RESUMEN
Contezolid is a novel oxazolidinone antibiotic with a promising safety profile. Oral contezolid and its intravenous (IV) prodrug contezolid acefosamil (CZA) are in development for treatment of diabetic foot and acute bacterial skin and skin structure infections (ABSSSI). The prodrug CZA is converted to active contezolid via intermediate MRX-1352. This study aimed to provide the pharmacokinetic rationale for safe, effective, and flexible dosage regimens with initial IV CZA followed by oral contezolid. We simultaneously modeled plasma concentrations from 110 healthy volunteers and 74 phase 2 patients with ABSSSI via population pharmacokinetics (using the importance sampling estimation algorithm), and optimized dosage regimens by Monte Carlo simulations. This included data on MRX-1352, contezolid, and its metabolite MRX-1320 from 66 healthy volunteers receiving intravenous CZA (150-2400 mg) for up to 28 days, and 74 patients receiving oral contezolid [800 mg every 12 h (q12h)] for 10 days. The apparent total clearance for 800 mg oral contezolid with food was 16.0 L/h (23.4% coefficient of variation) in healthy volunteers and 17.7 L/h (53.8%) in patients. CZA was rapidly converted to MRX-1352, which subsequently transformed to contezolid. The proposed dosage regimen used an IV CZA 2000 mg loading dose with 1000 mg IV CZA q12h as maintenance dose(s), followed by 800 mg oral contezolid q12h (with food). During each 24-h period, Monte Carlo simulations predicted this regimen to achieve consistent areas under the curve of 91.9 mg·h/L (range: 76.3-106 mg·h/L) under all scenarios. Thus, this regimen was predicted to reliably achieve efficacious contezolid exposures independent of timing of switch from IV CZA to oral contezolid.IMPORTANCEThis study provides the population pharmacokinetic rationale for the dosage regimen of the intravenous (IV) prodrug contezolid acefosamil (CZA) followed by oral contezolid. We developed the first integrated population model for the pharmacokinetics of the MRX-1352 intermediate prodrug, active contezolid, and its main metabolite MRX-1320 based on data from three clinical studies in healthy volunteers and phase 2 patients. The proposed regimen was predicted to reliably achieve efficacious contezolid exposures independent of timing of switch from IV CZA to oral contezolid.
Asunto(s)
Oxazolidinonas , Profármacos , Humanos , Antibacterianos/farmacocinética , Oxazolidinonas/farmacocinética , Piridonas/farmacocinéticaRESUMEN
Contezolid is a new oxazolidinone with in vitro and in vivo activity against Mycobacterium tuberculosis comparable to that of linezolid. Pre-clinical and clinical safety studies suggest it may be less toxic than linezolid, making contezolid a potential candidate to replace linezolid in the treatment of drug-resistant tuberculosis. We evaluated the dose-ranging activity of contezolid, alone and in combination with bedaquiline and pretomanid, and compared it with linezolid at similar doses, in an established BALB/c mouse model of tuberculosis. Contezolid had an MIC of 1 µg/mL, similar to linezolid, and exhibited similar bactericidal activity in mice. Contezolid-resistant mutants selected in vitro had 32- to 64-fold increases in contezolid MIC and harbored mutations in the mce3R gene. These mutants did not display cross-resistance to linezolid. Our results indicate that contezolid has the potential to replace linezolid in regimens containing bedaquiline and pretomanid and likely other regimens.
Asunto(s)
Mycobacterium tuberculosis , Oxazolidinonas , Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis , Animales , Ratones , Linezolid/farmacología , Linezolid/uso terapéutico , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Modelos Animales de Enfermedad , Oxazolidinonas/farmacología , Oxazolidinonas/uso terapéutico , Diarilquinolinas/farmacología , Diarilquinolinas/uso terapéutico , Tuberculosis/tratamiento farmacológico , Mycobacterium tuberculosis/genética , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/microbiologíaRESUMEN
The in vitro activity of contezolid (MRX-I) against clinical isolates of Mycobacterium tuberculosis was evaluated using a microtiter broth dilution assay. MRX-I was as effective as linezolid (LZD) in vitro MRX-I and LZD were subsequently studied in BALB/c mice infected intranasally with M. tuberculosis Erdman. MRX-I and LZD at 100 mg/kg significantly reduced the bacterial load in lungs compared to the untreated early and late controls.
