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1.
Br J Cancer ; 123(9): 1360-1369, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32741975

RESUMEN

BACKGROUND: BAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents. METHODS: This two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. The MTD was determined using a modified accelerated titration design in phase I. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D). RESULTS: Seventy-three patients received BAL101553 at doses of 15-80 mg/m2 (phase 1, n = 24; phase 2a, n = 49). The MTD was 60 mg/m2; DLTs observed at doses ≥60 mg/m2 were reversible Grade 2-3 gait disturbance with Grade 2 peripheral sensory neuropathy. In phase 2a, asymptomatic myocardial injury was observed at doses ≥45 mg/m2. The RP2D for 2-h intravenous infusion was 30 mg/m2. The overall disease control rate was 26.3% in the efficacy population. CONCLUSIONS: The RP2D for 2-h infusion of BAL101553 was well tolerated. Dose-limiting neurological and myocardial side effects were consistent with the agent's vascular-disrupting properties. CLINICAL TRIAL REGISTRATION: EudraCT: 2010-024237-23.


Asunto(s)
Bencimidazoles/administración & dosificación , Neoplasias/tratamiento farmacológico , Oxadiazoles/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Progresión de la Enfermedad , Femenino , Humanos , Infusiones Intravenosas , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Oxadiazoles/efectos adversos , Oxadiazoles/farmacocinética , Profármacos/administración & dosificación , Profármacos/efectos adversos , Profármacos/farmacocinética , Huso Acromático/efectos de los fármacos , Reino Unido
2.
Mycoses ; 61(7): 485-497, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-29611227

RESUMEN

The optimal approach to treat invasive fungal disease (IFD) caused by more than one fungal species is unknown. We documented the efficacy and safety of isavuconazole for treatment of IFDs caused by more than one fungal species. VITAL was a single-arm, international, open-label study evaluating the efficacy and safety of isavuconazole (200 mg orally or intravenously every 8 hours for 48 hours, then once daily) for treatment of rare IFDs. The primary outcome was the overall response at Day 42; key secondary outcomes were overall responses at Day 84 and end of treatment (EOT), mortality at Days 42 and 84, and safety. This analysis includes patients with IFD caused by multiple fungal species. Fifteen patients were included in this analysis (including Aspergillus spp., n = 11; without Aspergillus spp., n = 4); median treatment duration was 97 days [range, 6-544] days). Overall treatment success was observed in 2/15 patients (13.3%) at Days 42 and 84, and 2/14 (14.3%) at EOT. All-cause mortality was 2/15 (13.3%) at Day 42 and 4/15 (26.7%) at Day 84. All patients had ≥1 treatment-emergent adverse event (TEAE); 12 patients (80.0%) had serious TEAEs; TEAEs led to discontinuation of isavuconazole in two patients (13.3%). Isavuconazole may be useful to treat some IFDs caused by multiple fungal species.


Asunto(s)
Antifúngicos/uso terapéutico , Coinfección/tratamiento farmacológico , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/microbiología , Nitrilos/uso terapéutico , Piridinas/uso terapéutico , Triazoles/uso terapéutico , Administración Intravenosa , Adulto , Anciano , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Aspergilosis/tratamiento farmacológico , Aspergillus/efectos de los fármacos , Coinfección/microbiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Infecciones Fúngicas Invasoras/mortalidad , Masculino , Persona de Mediana Edad , Mucorales/efectos de los fármacos , Mucormicosis/tratamiento farmacológico , Nitrilos/administración & dosificación , Nitrilos/efectos adversos , Piridinas/administración & dosificación , Piridinas/efectos adversos , Resultado del Tratamiento , Triazoles/administración & dosificación , Triazoles/efectos adversos
3.
Mycoses ; 61(8): 518-533, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29611246

RESUMEN

Data regarding treatment of rare invasive fungal diseases (IFDs) are scarce. We documented the efficacy and safety of isavuconazole for treatment of uncommonly diagnosed IFDs. VITAL was a single-arm, international, open-label study evaluating the efficacy and safety of isavuconazole (200 mg orally or intravenously every 8 hours for 48 hours, then once daily). The primary outcome was overall response at Day 42; key secondary outcomes were overall responses at Day 84 and end of treatment (EOT), mortality at Days 42 and 84, and safety. This analysis includes patients with IFD caused by rare or unidentified pathogens. Twenty-six patients with IFDs caused by rare moulds (n = 17), non-Candida yeasts (n = 2), or unidentified moulds (n = 7) were enrolled (median treatment duration [range], 114.5 [1-496]) days. Overall treatment success was observed in 11/26 (42.3%), 10/26 (38.5%), and 15/26 (57.7%) patients at Days 42, 84, and EOT, respectively. All-cause mortality rates were 2/26 patients (7.7%) at Day 42 and 4/26 patients (15.4%) at Day 84; another two patients died after Day 84. All patients had ≥1 treatment-emergent adverse event (TEAE); 15 patients (57.7%) had serious TEAEs, and TEAEs led to discontinuation of isavuconazole in four patients (15.4%). Isavuconazole may be efficacious for treatment of a range of rare IFDs.


