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1.
Bioanalysis ; 11(15): 1419-1435, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31490107

RESUMO

Aim: To develop a bioanalytical method to support pharmacokinetic evaluation of DNDI-VL-2098 in mouse, rat, dog and hamster following oral administration. Results & methodology: A robust LC-MS/MS bioanalytical method was developed to quantify DNDI-VL-2098. DNDI-VL-2098 showed time-dependent recovery loss in acetonitrile precipitated plasma in all species. Acid-lysed whole blood was identified as a matrix in which recovery was stable over time. A two-step extraction procedure was used, with protein precipitation followed by liquid-liquid extraction with methyl tert-butyl ether. The assay was validated in the dynamic range of 5-5000 ng/ml for mouse, rat and dog blood, and a fit-for-purpose method was developed for hamster. Conclusion: A specific LC-MS/MS assay for DNDI-VL-2098 was developed and validated in hemolyzed blood.


Assuntos
Análise Química do Sangue/métodos , Cromatografia Líquida/métodos , Nitroimidazóis/sangue , Oxazóis/sangue , Espectrometria de Massas em Tandem/métodos , Métodos Analíticos de Preparação de Amostras , Animais , Cricetinae , Marcação por Isótopo , Camundongos , Ratos
2.
J Pharmacol Exp Ther ; 369(3): 337-344, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30886125

RESUMO

Nemiralisib (GSK2269557), a potent inhaled inhibitor of phosphoinositide 3-kinase δ (PI3Kδ), is being developed for the treatment of respiratory disorders including chronic obstructive pulmonary disease. Determining the pharmacokinetic (PK) and pharmacodynamic (PD) responses of inhaled drugs early during drug development is key to informing the appropriate dose and preferred dose regimen in patients. We set out to measure PD changes in induced sputum in combination with drug concentrations in plasma and bronchoalveolar lavage (BAL) taken from healthy smokers (n = 56) treated for up to 14 days with increasing doses of inhaled nemiralisib (0.1-6.4 mg). Induced sputum analysis demonstrated a dose-dependent reduction in phosphatidylinositol-(4,5)-trisphosphate (PIP3, the product of PI3K activation), with a maximum placebo-corrected reduction of 23% (90% confidence interval [CI], 11%-34%) and 36% (90% CI, 11%-64%) after a single dose or after 14 days of treatment with nemiralisib, respectively (2 mg, once daily). Plasma analysis suggested a linear PK relationship with an observed accumulation of ∼3- to 4.5-fold (peak vs. trough) in plasma exposure after 14 days of nemiralisib treatment. The BAL analysis at trough confirmed higher levels of the drug in the lungs versus plasma (32-fold in the BAL fluid component, and 214-fold in the BAL cellular fraction). A comparison of the drug levels in plasma and the reductions in sputum PIP3 showed a direct relationship between exposure and PIP3 reduction. These results demonstrated target engagement upon treatment with inhaled nemiralisib and provide confidence for a once-daily dosing regimen.


Assuntos
Voluntários Saudáveis , Indazóis/farmacologia , Indazóis/farmacocinética , Indóis/farmacologia , Indóis/farmacocinética , Oxazóis/farmacologia , Oxazóis/farmacocinética , /farmacocinética , Piperazinas/farmacologia , Piperazinas/farmacocinética , Fumantes , Adulto , Líquido da Lavagem Broncoalveolar/química , Relação Dose-Resposta a Droga , Feminino , Humanos , Indazóis/sangue , Indóis/sangue , Masculino , Pessoa de Meia-Idade , Oxazóis/sangue , Fosfatidilinositóis/metabolismo , Piperazinas/sangue , Escarro/efeitos dos fármacos , Escarro/metabolismo
3.
ACS Chem Biol ; 14(4): 751-757, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30840432

RESUMO

Colloidal drug aggregates have been a nuisance in drug screening, yet, because they inherently comprise drug-rich particles, they may be useful in vivo if issues of stability can be addressed. As the first step toward answering this question, we optimized colloidal drug aggregate formulations using a fluorescence-based assay to study fulvestrant colloidal formation and stability in high (90%) serum conditions in vitro. We show, for the first time, that the critical aggregation concentration of fulvestrant depends on media composition and increases with serum concentration. Excipients, such as polysorbate 80, stabilize fulvestrant colloids in 90% serum in vitro for over 48 h. Using fulvestrant and an investigational pro-drug, pentyloxycarbonyl-( p-aminobenzyl) doxazolidinylcarbamate (PPD), as proof-of-concept colloidal formulations, we demonstrate that the in vivo plasma half-life for stabilized colloids is greater than their respective monomeric forms. These studies demonstrate the potential of turning the nuisance of colloidal drug aggregation into an opportunity for drug-rich formulations.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacocinética , Carbamatos/química , Carbamatos/farmacocinética , Doxorrubicina/análogos & derivados , Oxazóis/química , Oxazóis/farmacocinética , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Animais , Antineoplásicos/sangue , Carbamatos/sangue , Coloides , Doxorrubicina/sangue , Doxorrubicina/química , Doxorrubicina/farmacocinética , Estabilidade de Medicamentos , Excipientes , Feminino , Fulvestranto/química , Humanos , Células MCF-7 , Camundongos , Transplante de Neoplasias , Oxazóis/sangue , Polissorbatos/química , Estudo de Prova de Conceito , Soro
4.
Clin Ther ; 40(8): 1410-1417, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30055824