Asunto(s)
Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Oxazolidinonas/farmacología , Piridonas/farmacología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Animales , Carga Bacteriana/efectos de los fármacos , Modelos Animales de Enfermedad , Esquema de Medicación , Femenino , Humanos , Isoniazida/farmacología , Linezolid/farmacología , Pulmón/efectos de los fármacos , Pulmón/microbiología , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/crecimiento & desarrollo , Mycobacterium tuberculosis/aislamiento & purificación , Tetrazoles/farmacología , Tuberculosis Resistente a Múltiples Medicamentos/microbiologíaRESUMEN
A multipart phase 1 study was conducted to determine the safety, tolerability, pharmacokinetics, and food effect of the novel oral oxazolidinone, MRX-I, in healthy adults, as well as the tolerability of longer-term exposure of both oral MRX-I and linezolid. Thirty subjects in part 1 received single ascending doses of MRX-I or placebo under fasting or fed condition in a double-blind crossover design. Twelve subjects in part 2 received MRX-I at 800 mg every 12 h (q12h) for 14 days in a double-blind, placebo-controlled design. In part 3, 24 subjects were randomized to receive 28 days of MRX-I at 800 mg q12h or oral linezolid at 600 mg q12h for 28 days in a double-blind, double-dummy design. Oral MRX-I was associated with a greater bioavailability and exposure when administered with food, and minimal accumulation of MRX-I occurred after multiple-dose administration. Oral MRX-I was well tolerated at single doses of up to 1,200 and 800 mg q12h for up to 28 days; all adverse events were mild to moderate in severity, and there was no drug discontinuation due to adverse events. These data support further clinical development of oral MRX-I in the treatment of resistant Gram-positive bacterial infections.
Asunto(s)
Antibacterianos/farmacocinética , Interacciones Alimento-Droga , Linezolid/farmacocinética , Modelos Estadísticos , Oxazolidinonas/farmacocinética , Piridonas/farmacocinética , Administración Oral , Adulto , Antibacterianos/sangre , Área Bajo la Curva , Disponibilidad Biológica , Índice de Masa Corporal , Estudios Cruzados , Método Doble Ciego , Esquema de Medicación , Cálculo de Dosificación de Drogas , Ayuno , Femenino , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/microbiología , Voluntarios Sanos , Humanos , Linezolid/sangre , Masculino , Oxazolidinonas/sangre , Seguridad del Paciente , Piridonas/sangreRESUMEN
The mechanism of action of AFN-1252, a selective inhibitor of Staphylococcus aureus enoyl-acyl carrier protein reductase (FabI), which is involved in fatty acid biosynthesis, was confirmed by using biochemistry, macromolecular synthesis, genetics, and cocrystallization of an AFN-1252-FabI complex. AFN-1252 demonstrated a low propensity for spontaneous resistance development and a time-dependent reduction of the viability of both methicillin-susceptible and methicillin-resistant S. aureus, achieving a ≥2-log(10) reduction in S. aureus counts over 24 h, and was extremely potent against clinical isolates of S. aureus (MIC(90), 0.015 µg/ml) and coagulase-negative staphylococci (MIC(90), 0.12 µg/ml), regardless of their drug resistance, hospital- or community-associated origin, or other clinical subgroup. AFN-1252 was orally available in mouse pharmacokinetic studies, and a single oral dose of 1 mg/kg AFN-1252 was efficacious in a mouse model of septicemia, providing 100% protection from an otherwise lethal peritoneal infection of S. aureus Smith. A median effective dose of 0.15 mg/kg indicated that AFN-1252 was 12 to 24 times more potent than linezolid in the model. These studies, demonstrating a selective mode of action, potent in vitro activity, and in vivo efficacy, support the continued investigation of AFN-1252 as a targeted therapeutic for staphylococcal infections.