Asunto(s)
Antifúngicos/administración & dosificación , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Nitrilos/administración & dosificación , Piridinas/administración & dosificación , Triazoles/administración & dosificación , Administración Intravenosa , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antifúngicos/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nitrilos/efectos adversos , Piridinas/efectos adversos , Análisis de Supervivencia , Resultado del Tratamiento , Triazoles/efectos adversos , Adulto Joven
4.
Artículo en Inglés | MEDLINE | ID: mdl-28971866

RESUMEN

Quantitative whole-body autoradiography was used to assess the distribution and tissue penetration of isavuconazole in rats following single and repeated oral-dose administration of radiolabeled isavuconazonium sulfate, the prodrug of isavuconazole. Following a single-dose administration of radiolabeled isavuconazonium sulfate (labeled on the active moiety), radioactivity was detectable within 1 h postdose in 56 of 65 tissue/fluid specimens. The highest maximum concentrations (Cmax) were observed in bile and liver (66.6 and 24.7 µg eq/g, respectively). The lowest Cmax values were in bone and eye lens (0.070 and 0.077 µg eq/g, respectively). By 144 h postdose, radioactivity was undetectable in all tissues/fluids except liver (undetectable at 336 h) and adrenal gland tissues (undetectable at 672 h). Following daily administration for up to 21 days, 1-h-postdose Cmax values were the highest on or before day 14 in all except seven tissues/fluids, of which only rectum mucosa and small intestine mucosa had Cmax values >25% higher than all other 1-h-postdose values. For 24-h-postdose Cmax values, only large intestine, large intestine mucosa, and urine had the highest Cmax values at day 21. The penetration of single oral doses of unlabeled isavuconazole (25 mg/kg of body weight isavuconazonium sulfate) and voriconazole (50 mg/kg) into rat brain (assessed using liquid chromatography-tandem mass spectrometry) was also compared. Brain concentration/plasma concentration ratios reached approximately 1.8:1 and 2:1, respectively. These data suggest that isavuconazole penetrates most tissues rapidly, reaches a steady state in most or all tissues/fluids within 14 days, does not accumulate in tissues/fluids over time, and achieves potentially efficacious concentrations in the brain.


Asunto(s)
Encéfalo/metabolismo , Nitrilos/farmacocinética , Piridinas/farmacocinética , Triazoles/farmacocinética , Voriconazol/farmacocinética , Administración Oral , Glándulas Suprarrenales/metabolismo , Animales , Autorradiografía , Bilis/metabolismo , Huesos/metabolismo , Mucosa Intestinal/metabolismo , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Cristalino/metabolismo , Hígado/metabolismo , Masculino , Nitrilos/metabolismo , Profármacos/análisis , Profármacos/metabolismo , Piridinas/metabolismo , Ratas , Ratas Long-Evans , Ratas Sprague-Dawley , Ratas Wistar , Distribución Tisular , Triazoles/metabolismo , Voriconazol/metabolismo
5.
Lancet ; 387(10020): 760-9, 2016 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-26684607

RESUMEN

BACKGROUND: Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease. METHODS: This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1:1 ratio using an interactive voice-web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat [ITT] population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00412893. FINDINGS: 527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of -1·0% (95% CI -7·8 to 5·7). Because the upper bound of the 95% CI (5·7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p=0·122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69%]) and infections and infestations (152 [59%] vs 158 [61%]). Proportions of patients with treatment-emergent adverse events by system organ class were similar overall. However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0·016), eye disorders (39 [15%] vs 69 [27%]; p=0·002), and skin or subcutaneous tissue disorders (86 [33%] vs 110 [42%]; p=0·037). Drug-related adverse events were reported in 109 (42%) patients receiving isavuconazole and 155 (60%) receiving voriconazole (p<0·001). INTERPRETATION: Isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease. Isavuconazole was well tolerated compared with voriconazole, with fewer study-drug-related adverse events. Our results support the use of isavuconazole for the primary treatment of patients with invasive mould disease. FUNDING: Astellas Pharma Global Development, Basilea Pharmaceutica International.


Asunto(s)
Antifúngicos/uso terapéutico , Micosis/tratamiento farmacológico , Nitrilos/uso terapéutico , Piridinas/uso terapéutico , Triazoles/uso terapéutico , Voriconazol/uso terapéutico , Administración Oral , Adulto , Anciano , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Aspergilosis/tratamiento farmacológico , Aspergilosis/mortalidad , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Micosis/mortalidad , Nitrilos/administración & dosificación , Nitrilos/efectos adversos , Piridinas/administración & dosificación , Piridinas/efectos adversos , Resultado del Tratamiento , Triazoles/administración & dosificación , Triazoles/efectos adversos , Voriconazol/administración & dosificación , Voriconazol/efectos adversos
6.
Arch Toxicol ; 91(11): 3647-3662, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28536862