RESUMO

PURPOSE: Novel therapies to treat chronic obstructive pulmonary disease are highly desirable. The safety, tolerability, and pharmacokinetic (PK) parameters of nemiralisib, a phosphoinositide 3-kinase δ inhibitor, administered via the Ellipta dry powder inhaler (GlaxoSmithKline, Research Triangle Park, North Carolina) was evaluated, including an assessment of oral bioavailability. METHODS: This single-center, 3-part, placebo-controlled trial in 22 healthy subjects evaluated single (100 and 200 µg) and repeat (200 µg for 10 days) doses of inhaled nemiralisib in parts A (n = 12) and B (n = 12) (double-blind) and single doses of inhaled nemiralisib (200 µg) with and without charcoal block in Part C (n = 6) (open-label, 2-period, crossover). There was a minimum 14-day washout period between dosing days. FINDINGS: 21 subjects completed the study, mean age was similar in the three parts (A: 49 years; B: 44 years; C: 55 years). After single doses of nemiralisib, observed plasma Cmax dropped rapidly, followed by a slower elimination phase. Near-dose proportionality was observed: mean (95% CI) plasma Cmax and AUC0-24 values were 174.3 pg/mL (96.9-313.3) and 694.6 pg·h/mL (503.5-958.2) for 100 µg and 398.9 pg/mL (318.3-500.1) and 1699.6 pg·h/mL (1273.3-2268.7) for 200 µg, respectively. Repeat dosing for 10 days showed exposures ∼2- to 4-fold higher than on the single dose (peak, trough, and AUC0-24 levels), achieving steady-state by day 6. Mean AUC0-24 was 2193.6 pg·h/mL and 1645.3 pg·h/mL in the absence/presence of charcoal. Two non-drug-related adverse events were observed; neither was serious or resulted in withdrawal. IMPLICATIONS: Inhalation of nemiralisib was well tolerated in these healthy subjects. Plasma pharmacokinetic variables were well defined, and charcoal block data indicate that ∼23% of the total systemic exposure after inhalation from Ellipta was attributable to orally absorbed drug. ClinicalTrials.gov identifier: NCT02691325.


Assuntos
Indazóis/farmacologia , Indóis/farmacologia , Oxazóis/farmacologia , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Administração por Inalação , Adulto , Idoso , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Método Duplo-Cego , Inaladores de Pó Seco , Feminino , Voluntários Saudáveis , Humanos , Indazóis/sangue , Indóis/sangue , Masculino , Pessoa de Meia-Idade , Oxazóis/sangue , Piperazinas/sangue , Inibidores de Proteínas Quinases/sangue
5.
Artigo em Inglês | MEDLINE | ID: mdl-29914949

RESUMO

Over the past decade, the prevalence of infections involving methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) has increased significantly. Tedizolid (TZD) demonstrates excellent activity against MRSA and a favorable safety profile. The pharmacokinetics of several antibiotics have been shown to be altered in CF patients. The purpose of this study was to characterize the pharmacokinetics of tedizolid in this population. Eleven patients with CF were randomized to receive tedizolid phosphate at 200 mg orally or intravenously once daily for 3 doses with a minimum 2-day washout, followed by crossover to the remaining dosage form. Plasma and expectorated sputum were collected following the third dose of each dosage form for analysis. Population pharmacokinetic analysis was performed using the maximum likelihood expectation maximization method, and the disposition of TZD was described by a two-compartment model. The sputum concentrations exceeded the unbound plasma concentrations with an estimated mean sputum-to-unbound plasma penetration ratio of 2.88 (coefficient of variation, 50.3%). The estimated population mean ± standard deviation of total clearance, central volume of distribution, and bioavailability were 9.72 ± 1.62 liters/h, 61.6 ± 6.94 liters, and 1.04 ± 0.232, respectively. The total clearance was higher in CF patients than in healthy volunteers; however, it was similar to published data for patients with complicated skin and skin structure infections (cSSSIs). This study demonstrates that the oral bioavailability of tedizolid is excellent in patients with CF and that the plasma pharmacokinetics are similar to those reported for patients with cSSSIs.