Asunto(s)
Antibacterianos/uso terapéutico , Proteínas Bacterianas/antagonistas & inhibidores , Benzofuranos/uso terapéutico , Enoil-ACP Reductasa (NADH)/antagonistas & inhibidores , Pironas/uso terapéutico , Sepsis/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Administración Oral , Animales , Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Benzofuranos/farmacología , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/microbiología , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/microbiología , Esquema de Medicación , Enoil-ACP Reductasa (NADH)/metabolismo , Femenino , Humanos , Cinética , Ratones , Pruebas de Sensibilidad Microbiana , Pironas/farmacología , Sepsis/microbiología , Sepsis/mortalidad , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/enzimología , Staphylococcus aureus/crecimiento & desarrollo , Tasa de SupervivenciaRESUMEN
AFN-1252, a potent inhibitor of enoyl-acyl carrier protein reductase (FabI), inhibited all clinical isolates of Staphylococcus aureus (n = 502) and Staphylococcus epidermidis (n = 51) tested, including methicillin (meticillin)-resistant isolates, at concentrations of
Asunto(s)
Antibacterianos/farmacología , Benzofuranos/farmacología , Enoil-ACP Reductasa (NADH)/antagonistas & inhibidores , Pironas/farmacología , Staphylococcus/efectos de los fármacos , Staphylococcus/enzimología , Enterobacteriaceae/efectos de los fármacos , Enterobacteriaceae/enzimología , Enterococcus/efectos de los fármacos , Enterococcus/enzimología , Pruebas de Sensibilidad Microbiana , Moraxella catarrhalis/efectos de los fármacos , Moraxella catarrhalis/enzimología , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Staphylococcus epidermidis/efectos de los fármacos , Staphylococcus epidermidis/enzimología , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/enzimologíaRESUMEN
BACKGROUND: AFN-1252 is a novel inhibitor of FabI, which is essential in Staphylococcus spp. This study evaluated the safety, tolerability and pharmacokinetics of multiple oral doses of AFN-1252 immediate-release tablets. METHODS: Part I evaluated AFN-1252 as a single 200 mg dose in fed versus fasted subjects. Part II evaluated 200, 300 and 400 mg doses of AFN-1252 administered once-daily for 10 days. RESULTS: Pharmacokinetics indicated good absorption with a median Tmax of 2-3 hours, and a mean t1/2 of 7-10 hours, for all doses. Cmax and AUC responses were non-linear. A high-fat meal reduced AUC0-t and Cmax values by 62% and 48%, respectively, and delayed Tmax by 2.5 hours. All adverse events, including possibly drug-related headache and nausea, were mild or moderate. CONCLUSIONS: Multiple ascending doses of AFN-1252 were safe and well tolerated. AFN-1252 has potential for once- or twice-daily dosing in the treatment of staphylococcal infections.
Asunto(s)
Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Benzofuranos/efectos adversos , Benzofuranos/farmacocinética , Pironas/efectos adversos , Pironas/farmacocinética , Administración Oral , Adolescente , Adulto , Antibacterianos/administración & dosificación , Área Bajo la Curva , Benzofuranos/administración & dosificación , Estudios de Cohortes , Estudios Cruzados , Ayuno , Femenino , Voluntarios Sanos , Humanos , Masculino , Pironas/administración & dosificación , Comprimidos , Distribución Tisular , Adulto JovenRESUMEN
AIMS: AFN-1252 is a novel inhibitor of FabI, an essential enzyme in Staphylococcus spp. This study was undertaken to assess the safety, tolerability and pharmacokinetic properties of AFN-1252, following oral administration in an ascending dose trial. MATERIALS & METHODS: This was a double-blind, randomized, placebo-controlled, two-part study. In Part I, single doses (QD) of 100, 200, 300, or 400 mg AFN-1252 were administered. In Part II, subjects received 200, 400, 600, or 800 mg (total daily dose) where 100, 200 and 400-mg doses were given twice in one day. RESULTS: AFN-1252 was well-absorbed with Cmax at 3-4 h when given once per day and 2.5-9 h when dosed twice in a single dosing day. T½ ranged from 8 to 11 h. Total and peak exposures of AFN-1252 increased nonlinearly. Adverse events were primarily mild and resolved promptly. CONCLUSIONS: Oral doses of AFN-1252 were safe and well tolerated. AFN-1252 has the potential for once or twice-a-day dosing for treatment of staphylococcal infections.
Asunto(s)
Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Benzofuranos/efectos adversos , Benzofuranos/farmacocinética , Pironas/efectos adversos , Pironas/farmacocinética , Administración Oral , Adolescente , Adulto , Antibacterianos/administración & dosificación , Benzofuranos/administración & dosificación , Método Doble Ciego , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Pironas/administración & dosificación , Comprimidos/administración & dosificación , Comprimidos/efectos adversos , Comprimidos/farmacocinética , Adulto JovenRESUMEN
Linezolid, the first available member of a new antibiotic class, the oxazolidinones, is broadly active against gram-positive bacteria, including drug-resistant strains. In this randomized, open-label trial, hospitalized adults with known or suspected methicillin-resistant Staphylococcus aureus (MRSA) infections were treated with linezolid (600 mg twice daily; n=240) or vancomycin (1 g twice daily; n=220) for 7-28 days. S. aureus was isolated from 53% of patients; 93% of these isolates were MRSA. Skin and soft-tissue infection was the most common diagnosis, followed by pneumonia and urinary tract infection. At the test-of-cure visit (15-21 days after the end of therapy), among evaluable patients with MRSA, there was no statistical difference between the 2 treatment groups with respect to clinical cure rates (73.2% of patients in the linezolid group and 73.1% in the vancomycin group) or microbiological success rates (58.9% in the linezolid group and 63.2% in the vancomycin group). Both regimens were well tolerated, with similar rates of adverse events.