RESUMEN

BAL30072 is a new monocyclic ß-lactam antibiotic under development which provides a therapeutic option for the treatment of severe infections caused by multi-drug-resistant Gram-negative bacteria. Despite the absence of liver toxicity in preclinical studies in rats and marmosets and in single dose clinical studies in humans, increased transaminase activities were observed in healthy subjects in multiple-dose clinical studies. We, therefore, initiated a comprehensive program to find out the mechanisms leading to hepatocellular injury using HepG2 cells (human hepatocellular carcinoma cell line), HepaRG cells (inducible hepatocytes derived from a human hepatic progenitor cell line), and human liver microtissue preparations. Our investigations demonstrated a concentration- and time-dependent reduction of the ATP content of BAL30072-treated HepG2 cells and liver microtissues. BAL30072 impaired oxygen consumption by HepG2 cells at clinically relevant concentrations, inhibited complexes II and III of the mitochondrial electron transport chain, increased the production of reactive oxygen species (ROS), and reduced the mitochondrial membrane potential. Furthermore, BAL 30072 impaired mitochondrial fatty acid metabolism, inhibited glycolysis, and was associated with hepatocyte apoptosis. Co-administration of N-acetyl-L-cysteine partially protected hepatocytes from BAL30072-mediated toxicity, underscoring the role of oxidative damage in the observed hepatocellular toxicity. In conclusion, BAL30072 is toxic for liver mitochondria and inhibits glycolysis at clinically relevant concentrations. Impaired hepatic mitochondrial function and inhibition of glycolysis can explain liver injury observed in human subjects receiving long-term treatment with this compound.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Hepatocitos/efectos de los fármacos , Monobactamas/toxicidad , Tiazoles/toxicidad , Adenosina Trifosfato/metabolismo , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Transporte de Electrón/efectos de los fármacos , Glucólisis/efectos de los fármacos , Células Hep G2 , Humanos , Macrófagos del Hígado/efectos de los fármacos , Lipopolisacáridos/toxicidad , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Monobactamas/efectos adversos , Monobactamas/sangre , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/metabolismo , Tiazoles/efectos adversos , Tiazoles/sangre
7.
Antimicrob Agents Chemother ; 60(5): 3025-31, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-26953193

RESUMEN

Isavuconazole, administered as the prodrug isavuconazonium sulfate, was recently approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of adults with invasive aspergillosis and mucormycosis. The objective of this analysis was to develop a population pharmacokinetic model using NONMEM (version 7.2) for subjects with hepatic impairment, using intravenous and oral administration data from two hepatic studies, and to simulate concentration profiles to steady state, thus evaluating the need for dose adjustment. A two-compartment model with Weibull absorption function and first-order elimination process adequately described plasma isavuconazole concentrations. The population mean clearance in healthy subjects was 2.5 liters/h (5th and 95th percentiles: 2.0 and 3.1). The mean clearance values for subjects with mild and moderate hepatic impairment decreased approximately to 1.55 liters/h (5th and 95th percentiles: 1.3 and 1.8 liters/h) and 1.32 liters/h (5th and 95th percentiles: 1.05 and 1.35), respectively. Peripheral volume of distribution increased with body mass index. Simulations of mean concentration time profiles to steady state showed less than a 2-fold increase in mean trough concentrations for subjects with mild and moderate hepatic impairment compared with healthy subjects. After administration of the single dose, safety data for subjects with mild and moderate hepatic impairment were generally comparable to those for healthy subjects in both studies. Due to the <2-fold increase in trough concentrations and the established safety margin, dose adjustment appears to be unnecessary in subjects with mild or moderate hepatic impairment.


Asunto(s)
Hepatopatías/metabolismo , Hígado/metabolismo , Hígado/patología , Nitrilos/farmacocinética , Piridinas/farmacocinética , Triazoles/farmacocinética , Administración Oral , Femenino , Voluntarios Sanos , Humanos , Masculino , Modelos Teóricos , Nitrilos/administración & dosificación , Piridinas/administración & dosificación , Triazoles/administración & dosificación
8.
Int J Clin Pharmacol Ther ; 54(8): 572-80, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27345284

RESUMEN

OBJECTIVE/METHODS: Two openlabel, single-dose, randomized crossover studies and one open-label, multiple-dose, parallel group study in healthy volunteers were conducted with the prodrug, isavuconazonium sulfate, to determine absolute bioavailability of the active triazole, isavuconazole (EudraCT 2007-004949-15; n = 14), and the effect of food (EudraCT 2007- 004940-63; n = 26), and pH (NCT02128893; n = 24) on the absorption of isavuconazole. Isavuconazonium sulfate 744 mg designed to deliver 400 mg of the active triazole isavuconazole was administered in the absolute bioavailability (oral or intravenous (IV) (2-hour infusion)) and food-effect studies (oral). In the pH-effect study, isavuconazonium sulfate 372 mg designed to deliver 200 mg of isavuconazole was administered orally three times daily (t.i.d.) for 2 days, followed by a single daily oral dose for 3 days, in the presence of steady state esomeprazole dosed orally at 40 mg/day. RESULTS: Isavuconazole was well tolerated in each study. Bioavailability: Geometric least squares mean ratios (GLSMR; oral/IV) for isavuconazole AUC∞, and Cmax were 98% (90% confidence interval (CI): 94, 101) and 78% (90% CI: 72, 85), respectively. Food-effect: GLSMR (fed/fasted) for AUC∞ and Cmax of isavuconazole in plasma were 110% (90% CI: 102, 118) and 92% (90% CI: 86, 98), respectively. Median tmax was 5 hours with food and 3 hours under fasted conditions. pH-effect: GLSMR for isavuconazole AUCtau and Cmax were 108% (90% CI: 89, 130) and 105% (90% CI: 89, 124), respectively. CONCLUSIONS: Orally administered isavuconazonium sulfate effectively delivers isavuconazole, as evidenced by the fact that oral isavuconazole is bioequivalent to the IV formulation. Dose adjustments are not required when switching between oral and IV formulations, regardless of food or drugs that increase gastric pH.