Assuntos
Antibacterianos/sangue , Antibacterianos/farmacocinética , Fibrose Cística/sangue , Fibrose Cística/microbiologia , Organofosfatos/sangue , Organofosfatos/farmacocinética , Oxazóis/sangue , Oxazóis/farmacocinética , Plasma/metabolismo , Administração Intravenosa/métodos , Administração Oral , Adulto , Disponibilidade Biológica , Estudos Cross-Over , Feminino , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Estudos Prospectivos , Escarro/metabolismo
6.
J Pharm Biomed Anal ; 158: 1-7, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-29843006

RESUMO

Parecoxib (PX), a prodrug of valdecoxib (VX), is an injectable selective COX-2 inhibitor, and is recommended for the treatment of cancer pain. PX can be rapidly hydrolyzed into its active metabolite VX, and VX is further metabolized into hydroxylated valdecoxib (OH-VX) by cytochrome P450 enzymes. However, cancer patients have been reported to possess reduced drug metabolism ability, which might cause excessive drug accumulation. Such overdose of PX significantly increased the risk of renal safety and cardiovascular events. Therefore, it is necessary to elucidate the concentration profiles of PX and its metabolites in cancer status. In this study, a sensitive, rapid and specific LC-MS/MS method for quantification of PX, VX and OH-VX in the plasma of tumor bearing mouse was developed and validated. After protein precipitation, all the analytes were separated on an Agilent ZORBAX Extend-C18 HPLC column (2.1 × 100 mm, 3.5 µm) with gradient elution. The analytes were detected by an electrospray negative ionization mass spectrometry in the multiple reaction monitoring mode. The transition m/z 369.0 → 119.0, m/z 312.9 → 117.9, m/z 329.0 → 196.0, and m/z 307.1 → 161.3 were used for monitoring PX, VX, OH-VX and IS respectively. The calibration curves of the analytes showed good linearity over the concentration range of 3-3000 ng/mL for PX and VX, and 3-1000 ng/mL for OH-VX. Intra- and inter-batch accuracies (in terms of relative error, RE < 9.9%) and precisions (in terms of relative standard deviation, RSD < 8.8%) satisfied the standard of validation. The matrix effect, recovery and stability were also within acceptable criteria. The method was successfully applied to the pharmacokinetics study of PX in tumor bearing mice, and PX and VX levels were found elevated with the growth of tumor volume, which might increase the risk of drug overdose.


Assuntos
Inibidores de Ciclo-Oxigenase 2/sangue , Monitoramento de Medicamentos/métodos , Isoxazóis/sangue , Neoplasias/metabolismo , Pró-Fármacos/análise , Animais , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Inibidores de Ciclo-Oxigenase 2/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Monitoramento de Medicamentos/instrumentação , Feminino , Humanos , Isoxazóis/metabolismo , Isoxazóis/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/sangue , Oxazóis/sangue , Oxazóis/metabolismo , Oxazóis/farmacocinética , Pró-Fármacos/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização por Electrospray , Sulfonamidas/sangue , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Drug Metab Dispos ; 46(2): 89-99, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29150544

RESUMO

(R)-4-((4-(((4-((tetrahydrofuran-3-yl)oxy)benzo[d]isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol (TBPT), a serotonin-4 receptor partial agonist, is metabolized to two metabolites: an N-dealkylation product [(R)-3-(piperidin-4-ylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)benzo[d]isoxazole (M1)] and a cyclized oxazolidine structure [7-(((4-(((R)-tetrahydrofuran-3-yl)oxy)benzo[d]isoxazol-3-yl)oxy)methyl)octahydro-3H (M2)]. After administration of TBPT to humans the exposure to M1 was low and the exposure to M2 was high, relative to the parent drug, despite this being the opposite in vitro. In this study, projection of the plasma metabolite/parent (M/P) ratios for M1 and M2 was attempted using in vitro metabolism, binding, and permeability data in static and dynamic physiologically based pharmacokinetic (PBPK) models. In the static model, the fraction of parent clearance yielding the metabolite (which also required taking into account secondary metabolites of M1 and M2), the clearance of the metabolites and parent, and an estimate of the availability of the metabolites from the liver were combined to yield estimated parent/metabolite ratios of 0.32 and 23 for M1 and M2, respectively. PBPK modeling that used in vitro and physicochemical data input yielded estimates of 0.26 and 20, respectively. The actual values were 0.12 for M1/TBPT and 58 for M2/TBPT. Thus, the ratio for M1 was overpredicted, albeit at values less than unity. The ratio for M2/TBPT was underpredicted, and the high ratio of 58 may exceed a limiting ceiling of the approach. Nevertheless, when considered in the context of determining whether a potential circulating metabolite may be quantitatively important prior to administration of a drug for the first time to humans, the approaches succeeded in highlighting the importance of M2 (M/P ratio >> 1) relative to M1, despite M1 being much greater than M2 in vitro.


