.084 ms increase in the QTc interval for every 1000 ng/mL increase in plasma concentration of moxifloxacin. In addition, the orally administered moxifloxacin was well tolerated by the subjects. CONCLUSION: Orally administered moxifloxacin significantly prolongs QTc, which supports its use as a positive control in ICH-E14 TQT studies in Chinese volunteers.

Asunto(s)

Fluoroquinolonas/administración & dosificación , Fluoroquinolonas/efectos adversos , Frecuencia Cardíaca/efectos de los fármacos , Síndrome de QT Prolongado/inducido químicamente , Inhibidores de Topoisomerasa II/administración & dosificación , Inhibidores de Topoisomerasa II/efectos adversos , Administración Oral , Adolescente , Adulto , Pueblo Asiatico , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Fluoroquinolonas/sangre , Humanos , Síndrome de QT Prolongado/fisiopatología , Masculino , Persona de Mediana Edad , Moxifloxacino , Método Simple Ciego , Inhibidores de Topoisomerasa II/sangre , Adulto Joven

RESUMEN

A series of dual targeting inhibitors of bacterial gyrase B and topoisomerase IV were identified and optimized to mid-to-low nanomolar potency against a variety of bacteria. However, in spite of seemingly adequate exposure achieved upon IV administration, the in vivo efficacy of the early lead compounds was limited by high levels of binding to serum proteins. To overcome this limitation, targeted serum shift prediction models were generated for each subclass of interest and were applied to the design of prospective analogs. As a result, numerous compounds with comparable antibacterial potency and reduced protein binding were generated. These efforts culminated in the synthesis of compound 10, a potent inhibitor with low serum shift that demonstrated greatly improved in vivo efficacy in two distinct rat infection models.

Asunto(s)

Antibacterianos/sangre , Bacterias/enzimología , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/antagonistas & inhibidores , Inhibidores de Topoisomerasa II/sangre , Animales , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/enzimología , Infecciones Bacterianas/microbiología , Proteínas Sanguíneas/metabolismo , Topoisomerasa de ADN IV/metabolismo , Humanos , Ratas , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/metabolismo , Inhibidores de Topoisomerasa II/farmacología

RESUMEN

Anacetrapib is a cholesteryl ester transfer protein inhibitor in Phase III development. This double-blind, double-dummy, randomized, placebo- and active-comparator-controlled, 4-period, balanced crossover study evaluated the effects of anacetrapib (100 mg and 800 mg) on QTcF interval in healthy subjects. QTcF measurements were made up to 24 h following administration of single doses of anacetrapib 100 or 800 mg, moxifloxacin 400 mg, or placebo in the fed state. The primary hypothesis was supported if the 90% CI for the least squares (LS) mean differences between anacetrapib 800 mg and placebo in QTcF interval change from baseline were entirely <10 msec at every post-dose time point (1, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 h). The upper bounds of the 90% CIs for LS mean differences from placebo in changes from baseline in QTcF intervals for anacetrapib 100 and 800 mg were <5 msec at every time point. In conclusion, single doses of anacetrapib 100 and 800 mg do not prolong the QTcF interval to a clinically meaningful degree relative to placebo and are generally well tolerated in healthy subjects.

Asunto(s)

Anticolesterolemiantes/administración & dosificación , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Drogas en Investigación/administración & dosificación , Corazón/efectos de los fármacos , Modelos Biológicos , Oxazolidinonas/administración & dosificación , Adolescente , Adulto , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Antibacterianos/sangre , Antibacterianos/farmacocinética , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/sangre , Anticolesterolemiantes/farmacocinética , Arritmias Cardíacas/inducido químicamente , Estudios de Cohortes , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Drogas en Investigación/efectos adversos , Drogas en Investigación/farmacocinética , Electrocardiografía/efectos de los fármacos , Femenino , Fluoroquinolonas/administración & dosificación , Fluoroquinolonas/efectos adversos , Fluoroquinolonas/sangre , Fluoroquinolonas/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Moxifloxacino , Oxazolidinonas/efectos adversos , Oxazolidinonas/sangre , Oxazolidinonas/farmacocinética , Inhibidores de Topoisomerasa II/administración & dosificación , Inhibidores de Topoisomerasa II/efectos adversos , Inhibidores de Topoisomerasa II/sangre , Inhibidores de Topoisomerasa II/farmacocinética , Adulto Joven