Asunto(s)
Interacciones Alimento-Droga , Nitrilos/farmacocinética , Piridinas/farmacocinética , Triazoles/farmacocinética , Administración Intravenosa , Administración Oral , Adulto , Disponibilidad Biológica , Estudios Cruzados , Interacciones Farmacológicas , Femenino , Humanos , Concentración de Iones de Hidrógeno , Masculino , Persona de Mediana Edad , Nitrilos/administración & dosificación , Piridinas/administración & dosificación , Estómago/química , Triazoles/administración & dosificación
9.
Antimicrob Agents Chemother ; 59(4): 2078-85, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25624327

RESUMEN

Isavuconazole is a novel broad-spectrum triazole antifungal agent. This open-label dose escalation study assessed the safety and pharmacokinetics of intravenous isavuconazole prophylaxis in patients with acute myeloid leukemia who had undergone chemotherapy and had preexisting/expected neutropenia. Twenty-four patients were enrolled, and 20 patients completed the study. The patients in the low-dose cohort (n = 11) received isavuconazole loading doses on day 1 (400/200/200 mg, 6 h apart) and day 2 (200/200 mg, 12 h apart), followed by once-daily maintenance dosing (200 mg) on days 3 to 28. The loading and maintenance doses were doubled in the high-dose cohort (n = 12). The mean ± standard deviation plasma isavuconazole areas under the concentration-time curves for the dosing period on day 7 were 60.1 ± 22.3 µg · h/ml and 113.1 ± 19.6 µg · h/ml for the patients in the low-dose and high-dose cohorts, respectively. The adverse events in five patients in the low-dose cohort and in eight patients in the high-dose cohort were considered to be drug related. Most were mild to moderate in severity, and the most common adverse events were headache and rash (n = 3 each). One patient in the high-dose cohort experienced a serious adverse event (unrelated to isavuconazole treatment), and two patients each in the low-dose and high-dose cohorts discontinued the study due to adverse events. Of the 20 patients who completed the study, 18 were classified as a treatment success. In summary, the results of this analysis support the safety and tolerability of isavuconazole administered at 200 mg and 400 mg once-daily as prophylaxis in immunosuppressed patients at high risk of fungal infections. (This study is registered at ClinicalTrials.gov under registration number NCT00413439.).


Asunto(s)
Antifúngicos/farmacocinética , Antifúngicos/uso terapéutico , Leucemia Mieloide Aguda/complicaciones , Micosis/prevención & control , Neutropenia/complicaciones , Nitrilos/farmacocinética , Nitrilos/uso terapéutico , Piridinas/farmacocinética , Piridinas/uso terapéutico , Triazoles/farmacocinética , Triazoles/uso terapéutico , Adulto , Anciano , Antifúngicos/efectos adversos , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Terapia de Inmunosupresión , Masculino , Persona de Mediana Edad , Micosis/tratamiento farmacológico , Nitrilos/efectos adversos , Seguridad del Paciente , Piridinas/efectos adversos , Triazoles/efectos adversos
10.
Antimicrob Agents Chemother ; 57(5): 2047-53, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23403430

RESUMEN

Monte Carlo simulation (MCS) of antimicrobial dosage regimens during drug development to derive predicted target attainment values is frequently used to choose the optimal dose for the treatment of patients in phase 2 and 3 studies. A criticism is that pharmacokinetic (PK) parameter estimates and variability in healthy volunteers are smaller than those in patients. In this study, the initial estimates of exposure from MCS were compared with actual exposure data in patients treated with ceftobiprole in a phase 3 nosocomial-pneumonia (NP) study (NTC00210964). Results of MCS using population PK data from ceftobiprole derived from 12 healthy volunteers were used (J. W. Mouton, A. Schmitt-Hoffmann, S. Shapiro, N. Nashed, N. C. Punt, Antimicrob. Agents Chemother. 48:1713-1718, 2004). Actual individual exposures in patients were derived after building a population pharmacokinetic model and were used to calculate the individual exposure to ceftobiprole (the percentage of time the unbound concentration exceeds the MIC [percent fT > MIC]) for a range of MIC values. For the ranges of percent fT > MIC used to determine the dosage schedule in the phase 3 NP study, the MCS using data from a single phase 1 study in healthy volunteers accurately predicted the actual clinical exposure to ceftobiprole. The difference at 50% fT > MIC at an MIC of 4 mg/liter was 3.5% for PK-sampled patients. For higher values of percent fT > MIC and MICs, the MCS slightly underestimated the target attainment, probably due to extreme values in the PK profile distribution used in the simulations. The probability of target attainment based on MCS in healthy volunteers adequately predicted the actual exposures in a patient population, including severely ill patients.