Assuntos
Furanos/sangue , Furanos/farmacocinética , Inativação Metabólica/fisiologia , Oxazóis/sangue , Oxazóis/farmacocinética , Agonistas do Receptor de Serotonina/sangue , Agonistas do Receptor de Serotonina/farmacocinética , Adulto , Ciclização/fisiologia , Remoção de Radical Alquila/fisiologia , Feminino , Hepatócitos/metabolismo , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Adulto Jovem
8.
Clin Ther ; 39(9): 1849-1857, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28865799

RESUMO

PURPOSE: Tedizolid phosphate is a next-generation oxazolidinone prodrug that is transformed into the active moiety tedizolid. Its indication is acute bacterial skin and skin structure infections caused by gram-positive species, including methicillin-resistant Staphylococcus aureus. Although tedizolid phosphate has been marketed in Korea, no data on the pharmacokinetic (PK) properties or tolerability of tedizolid phosphate in Korean subjects are available. This study was designed to evaluate the PK properties, oral bioavailability, and tolerability with a single-dose oral and intravenous administration of tedizolid phosphate in healthy Korean male subjects. METHODS: A block-randomized, double-blind, placebo-controlled, single-dose study was conducted in 3 groups (200, 400, and 600 mg; 10 subjects in each group). In the second part of the study, subjects from the 200-mg group received administration orally and intravenously (1-hour infusion) via 2-way crossover for the evaluation of absolute bioavailability. There was a 7-day washout period between treatments in the absolute bioavailability part of the study. Serial blood samples for PK analysis were collected for up to 72 hours. Tolerability was assessed by analysis of adverse events. FINDINGS: Thirty healthy Korean subjects completed the study and were included in the PK and tolerability analyses. Tedizolid phosphate was rapidly converted into tedizolid. After a single oral dose, the Tmax of tedizolid was observed to be 1.5 to 2.5 hours, and the plasma concentration-time curve of tedizolid showed a 2-phase elimination pattern, with a half-life of ~11 hours. Dose-dependent increases were observed in the AUClast value (29,441-78,062 µg · h/L) and in the Cmax value (2679-6980 µg/L) with the administration of tedizolid phosphate 200 to 600 mg PO. The absolute bioavailability of tedizolid was 95.2% (90% CI, 92.7%-97.8%) in the 200-mg administration group. There were no serious adverse events or clinically significant changes in the tolerability assessment. IMPLICATIONS: Tedizolid phosphate at doses of up to 600 mg was well-tolerated in these healthy Korean male subjects. Tedizolid shows dose linearity with oral administration, and no dose adjustment of tedizolid phosphate 200 mg would be needed when switching administration routes. ClinicalTrials.gov identifier: NCT02097043.


Assuntos
Antibacterianos , Organofosfatos , Oxazóis , Pró-Fármacos , Administração Intravenosa , Administração Oral , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/sangue , Antibacterianos/farmacocinética , Disponibilidade Biológica , Estudos Cross-Over , Método Duplo-Cego , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Organofosfatos/administração & dosagem , Organofosfatos/efeitos adversos , Organofosfatos/sangue , Organofosfatos/farmacocinética , Oxazóis/administração & dosagem , Oxazóis/efeitos adversos , Oxazóis/sangue , Oxazóis/farmacocinética , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , República da Coreia , Adulto Jovem
9.
J Clin Pharmacol ; 57(10): 1258-1267, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28581633

RESUMO

Zolmitriptan is a serotonin (5-HT) 1B/1D receptor agonist effective for the treatment of migraine. This analysis aimed to develop a population pharmacokinetic (PK) model for zolmitriptan and its active metabolite in adults and adolescents and provide appropriate dosing regimens to be used in clinical trials for children 6-11 years old. The data from a single-dose clinical study of 5.0-mg zolmitriptan nasal spray (ZNS) conducted in adult and adolescent patients with migraine between migraine attacks was applied. Similar plasma concentration profiles of zolmitriptan and its metabolite, 183C91, were observed in adults and adolescents. A 1-compartment model with first-order absorption and first-order elimination reasonably described the zolmitriptan PK. With a portion of elimination of zolmitriptan being treated as the conversion from zolmitriptan to 183C91, the disposition of 183C91 was described by a 1-compartment model with first-order elimination. The estimated typical apparent volume of distribution and clearance of zolmitriptan were 136 L and 121 L/h, respectively, with 56.5% and 42.6% between-subject variability, respectively. Based on the simulation results with the final population PK model, a body weight-based dosing scheme of 5.0 and 2.5 mg ZNS in children greater than and less than 50 kg is recommended to achieve exposures similar to those of the adult and adolescent population administered 5.0 mg ZNS. The recommended doses for children to achieve exposure similar to that observed in adults given 2.5 mg ZNS are 2.5 mg (≥50 kg) and 1.0 mg (15-50 kg). These dosing regimens could be used in future clinical trials.