RESUMEN

Combination therapy is increasingly being utilized for the treatment of metastatic breast cancer. However, coadministration of drugs, particularly agents that are substrates for or inhibitors of p-glycoprotein, can result in increased tissue toxicity. Unfortunately, determination of levels of chemotherapeutics in human tissues is challenging, and plasma drug concentrations are not always indicative of tissue toxicokinetics or toxicodynamics, especially when tissue penetration is altered. The aim of the present work was to determine whether concomitant administration of compounds currently being combined in clinical trials for metastatic breast cancer treatment alters plasma and tissue pharmacokinetics in mice if both agents are p-glycoprotein substrates and/or inhibitors. Accordingly, we investigated the pharmacokinetic interactions of the classic cytotoxics and p-glycoprotein substrates docetaxel and doxorubicin when administered concurrently with the targeted agent and p-glycoprotein inhibitor lapatinib. Our time-course plasma and tissue distribution studies showed that coadministration of lapatinib with doxorubicin did not appreciably alter the pharmacokinetics of this anthracycline in the plasma or six tissues evaluated in mice, presumably because, at doses relevant to human exposure, lapatinib inhibition of p-glycoprotein did not significantly alter doxorubicin transport out of these tissue compartments. However, combining lapatinib with docetaxel significantly increased intestinal exposure to this chemotherapeutic, which has clinical implications for enhancing gastrointestinal toxicity. The significant lapatinib-docetaxel interaction is likely CYP3A4-mediated, suggesting that caution should be exercised when this combination is administered, particularly to patients with compromised CYP3A activity, and recipients should be monitored closely for enhanced toxicity, particularly for adverse effects on the intestine.

Asunto(s)

Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Doxorrubicina/farmacocinética , Intestino Delgado/efectos de los fármacos , Quinazolinas/farmacocinética , Taxoides/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Ensayos Clínicos Fase I como Asunto , Citocromo P-450 CYP3A/metabolismo , Docetaxel , Doxorrubicina/efectos adversos , Doxorrubicina/sangre , Doxorrubicina/metabolismo , Interacciones Farmacológicas , Femenino , Semivida , Humanos , Intestino Delgado/metabolismo , Lapatinib , Moduladores del Transporte de Membrana/efectos adversos , Moduladores del Transporte de Membrana/sangre , Moduladores del Transporte de Membrana/metabolismo , Moduladores del Transporte de Membrana/farmacocinética , Ratones , Ratones Endogámicos , Metástasis de la Neoplasia/tratamiento farmacológico , Quinazolinas/efectos adversos , Quinazolinas/sangre , Quinazolinas/metabolismo , Taxoides/efectos adversos , Taxoides/sangre , Taxoides/metabolismo , Distribución Tisular/efectos de los fármacos , Inhibidores de Topoisomerasa II/sangre , Inhibidores de Topoisomerasa II/metabolismo , Inhibidores de Topoisomerasa II/farmacocinética , Moduladores de Tubulina/efectos adversos , Moduladores de Tubulina/sangre , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/farmacocinética

RESUMEN

Drug lipophilicity is a vital physicochemical parameter that influences drug absorption, distribution, metabolism, excretion and toxicology. A comparative study of a homologous series based on a pharmaceutically active drug represents a powerful approach to the study of the effects of drug lipophilicity. We have developed a rapid and sensitive LC-MS/MS method suitable for such a homologous series and applied it to a series of DNA binding benzonaphthyridine-based antitumour drugs of differing lipophilicity. The method used a gradient elution with a run time of 7 min for simultaneous quantitation of five analogues in a pooled sample. Method validation was carried out in plasma (human and mouse) and mouse tissues (brain, heart, kidney, liver and lung). It had a limit of quantitation of 0.001 µmol/L and was linear (0.001-0.3 µmol/L) in all matrices with acceptable intra- and inter-assay precision and accuracy. This method allowed the pharmacokinetic parameters of these compounds in mice to be related to their lipophilicity as determined by their partition coefficient (LogD). Both the plasma CL (r=0.95; P=2×10⁻7) and V(ss) (r=0.95; P=2×10⁻7) exhibited a significant positive correlation with LogD values after intravenous bolus administration to mice. Consequently the plasma mean residence time for each of these five analogues decreased with increasing lipophilicity. There was also a significant positive correlation (r=0.91; P=2×10⁻7) between LogD values and the brain to plasma AUC ratio indicating the importance of lipophilicity in the distribution of these compounds into the brain tissue.

Asunto(s)

Cromatografía Liquida , Descubrimiento de Drogas , Naftiridinas/farmacocinética , Espectrometría de Masas en Tándem , Inhibidores de Topoisomerasa II/farmacocinética , Animales , Área Bajo la Curva , Cromatografía Liquida/normas , Descubrimiento de Drogas/normas , Femenino , Humanos , Inyecciones Intravenosas , Límite de Detección , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Naftiridinas/administración & dosificación , Naftiridinas/sangre , Naftiridinas/química , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/normas , Distribución Tisular , Inhibidores de Topoisomerasa II/administración & dosificación , Inhibidores de Topoisomerasa II/sangre , Inhibidores de Topoisomerasa II/química