Asunto(s)
Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Infección Hospitalaria/sangre , Cálculo de Dosificación de Drogas , Método de Montecarlo , Neumonía Bacteriana/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/sangre , Cefalosporinas/sangre , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase III como Asunto , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/microbiología , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/microbiología
11.
J Antimicrob Chemother ; 68(5): 1120-9, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23344577

RESUMEN

OBJECTIVES: Carbapenem resistance in Gram-negative bacteria, mediated by restricted net influx and carbapenem-hydrolysing ß-lactamases, is a growing problem. The monosulfactam antibiotic BAL30072 is stable to most carbapenemases, suggesting that it could be complementary to carbapenems. We have investigated the antimicrobial activity of BAL30072 combined with imipenem, meropenem and doripenem. METHODS: The in vitro activities of the combinations were evaluated using broth microdilution susceptibility and agar disc diffusion tests, broth dilution chequerboard titration and time-kill studies, using strains of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter with carbapenem MICs ≥ 2 mg/L. RESULTS: The combinations were effective against 70%-80% of the isolates tested in the presence of 1 mg/L of each antibiotic, whereas the carbapenems were ineffective and BAL30072 alone was effective against 20%-40% of the strains. Synergistic effects were observed with many Enterobacteriaceae and P. aeruginosa, but were less common among the Acinetobacter, although additive effects, where the activity of one partner compensated for lack of activity of the other, were common. None of the combinations exhibited an antagonistic effect in all tests, in contrast to other ß-lactams where negative interactions were frequently observed. Animal models of septicaemia demonstrated that the synergy observed in vitro with BAL30072 and meropenem can translate into greater in vivo efficacy. CONCLUSIONS: BAL30072/carbapenem combinations were effective against a broader range of multidrug-resistant Gram-negative bacteria than either of the single agents. Additive and synergistic effects were observed in Enterobacteriaceae and P. aeruginosa, and this enhanced activity was frequently associated with suppression of resistance development. The in vitro activity translated into improved in vivo efficacy.


Asunto(s)
Acinetobacter/efectos de los fármacos , Antibacterianos/farmacología , Carbapenémicos/farmacología , Farmacorresistencia Bacteriana Múltiple , Enterobacteriaceae/efectos de los fármacos , Monobactamas/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Tiazoles/farmacología , Doripenem , Sinergismo Farmacológico , Imipenem/farmacología , Meropenem , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Tienamicinas/farmacología
12.
Neuro Oncol ; 24(3): 384-395, 2022 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-34232318

RESUMEN

BACKGROUND: Glioblastoma (GBM) is an incurable disease with few approved therapeutic interventions. Radiation therapy (RT) and temozolomide (TMZ) remain the standards of care. The efficacy and optimal deployment schedule of the orally bioavailable small-molecule tumor checkpoint controller lisavanbulin alone, and in combination with, standards of care were assessed using a panel of IDH-wildtype GBM patient-derived xenografts. METHODS: Mice bearing intracranial tumors received lisavanbulin +/-RT +/-TMZ and followed for survival. Lisavanbulin concentrations in plasma and brain were determined by liquid chromatography with tandem mass spectrometry, while flow cytometry was used for cell cycle analysis. RESULTS: Lisavanbulin monotherapy showed significant benefit (P < .01) in 9 of 14 PDXs tested (median survival extension 9%-84%) and brain-to-plasma ratios of 1.3 and 1.6 at 2- and 6-hours postdose, respectively, validating previous data suggesting significant exposure in the brain. Prolonged lisavanbulin dosing from RT start until moribund was required for maximal benefit (GBM6: median survival lisavanbulin/RT 90 vs. RT alone 69 days, P = .0001; GBM150: lisavanbulin/RT 143 days vs. RT alone 73 days, P = .06). Similar observations were seen with RT/TMZ combinations (GBM39: RT/TMZ/lisavanbulin 502 days vs. RT/TMZ 249 days, P = .0001; GBM26: RT/TMZ/lisavanbulin 172 days vs. RT/TMZ 121 days, P = .04). Immunohistochemical analyses showed a significant increase in phospho-histone H3 with lisavanbulin treatment (P = .01). CONCLUSIONS: Lisavanbulin demonstrated excellent brain penetration, significant extension of survival alone or in RT or RT/TMZ combinations, and was associated with mitotic arrest. These data provide a strong clinical rationale for testing lisavanbulin in combination with RT or RT/TMZ in GBM patients.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Animales , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/patología , Glioblastoma/patología , Xenoinjertos , Humanos , Ratones , Microtúbulos/metabolismo , Microtúbulos/patología , Temozolomida/uso terapéutico
13.
Antimicrob Agents Chemother ; 55(4): 1510-9, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21245441

RESUMEN

BAL30376 is a triple combination comprising a siderophore monobactam, BAL19764; a novel bridged monobactam, BAL29880, which specifically inhibits class C ß-lactamases; and clavulanic acid, which inhibits many class A and some class D ß-lactamases. The MIC(90) was ≤ 4 µg/ml (expressed as the concentration of BAL19764) for most species of the Enterobacteriaceae family, including strains that produced metallo-ß-lactamases and were resistant to all of the other ß-lactams tested. The MIC(90) for Stenotrophomonas maltophilia was 2 µg/ml, for multidrug-resistant (MDR) Pseudomonas aeruginosa it was 8 µg/ml, and for MDR Acinetobacter and Burkholderia spp. it was 16 µg/ml. The presence of the class C ß-lactamase inhibitor BAL29880 contributed significantly to the activity of BAL30376 against strains of Citrobacter freundii, Enterobacter species, Serratia marcescens, and P. aeruginosa. The presence of clavulanic acid contributed significantly to the activity against many strains of Escherichia coli and Klebsiella pneumoniae that produced class A extended-spectrum ß-lactamases. The activity of BAL30376 against strains with metallo-ß-lactamases was largely attributable to the intrinsic stability of the monobactam BAL19764 toward these enzymes. Considering its three components, BAL30376 was unexpectedly refractory toward the development of stable resistance.