Assuntos
Modelos Biológicos , Oxazolidinonas/administração & dosagem , Oxazolidinonas/farmacocinética , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Agonistas do Receptor 5-HT1 de Serotonina/farmacocinética , Triptaminas/administração & dosagem , Triptaminas/farmacocinética , Administração Intranasal , Adolescente , Adulto , Peso Corporal , Criança , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/metabolismo , Oxazóis/sangue , Oxazolidinonas/sangue , Oxazolidinonas/uso terapêutico , Agonistas do Receptor 5-HT1 de Serotonina/sangue , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Triptaminas/sangue , Triptaminas/uso terapêutico , Adulto Jovem
10.
Biomed Chromatogr ; 31(2)2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27460063

RESUMO

A sensitive and specific UPLC-MS/MS method was developed and validated for the simultaneous determination of 2-amino-2-(2-(4'-(2-propyloxazol-4-yl)-[1,1'-biphenyl]-4-yl)ethyl)propane-1,3-diol (SYL930), phosphorylated metabolite (SYL930-P) and hydroxylated metabolite (SYL930-M) in dog blood using SYL927 and SYL927-P, analogues of SYL930, as the internal standards. Analytes were extracted with protein precipitation followed by chromatographic separation on a ZorbaxSB-C18 column (3.5 µm, 2.1 × 100 mm) with a gradient elution of methanol-water containing 0.1% formic acid (v/v). A triple quadrupole tandem mass spectrometer operating in the positive electrospray ionization mode was used to detect SYL930, SYL930-P, SYL930-M and IS transitions of 381.2 → 364.2, 461.2 → 334.2, 397.3 → 380.3, 367.1 → 350.4 and 447.5 → 320.2, respectively. The linear calibration curves for SYL930, SYL930-P and SYL930-M were 0.5-500, 0.2-100 and 0.5-100 ng/mL, respectively (r2 > 0.99). The intra-day and inter-day precisions (RSD, %) of analytes did not exceed 9.16% except for low QCs (≤16.22%), and the accuracy (RE, %) ranged from -14 to 11.4%. The mean recoveries for SYL930, SYL930-P and SYL930-M in dog blood were 85.13-107.94, 73.84-80.08 and 85.64-95.44%, respectively. The validated method was successfully applied to pharmacokinetic and PK/PD studies of SYL930 and its two major metabolites in dogs after an oral administration of SYL930.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Oxazóis/sangue , Oxazóis/metabolismo , Propanolaminas/sangue , Propanolaminas/metabolismo , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Cães , Humanos , Hidroxilação , Oxazóis/administração & dosagem , Fosforilação , Propanolaminas/administração & dosagem , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Espectrometria de Massas por Ionização por Electrospray/métodos
11.
Artigo em Inglês | MEDLINE | ID: mdl-27799200

RESUMO

Given that tedizolid exhibits substantial lung penetration, we hypothesize that it could achieve good efficacy against Streptococcus pneumoniae lung infections. We evaluated the pharmacodynamics of tedizolid for treatment of S. pneumoniae lung infections and compared the efficacies of tedizolid human-simulated epithelial lining fluid (ELF) exposures in immunocompetent and neutropenic murine lung infection models. ICR mice were rendered neutropenic via intraperitoneal cyclophosphamide injections and then inoculated intranasally with S. pneumoniae suspensions. Immunocompetent CBA/J mice were inoculated similarly. Single daily tedizolid doses were administered 4 h postinoculation (termed 0 h). Changes in log10 CFU at 24 h compared with 0-h controls were estimated. Ratios of area under the free-drug concentration-time curve to MIC (fAUC0-24/MIC) required to achieve various efficacy endpoints against each isolate were estimated using the Hill equation. Tedizolid doses in neutropenic and immunocompetent mice that mimic the human-simulated ELF exposure were examined. Stasis, 1-log reduction, and 2-log reduction were achieved at fAUC0-24/MIC of 8.96, 24.62, and 48.34, respectively, in immunocompetent mice and 19.21, 48.29, and 103.95, respectively, in neutropenic mice. Tedizolid at 40 mg/kg of body weight/day and 55 mg/kg/day in immunocompetent and neutropenic mice, respectively, resulted in ELF AUC0-24 comparable to that achieved in humans following a 200-mg once-daily clinical dose. These human-simulated ELF exposures were adequate to attain >2-log reduction in bacterial burden at 24 h in 3 out of 4 isolates in both models and 1.58- and 0.74-log reductions with the fourth isolate in immunocompetent and neutropenic mice, respectively. Tedizolid showed potent in vivo efficacy against S. pneumoniae in both immunocompetent and neutropenic lung infection models, which support its consideration for S. pneumoniae lung infections.