Asunto(s)
Acetamidas/uso terapéutico , Antibacterianos/uso terapéutico , Oxazolidinonas/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus , Vancomicina/uso terapéutico , Acetamidas/efectos adversos , Antibacterianos/efectos adversos , Femenino , Humanos , Linezolid , Masculino , Resistencia a la Meticilina , Persona de Mediana Edad , Oxazolidinonas/efectos adversos , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Resultado del Tratamiento , Vancomicina/efectos adversosRESUMEN
OBJECTIVES: To investigate the absorption, distribution, metabolism and excretion of AFN-1252, a novel inhibitor of the essential FabI enzyme in Staphylococcus spp., in vitro and following microdosing in healthy adult male subjects following intravenous and oral administration. METHODS: Three ADME studies, comprising a Caco-2 assay, a rat intestinal perfusion model and a microdosing study in healthy human volunteers, were conducted. RESULTS: The Caco-2 assay indicated that AFN-1252 in solution is well-absorbed and undergoes insignificant efflux, and its transport across the intestinal wall is probably passive. In the rat intestinal perfusion model, AFN-1252 exhibited high permeability potential across three segments, in the rank order of jejunum=ileum>colon. Taken together with the low aqueous solubility, the data from these studies indicate that AFN-1252 is a BCS Class II molecule with solubility-limited absorption. Analysis of the [(14)C]-AFN-1252 radioactivity concentration-time data indicated similar pharmacokinetics following intravenous and oral administration in the microdosing study in healthy volunteers. These included long terminal half-lives of â¼7 h and 83% bioavailability, indicating that there was little first-pass metabolism following oral dosing. AFN-1252 exhibited good distribution to skin and skin structures where its anti-staphylococcal activity may be required. Urinary and faecal excretion are major elimination routes for [(14)C]-AFN-1252 following intravenous or oral administration. CONCLUSIONS: AFN-1252 has the potential for both intravenous and oral administration, once- or twice-daily dosing and good tissue distribution in humans. Further safety, efficacy and pharmacokinetic studies in man are required to investigate therapeutically-relevant doses for this novel agent and its targeted selectivity and high potency against Staphylococcus spp.
Asunto(s)
Antibacterianos/administración & dosificación , Benzofuranos/administración & dosificación , Pironas/administración & dosificación , Absorción , Adolescente , Adulto , Animales , Antibacterianos/sangre , Antibacterianos/farmacocinética , Antibacterianos/orina , Benzofuranos/sangre , Benzofuranos/farmacocinética , Benzofuranos/orina , Vesícula/metabolismo , Células CACO-2 , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Heces/química , Humanos , Mucosa Intestinal/metabolismo , Masculino , Persona de Mediana Edad , Plasma/química , Pironas/sangre , Pironas/farmacocinética , Pironas/orina , Ratas , Ratas Sprague-Dawley , Adulto JovenRESUMEN
AFN-1252, a new antimicrobial agent, specifically and potently inhibits fatty acid synthesis in Staphylococcus aureus. We characterized in vivo pharmacokinetic and pharmacodynamic profiles of AFN-1252 administered orally to neutropenic mice inoculated in thighs (â¼10(6) CFU) with methicillin-susceptible S. aureus (MSSA) ATCC 29213. Efficacy was also assessed in mice inoculated with MSSA, hospital-acquired Methicillin-resistant Staphylococcus aureus (HA-MRSA) or community-acquired (CA)-MRSA, and administered AFN-1252 or linezolid orally. Bacterial density was determined after 24 hours and efficacy defined as the change in CFU/thigh versus untreated controls at time 0. With MSSA, antibacterial reductions of ≥1 log were observed at ≥20 mg/kg doses, with ƒAUC/minimum inhibitory concentration (MIC) best describing the pharmacodynamic profile of AFN-1252. The 80, 50 and 5% maximum effects were observed with ƒAUC/MIC values of 22·3, 17·0, and 9·6, respectively. Similar values were obtained for CA-MRSA and HA-MRSA. AFN-1252 was 4-40 fold more effective than linezolid against CA-MRSA and HA-MRSA. These data demonstrate the excellent in vivo potency of AFN-1252 against phenotypically diverse S. aureus.