Asunto(s)
Antibacterianos/farmacología , Ácido Clavulánico/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Monobactamas/farmacología , Compuestos de Fenilurea/farmacología , Inhibidores de beta-Lactamasas , Animales , Citrobacter freundii/efectos de los fármacos , Enterobacter/efectos de los fármacos , Bacterias Gramnegativas/patogenicidad , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Klebsiella pneumoniae/efectos de los fármacos , Masculino , Ratones , Pseudomonas aeruginosa/efectos de los fármacos , Sepsis/tratamiento farmacológico , Sepsis/microbiología , Serratia marcescens/efectos de los fármacos
14.
Antimicrob Agents Chemother ; 53(9): 3620-7, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19546364

RESUMEN

Racemic 2,4-diaminopyrimidine dihydrophthalazine derivatives BAL0030543, BAL0030544, and BAL0030545 exhibited low in vitro MICs toward small, selected panels of Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Moraxella catarrhalis, and Mycobacterium avium, though the compounds were less active against Haemophilus influenzae. The constellation of dihydrofolate reductases (DHFRs) present in 20 enterococci and 40 staphylococci was analyzed and correlated with the antibacterial activities of the dihydrophthalazines and trimethoprim. DHFRs encoded by dfrB, dfrA (S1 isozyme), dfrE, and folA were susceptible to the dihydrophthalazines, whereas DHFRs encoded by dfrG (S3 isozyme) and dfrF were not. Studies with the separated enantiomers of BAL0030543, BAL0030544, and BAL0030545 revealed preferential inhibition of susceptible DHFRs by the (R)-enantiomers. BAL0030543, BAL0030544, and BAL0030545 were well tolerated by mice during 5- and 10-day oral toxicity studies at doses of up to 400 mg/kg of body weight. Using a nonoptimized formulation, the dihydrophthalazines displayed acceptable oral bioavailabilities in mice, and efficacy studies with a septicemia model of mice infected with trimethoprim-resistant, methicillin-resistant Staphylococcus aureus gave 50% effective dose values in the range of 1.6 to 6.25 mg/kg.


Asunto(s)
Antibacterianos/farmacología , Antibacterianos/farmacocinética , Antagonistas del Ácido Fólico/farmacología , Antagonistas del Ácido Fólico/farmacocinética , Ftalazinas/farmacología , Ftalazinas/farmacocinética , Trimetoprim/farmacología , Animales , Antibacterianos/química , Supervivencia Celular/efectos de los fármacos , Enterococcus/efectos de los fármacos , Enterococcus/enzimología , Antagonistas del Ácido Fólico/química , Haemophilus influenzae/efectos de los fármacos , Haemophilus influenzae/enzimología , Células HeLa , Humanos , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Moraxella catarrhalis/efectos de los fármacos , Moraxella catarrhalis/enzimología , Mycobacterium avium/efectos de los fármacos , Mycobacterium avium/enzimología , Ftalazinas/química , Reacción en Cadena de la Polimerasa , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/enzimología , Tetrahidrofolato Deshidrogenasa/genética , Trimetoprim/química , Trimetoprim/farmacocinética
15.
Antimicrob Agents Chemother ; 52(5): 1618-22, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18332175

RESUMEN

The pharmacokinetics and distribution into bone tissue of ceftobiprole in uninfected New Zealand White rabbits were determined after subcutaneous administration of the prodrug ceftobiprole medocaril. Serum exposure (maximum concentration of the drug in serum, trough concentration, area under the concentration-time curve) to ceftobiprole at 20 and 80 mg/kg was dose proportional, and there was no accumulation of ceftobiprole following repeated (every 6 h [q6h]) injections of the antibiotic. Ceftobiprole titers in the tibial matrix and marrow were 3.2 +/- 1.3 microg/g and 11.2 +/- 6.5 microg/g, respectively, in uninfected animals treated with 20 mg/kg of the antibiotic and 13.4 +/- 7.3 microg/g and 66.3 +/- 43.2 microg/g, respectively, in uninfected animals treated with 80 mg/kg of the antibiotic. No differences in ceftobiprole titers were observed between right and left tibiae for either bone matrix or marrow. The efficacies of 4 weeks of treatment with ceftobiprole (40 mg/kg administered subcutaneously [s.c.] q6h), vancomycin (30 mg/kg administered s.c. q12h), or linezolid (60 mg/kg administered orally q8h) were compared, using a rabbit model of methicillin-resistant Staphylococcus aureus tibial osteomyelitis. After treatment with ceftobiprole, the bacterial titers in all infected left tibiae from evaluable rabbits were below the level of detection, whereas only 73% of infected left tibiae from vancomycin- or linezolid-treated animals had bacterial titers below the level of detection; the mean titers of ceftobiprole were 3 to 5 times higher in infected left tibiae than in uninfected right tibiae. These results indicate that ceftobiprole provided effective parenteral treatment of osteomyelitis in this rabbit model.