Assuntos
Antibacterianos/farmacologia , Modelos Estatísticos , Neutropenia/tratamento farmacológico , Organofosfatos/farmacologia , Oxazóis/farmacologia , Pneumonia Pneumocócica/tratamento farmacológico , Streptococcus pneumoniae/efeitos dos fármacos , Animais , Antibacterianos/sangue , Antibacterianos/farmacocinética , Área Sob a Curva , Ciclofosfamida , Modelos Animais de Doenças , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Humanos , Imunocompetência , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos CBA , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Neutropenia/induzido quimicamente , Neutropenia/imunologia , Neutropenia/microbiologia , Organofosfatos/sangue , Organofosfatos/farmacocinética , Oxazóis/sangue , Oxazóis/farmacocinética , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/microbiologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Mucosa Respiratória/microbiologia , Streptococcus pneumoniae/crescimento & desenvolvimento
12.
Drug Test Anal ; 9(6): 870-879, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27509066

RESUMO

4,4'-DMAR is an analogue of the known psychostimulants 4-methylaminorex and aminorex. In the light of reports of deaths associated with its abuse, and the easy access from Internet vendors, the EU Council recently decided on control measures across member states. Here we describe a validated method for measuring plasma levels of cis-4,4'-DMAR, crucial for preclinical studies and analysis in human plasma. Chromatographic separation was done by gradient elution on a Kinetex C18 column with 0.1% formic acid in water and 0.1% formic acid in acetonitrile at 0.2 mL/min. Detection was by positive electrospray ionization (ESI+) in multiple reaction monitoring mode monitoring the quantifier transitions m/z 191.4 → m/z 148.3 for cis-4,4'-DMAR and m/z 259.3 → m/z 194.2 for carbamazepine (internal standard). Protein precipitation with 1% of formic acid in acetonitrile was used in cis-4,4'-DMAR extraction from plasma; recovery was high (>93%) with a negligible matrix effect. This method provides an accurate, precise, and sensitive method for cis-4,4'-DMAR quantification in human and rat plasma, following European Medicine Agency guidelines for bioanalytical method validation. Pharmacokinetic studies were conducted in rats. After an intravenous dose of 1 mg/kg, plasma levels declined rapidly (≥80% in 4 h), followed by a slow elimination phase (t1/2 of 5.14 ± 0.65 h). Absorption was rapid after intraperitoneal injection (tmax = 15 min) with a rapid decline thereafter; Cmax and AUC0-240min showed dose-proportionality over the dose range 1-10 mg/kg. This method was successfully applied to investigate pharmacokinetic properties in rats and could be used to quantify cis-4,4'-DMAR levels in human plasma. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Oxazóis/sangue , Psicotrópicos/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Humanos , Limite de Detecção , Masculino , Ratos , Ratos Wistar , Detecção do Abuso de Substâncias/métodos
13.
Antimicrob Agents Chemother ; 60(11): 6568-6572, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27550347

RESUMO

We compared tedizolid alone and tedizolid with rifampin to rifampin and vancomycin plus rifampin in a rat model of methicillin-resistant Staphylococcus aureus (MRSA) foreign body-associated osteomyelitis. The study strain was a prosthetic joint infection-associated isolate. Steady-state pharmacokinetics for intraperitoneal administration of tedizolid, vancomycin, and rifampin were determined in uninfected rats. MRSA was inoculated into the proximal tibia, and a wire was implanted. Four weeks later, the rats were treated intraperitoneally for 21 days with tedizolid (n = 14), tedizolid plus rifampin (n = 11), rifampin (n = 16), or vancomycin plus rifampin (n = 13). Seventeen rats received no treatment. After treatment, quantitative bone cultures were performed. Blood was obtained for determination of drug trough concentrations in the tedizolid and tedizolid plus rifampin groups. The mean peak plasma concentration and mean area under the concentration-time curve from time zero to 24 h for tedizolid were 12 µg/ml and 60 µg · h/ml, respectively. The bacterial loads in all treatment groups were significantly lower than those in the control group; those in the tedizolid- plus rifampin-treated animals were not significantly different from those in the vancomycin- plus rifampin-treated animals. The range of mean plasma trough concentrations in the tedizolid group was 0.44 to 0.73 µg/ml. Although neither tedizolid nor vancomycin resistance was detected in isolates recovered from bones, rifampin resistance was detected in 10 animals (63%) in the rifampin group, 8 animals (73%) in the tedizolid plus rifampin group, and a single animal (8%) in the vancomycin plus rifampin group. Tedizolid alone or tedizolid combined with rifampin was active in a rat model of MRSA foreign body-associated osteomyelitis. The emergence of rifampin resistance was noted in animals receiving tedizolid plus rifampin.