Asunto(s)
Antibacterianos/farmacología , Antibacterianos/farmacocinética , Benzofuranos/farmacología , Benzofuranos/farmacocinética , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pironas/farmacología , Pironas/farmacocinética , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/metabolismo , Acetamidas/farmacología , Animales , Infecciones Comunitarias Adquiridas/tratamiento farmacológico , Infecciones Comunitarias Adquiridas/metabolismo , Infecciones Comunitarias Adquiridas/microbiología , Femenino , Linezolid , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Oxazolidinonas/farmacología , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Muslo/microbiologíaRESUMEN
AFN-1252 is a novel inhibitor of FabI, an essential enzyme in fatty acid biosynthesis in Staphylococcus spp. AFN-1252 exhibits typical MIC(90) values of ≤0·015 µg/ml against diverse clinical isolates of S. aureus, oral absorption, long elimination half-live and efficacy in animal models. We now report high binding (â¼95%) to serum proteins of mouse, rat, dog and humans, associated with an eight-fold increase in minimal inhibitory concentration (MIC) and which may be responsible for the long elimination half-lives on pharmacokinetic studies. Unlike daptomycin, AFN-1252 activity is not reduced in the presence of lung surfactant. AFN-1252 exhibits a short post-antibiotic effect of 1·1 hours against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) following a 4-hour exposure period. The AFN-1252 unique spectrum of activity is not compromised by interactions with major antibiotic classes, but demonstrates synergy with low concentrations of gentamicin against MSSA and MRSA. These studies support the continued investigation of AFN-1252 as a targeted therapeutic for staphylococcal infections.
Asunto(s)
Antibacterianos/sangre , Antibacterianos/farmacología , Benzofuranos/sangre , Benzofuranos/farmacología , Proteínas Sanguíneas/metabolismo , Pironas/sangre , Pironas/farmacología , Animales , Daptomicina/sangre , Daptomicina/farmacología , Perros , Gentamicinas/sangre , Gentamicinas/farmacología , Semivida , Humanos , Masculino , Meticilina/sangre , Meticilina/farmacología , Resistencia a la Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Ratones , Pruebas de Sensibilidad Microbiana , Surfactantes Pulmonares/metabolismo , Ratas , Infecciones Estafilocócicas/metabolismo , Staphylococcus aureus/efectos de los fármacosRESUMEN
Linezolid has been associated with reversible myelosuppression. Clinical trial data were evaluated for anemia, thrombocytopenia, and neutropenia. Thrombocytopenia and a slight increased risk for anemia were evident at > or =2 weeks of linezolid treatment. Hematologic abnormalities were consistent with mild, reversible, duration-dependent myelosuppression. Appropriate monitoring is warranted with linezolid use.
Asunto(s)
Acetamidas/efectos adversos , Anemia/sangre , Anemia/inducido químicamente , Antiinfecciosos/efectos adversos , Oxazolidinonas/efectos adversos , Recuento de Células Sanguíneas , Ensayos Clínicos como Asunto , Hemoglobinas/metabolismo , Humanos , Linezolid , Neutropenia/sangre , Neutropenia/inducido químicamente , Estudios Retrospectivos , Trombocitopenia/sangre , Trombocitopenia/inducido químicamenteRESUMEN
Linezolid, an oxazolidinone antibiotic, has 100% oral bioavailability and favorable activities against gram-positive pathogens including multidrug-resistant staphylococci, enterococci, and pneumococci. Safety assessments were conducted for 2,046 linezolid-treated patients and 2,001 comparator drug-treated patients from seven controlled clinical trials comparing the activities of linezolid and comparator drugs against nosocomial and community-acquired pneumonia, skin and skin structure infections, and methicillin-resistant staphylococcal infections. Drug-related adverse events were primarily transient. The most frequent (> or = 2%) adverse events caused by linezolid and the comparator drugs were diarrhea (4.3 and 3.2%, respectively; P = 0.074), nausea (3.4 and 2.3%, respectively; P = 0.036), and headache (2.2 and 1.3%, respectively; P = 0.047). Treatment discontinuations due to drug-related events (2.4 and 1.9%, respectively), serious adverse events (11.4 and 10.6%, respectively), and deaths (4.8 and 4.9%, respectively) were similar. No clinically significant drug-related hematologic events were reported, and laboratory safety data were comparable. In the first 6 months of postmarketing surveillance, hematologic abnormalities were reported in 0.1% of linezolid-treated patients, but no irreversible blood dyscrasias were documented. The risk for transient, reversible hematologic effects from treatment with linezolid should be considered together with the clinical benefits associated with its use.