Asunto(s)
Cefalosporinas/farmacología , Resistencia a la Meticilina , Osteomielitis/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Cefalosporinas/farmacocinética , Modelos Animales de Enfermedad , Pruebas de Sensibilidad Microbiana , Osteomielitis/metabolismo , Osteomielitis/microbiología , Conejos , Infecciones Estafilocócicas/metabolismo , Infecciones Estafilocócicas/microbiología , Tibia/efectos de los fármacos , Tibia/microbiología , Tibia/patología
16.
Clin Pharmacokinet ; 47(1): 21-33, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18076216

RESUMEN

Ceftobiprole, a beta-lactam, is the first of a new generation of broad-spectrum cephalosporins in late-stage development with activity against methicillin-resistant Staphylococcus aureus (MRSA) in addition to broad-spectrum bactericidal activity against other Gram-positive and Gram-negative pathogens. The prodrug, ceftobiprole medocaril, is converted rapidly and almost completely to the active drug, ceftobiprole, upon infusion by type A esterases. In humans, ceftobiprole binds minimally (16%) to plasma proteins, and binding is independent of the drug and protein concentrations. Its steady-state volume of distribution (18.4 L) approximates the extracellular fluid volume in humans. Ceftobiprole undergoes minimal hepatic metabolism, and the primary metabolite is the beta-lactam ring-opened hydrolysis product (open-ring metabolite). Systemic exposure of the open-ring metabolite accounts for 4% of ceftobiprole exposure following single-dose administration; approximately 5% of the dose is excreted in the urine as the metabolite. Ceftobiprole does not significantly induce or inhibit relevant cytochrome P450 enzymes and is neither a substrate nor an inhibitor of P-glycoprotein. Ceftobiprole is rapidly eliminated, primarily unchanged, by renal excretion, with a terminal elimination half-life of 3 hours; the predominant mechanism responsible for elimination is glomerular filtration, with approximately 89% of the dose being excreted as the prodrug, active drug (ceftobiprole) and open-ring metabolite. The pharmacokinetics of ceftobiprole are linear following single and multiple infusions of 125-1000 mg. Steady-state drug concentrations are attained on the first day of dosing, with no appreciable accumulation when administered three times daily (every 8 hours) and twice daily (every 12 hours) in subjects with normal renal function. Low intersubject variability has been seen across studies. Ceftobiprole exposure is slightly higher (~15%) in females than in males; this difference has been attributed to bodyweight. However, the pharmacodynamics of ceftobiprole are similar in males and females, and dosing adjustments are not required based on gender. In patients with moderate to severe renal impairment, systemic clearance of ceftobiprole correlated well with creatinine clearance. For these patients, dose adjustments for the treatment of infections caused by target pathogens, including MRSA, should be based on creatinine clearance. Ceftobiprole is undergoing clinical evaluation in phase III trials in patients with complicated skin and skin structure infections, patients with nosocomial pneumonia, and community-acquired pneumonia in hospitalized patients.


Asunto(s)
Cefalosporinas/farmacocinética , Resistencia a la Meticilina/efectos de los fármacos , Animales , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Cefalosporinas/química , Cefalosporinas/uso terapéutico , Ensayos Clínicos Fase III como Asunto , Bacterias Gramnegativas/clasificación , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/clasificación , Bacterias Grampositivas/efectos de los fármacos , Humanos , Estructura Molecular
17.
Clin Transl Sci ; 11(5): 498-505, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29877622

RESUMEN

Elevations of liver enzymes have been observed in clinical trials with BAL30072, a novel antibiotic. In vitro assays have identified potential mechanisms for the observed hepatotoxicity, including electron transport chain (ETC) inhibition and reactive oxygen species (ROS) generation. DILIsym, a quantitative systems pharmacology (QSP) model of drug-induced liver injury, has been used to predict the likelihood that each mechanism explains the observed toxicity. DILIsym was also used to predict the safety margin for a novel BAL30072 dosing scheme; it was predicted to be low. DILIsym was then used to recommend potential modifications to this dosing scheme; weight-adjusted dosing and a requirement to assay plasma alanine aminotransferase (ALT) daily and stop dosing as soon as ALT increases were observed improved the predicted safety margin of BAL30072 and decreased the predicted likelihood of severe injury. This research demonstrates a potential application for QSP modeling in improving the safety profile of candidate drugs.


Asunto(s)
Antibacterianos/efectos adversos , Antibacterianos/farmacología , Modelos Biológicos , Simulación por Computador , Relación Dosis-Respuesta a Droga , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo
18.
Clin Pharmacol Drug Dev ; 6(1): 44-53, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27273461

RESUMEN

This report describes the phase 1 trials that evaluated the metabolism of the novel triazole antifungal isavuconazole by cytochrome P450 3A4 (CYP3A4) and isavuconazole's effects on CYP3A4-mediated metabolism in healthy adults. Coadministration of oral isavuconazole (100 mg once daily) with oral rifampin (600 mg once daily; CYP3A4 inducer) decreased isavuconazole area under the concentration-time curve (AUCτ ) during a dosing interval by 90% and maximum concentration (Cmax ) by 75%. Conversely, coadministration of isavuconazole (200 mg single dose) with oral ketoconazole (200 mg twice daily; CYP3A4 inhibitor) increased isavuconazole AUC from time 0 to infinity (AUC0-∞ ) and Cmax by 422% and 9%, respectively. Isavuconazole was coadministered (200 mg 3 times daily for 2 days, then 200 mg once daily) with single doses of oral midazolam (3 mg; CYP3A4 substrate) or ethinyl estradiol/norethindrone (35 µg/1 mg; CYP3A4 substrate). Following coadministration, AUC0-∞ increased 103% for midazolam, 8% for ethinyl estradiol, and 16% for norethindrone; Cmax increased by 72%, 14%, and 6%, respectively. Most adverse events were mild to moderate in intensity; there were no deaths, and serious adverse events and adverse events leading to study discontinuation were rare. These results indicate that isavuconazole is a sensitive substrate and moderate inhibitor of CYP3A4.