Assuntos
Antibacterianos/farmacocinética , Corpos Estranhos/tratamento farmacológico , Organofosfatos/farmacocinética , Osteomielite/tratamento farmacológico , Oxazóis/farmacocinética , Rifampina/farmacocinética , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina/farmacocinética , Animais , Antibacterianos/sangue , Carga Bacteriana/efeitos dos fármacos , Fios Ortopédicos , Modelos Animais de Doenças , Combinação de Medicamentos , Farmacorresistência Bacteriana , Corpos Estranhos/microbiologia , Corpos Estranhos/patologia , Injeções Intraperitoneais , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Testes de Sensibilidade Microbiana , Organofosfatos/sangue , Osteomielite/microbiologia , Osteomielite/patologia , Oxazóis/sangue , Ratos , Ratos Wistar , Rifampina/sangue , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia , Tíbia/efeitos dos fármacos , Tíbia/lesões , Tíbia/microbiologia , Vancomicina/sangue
14.
Artigo em Inglês | MEDLINE | ID: mdl-27322629

RESUMO

Gout is a common metabolic disorder caused by the deposition of monosodium urate crystals within joints. A new kind of xanthine oxidase inhibitor, WSJ-537, was developed as a potential drug. In order to investigate the pharmacokinetic behavior in vivo, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination the concentration of WSJ-537 in rat plasma was developed. After extraction by protein precipitation method with acetonitrile, the chromatographic separation was accomplished on a Venusil ASB C18 column(2.1mm×50mm, 3mm)at a flow rate of 0.3mLmin(-1) with the mobile phase consisting of acetonitrile-ammonium acetate (33:67, v/v). An electrospray ionization (ESI) source was applied and operated in the positive ion mode. The plasma concentration was detected by multiple reactions monitoring (MRM) mode with the target fragment ions m/z 410.2→m/z 368.1 for WSJ-537 and m/z 244.1→m/z 185.0 for the IS. Good linearity was observed in the range of 20-800ngmL(-1) (r=0.9947). The recovery of WSJ-537 in rats plasma was more than 85%. This method was suitable for pharmacokinetic studies after oral administration of 10mg/kg WSJ-537 in rats.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Inibidores Enzimáticos/sangue , Oxazóis/sangue , Espectrometria de Massas em Tandem/métodos , Xantina Oxidase/antagonistas & inibidores , Animais , Benzotiazóis/sangue , Benzotiazóis/química , Cromatografia Líquida de Alta Pressão/economia , Inibidores Enzimáticos/química , Limite de Detecção , Masculino , Oxazóis/química , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/economia
15.
Elife ; 52016 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-27215734

RESUMO

There is an urgent requirement for safe, oral and cost-effective drugs for the treatment of visceral leishmaniasis (VL). We report that delamanid (OPC-67683), an approved drug for multi-drug resistant tuberculosis, is a potent inhibitor of Leishmania donovani both in vitro and in vivo. Twice-daily oral dosing of delamanid at 30 mg kg(-1) for 5 days resulted in sterile cures in a mouse model of VL. Treatment with lower doses revealed a U-shaped (hormetic) dose-response curve with greater parasite suppression at 1 mg kg(-1) than at 3 mg kg(-1) (5 or 10 day dosing). Dosing delamanid for 10 days confirmed the hormetic dose-response and improved the efficacy at all doses investigated. Mechanistic studies reveal that delamanid is rapidly metabolised by parasites via an enzyme, distinct from the nitroreductase that activates fexinidazole. Delamanid has the potential to be repurposed as a much-needed oral therapy for VL.


Assuntos
Antiprotozoários/farmacologia , Antituberculosos/farmacologia , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Nitroimidazóis/farmacologia , Oxazóis/farmacologia , Administração Oral , Animais , Antiprotozoários/sangue , Antiprotozoários/farmacocinética , Antituberculosos/sangue , Antituberculosos/farmacocinética , Biotransformação , Modelos Animais de Doenças , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Reposicionamento de Medicamentos , Feminino , Hormese , Leishmania donovani/crescimento & desenvolvimento , Leishmania donovani/patogenicidade , Leishmaniose Visceral/sangue , Leishmaniose Visceral/parasitologia , Leishmaniose Visceral/patologia , Camundongos , Camundongos Endogâmicos BALB C , Nitroimidazóis/sangue , Nitroimidazóis/farmacocinética , Oxazóis/sangue , Oxazóis/farmacocinética , Testes de Sensibilidade Parasitária , Resultado do Tratamento
16.
Biomed Chromatogr ; 30(11): 1750-1756, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27105920

RESUMO

Tedizolid (TDZ) is a novel oxazolidinone class antibiotic, indicated for the treatment of acute bacterial skin and skin structure infections in adults. In this study a highly sensitive UPLC-MS/MS assay was developed and validated for the determination of TDZ in rat plasma using rivaroxaban as an internal standard (IS). Both TDZ and IS were separated on an Acquity UPLC BEH™ C18 column using an isocratic mobile phase comprising of acetonitrile-20 mm ammonium acetate (85:15, v/v), eluted at 0.3 mL/min flow rate. The plasma sample was processed by liquid liquid extraction technique using ethyl acetate as an extracting agent. The analyte and IS were detected in positive mode using electrospray ionization source. The precursor to product ion transitions at m/z 371.09 > 343.10 for TDZ and m/z 435.97 > 144.94 for IS were used for the quantification in multiple reaction monitoring mode. The calibration curve was linear in the concentration range of 0.74-1500 ng/mL and the lower limit of quantification was 0.74 ng/mL only. The developed assay was validated following standard guidelines for bioanalytical method validation (US Food and Drug Administration) and all the validation results were within the acceptable limits. The developed assay was successfully applied into a pharmacokinetic study in rats. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Antibacterianos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Organofosfatos/sangue , Oxazóis/sangue , Oxazolidinonas/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Cromatografia Líquida de Alta Pressão/economia , Feminino , Limite de Detecção , Extração Líquido-Líquido/métodos , Ratos Wistar , Espectrometria de Massas em Tandem/economia
17.
Artigo em Inglês | MEDLINE | ID: mdl-26319300