Asunto(s)
Antifúngicos/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Cetoconazol/administración & dosificación , Midazolam/administración & dosificación , Nitrilos/farmacocinética , Piridinas/farmacocinética , Rifampin/administración & dosificación , Triazoles/farmacocinética , Adulto , Antifúngicos/administración & dosificación , Área Bajo la Curva , Estudios Cruzados , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Nitrilos/administración & dosificación , Noretindrona/administración & dosificación , Piridinas/administración & dosificación , Triazoles/administración & dosificación
19.
J Mass Spectrom ; 41(7): 903-10, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16810647

RESUMEN

The metabolic profile of BAL4815, an antifungal azole drug, was determined using in vitro rat hepatocyte incubations and subsequent analysis by capillary LC-qTof-MS and MS/MS including accurate mass determination. For the detection of the metabolites, a mixture of the drug and its deuterium-labelled analogue was used for incubations. Metabolic stability of BAL4815 was high in cultured rat hepatocytes. However, several low-abundant metabolites were detected by the use of capillary LC-qTof-MS and manual investigation of the data. The peak intensity of the most abundant metabolite was close to the limit of detection. Except for an apparent oxidation product, the masses of the other detected metabolites could not be assigned to a single and frequently occurring biotransformation. Accurate mass determination and possible elemental compositions suggested that metabolism occurred through a combination of glutathionylation and defluorination. This was verified using accurate mass MS/MS. The use of accurate mass measurements and the derived suggestions for the elemental compositions were essential to elucidate this atypical metabolic pathway. A mass accuracy better than 8 ppm could be achieved for most assigned MS and MS/MS signals with intensities less than 6 cps in the spectra.


Asunto(s)
Antifúngicos/química , Hepatocitos/metabolismo , Nitrilos/química , Nitrilos/metabolismo , Triazoles/química , Triazoles/metabolismo , Animales , Antifúngicos/aislamiento & purificación , Acción Capilar , Cromatografía Liquida/métodos , Deuterio , Marcaje Isotópico , Masculino , Espectrometría de Masas/métodos , Modelos Moleculares , Nitrilos/aislamiento & purificación , Ratas , Ratas Wistar , Espectrometría de Masa por Ionización de Electrospray/métodos , Triazoles/aislamiento & purificación
20.
J Med Chem ; 47(6): 1487-513, 2004 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-14998336

RESUMEN

Cyclothialidine (1, Ro 09-1437) is a potent DNA gyrase inhibitor that was isolated from Streptomyces filipinensis NR0484 and is a member of a new family of natural products. It acts by competitively inhibiting the ATPase activity exerted by the B subunit of DNA gyrase but barely exhibits any growth inhibitory activity against intact bacterial cells, presumably due to insufficient permeation of the cytoplasmic membrane. To explore the antibacterial potential of 1, we developed a flexible synthetic route allowing for the systematic modification of its structure. From a first set of analogues, structure-activity relationships (SAR) were established for different substitution patterns, and the 14-hydroxylated, bicyclic core (X) of 1 seemed to be the structural prerequisite for DNA gyrase inhibitory activity. The variation of the lactone ring size, however, revealed that activity can be found among 11- to 16-membered lactones, and even seco-analogues were shown to maintain some enzyme inhibitory properties, thereby reducing the minimal structural requirements to a rather simple, hydroxylated benzyl sulfide (XI). On the basis of these "minimal structures" a modification program afforded a number of inhibitors that showed in vitro activity against Gram-positive bacteria. The best activities were displayed by 14-membered lactones, and representatives of this subclass exhibit excellent and broad in vitro antibacterial activity against Gram-positive pathogens, including Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis, and overcome resistance against clinically used drugs. By improving the pharmacokinetic properties of the most active compounds (94, 97), in particular by lowering their lipophilic properties, we were able to identify congeners of cyclothialidine (1) that showed efficacy in vivo.


Asunto(s)
Antibacterianos/síntesis química , Lactamas/síntesis química , Lactonas/síntesis química , Oxadiazoles/síntesis química , Péptidos Cíclicos/síntesis química , Inhibidores de Topoisomerasa II , Animales , Antibacterianos/química , Antibacterianos/farmacología , Girasa de ADN/química , Farmacorresistencia Bacteriana Múltiple , Bacterias Grampositivas/efectos de los fármacos , Células HeLa , Humanos , Lactamas/química , Lactamas/farmacología , Lactonas/química , Lactonas/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Oxadiazoles/química , Oxadiazoles/farmacología , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Subunidades de Proteína/antagonistas & inhibidores , Infecciones Estafilocócicas/tratamiento farmacológico , Estereoisomerismo , Relación Estructura-Actividad , Pruebas de Toxicidad
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