RESUMO

Delamanid (OPC-67683) is a novel nitro-dihydroimidazo-oxazole derivative that is being developed by Otsuka Pharmaceutical Co., Ltd., Japan (referred to as Otsuka hereafter) for the treatment of tuberculosis (TB). An ultra-high performance liquid chromatographic-tandem mass spectrometry (UHPLC-MS/MS) method has been developed and validated for the determination of OPC-67683 and its eight metabolites, DM-6704, DM-6705, DM-6706, DM-6717, DM-6718, DM-6720, DM-6721 and DM-6722 in human plasma to support regulated clinical development. During method development several technical challenges such as poor chromatography, separation of structural isomers, conversion of the analytes, instability in matrix and long cycle time were encountered and overcome. A protein precipitation extraction (PPE) was used to extract plasma samples (50µL) and the resulting extracts were analyzed using reversed phase UHPLC-MS/MS with a electrospray (ESI) and selected reaction monitoring (SRM). The method was fully validated over the calibration curve range of 1.00-500ng/mL for all nine analytes with linear regression and 1/x(2) weighting according to regulatory guidance for bioanalysis. Based on three inter-day precision and accuracy runs, the between-run % relative standard deviation (RSD) for all nine analytes varied from 0.0 to 11.9% and the accuracy ranged from 92.7% to 102.5% of nominal at all quality controls (QC) concentrations, including the lower limit of quantitation (LLOQ) QC at 1.00ng/mL. The extraction recovery of OPC-67683 and its eight metabolites were above 95%. Various short term and long term solution and matrix stability were established including the stability of OPC-67683 and its eight metabolites in human plasma for 708 days at -70°C. Although this method has been used to support regulated clinic studies during the last decade and over ten thousand samples have been analyzed, this is the first time that the method development process and validation data have been published.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Nitroimidazóis/sangue , Oxazóis/sangue , Espectrometria de Massas em Tandem/métodos , Método Duplo-Cego , Humanos , Limite de Detecção , Placebos , Reprodutibilidade dos Testes
18.
Drug Metab Dispos ; 43(8): 1277-83, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26055621

RESUMO

The metabolism of delamanid (OPC-67683, Deltyba), a novel treatment of multidrug-resistant tuberculosis, was investigated in vitro using plasma and purified protein preparations from humans and animals. Delamanid was rapidly degraded by incubation in the plasma of all species tested at 37°C, with half-life values (hours) of 0.64 (human), 0.84 (dog), 0.87 (rabbit), 1.90 (mouse), and 3.54 (rat). A major metabolite, (R)-2-amino-4,5-dihydrooxazole derivative (M1), was formed in the plasma by cleavage of the 6-nitro-2,3-dihydroimidazo(2,1-b)oxazole moiety of delamanid. The rate of M1 formation increased with temperature (0-37°C) and pH (6.0-8.0). Delamanid was not converted to M1 in plasma filtrate, with a molecular mass cutoff of 30 kDa, suggesting that bioconversion is mediated by plasma proteins of higher molecular weight. When delamanid was incubated in plasma protein fractions separated by gel filtration chromatography, M1 was observed in the fraction consisting of albumin, γ-globulin, and α1-acid glycoprotein. In pure preparations of these proteins, only human serum albumin (HSA) metabolized delamanid to M1. The formation of M1 followed Michaelis-Menten kinetics in both human plasma and the HSA solution, with similar Km values: 67.8 µM in plasma and 51.5 µM in HSA. The maximum velocity and intrinsic clearance values for M1 were also comparable in plasma and HSA. These results strongly suggest that albumin is predominantly responsible for metabolizing delamanid to M1. We propose that delamanid degradation by albumin begins with a nucleophilic attack of amino acid residues on the electron-poor carbon at the 5 position of nitro-dihydro-imidazooxazole, followed by cleavage of the imidazooxazole moiety to form M1.


Assuntos
Antituberculosos/sangue , Nitroimidazóis/sangue , Oxazóis/sangue , Animais , Antituberculosos/farmacocinética , Biotransformação , Cães , Meia-Vida , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Peso Molecular , Nitroimidazóis/farmacocinética , Oxazóis/farmacocinética , Coelhos , Ratos , Albumina Sérica/metabolismo , Temperatura Ambiente
19.
Antimicrob Agents Chemother ; 58(11): 6462-70, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25136028

RESUMO

Tedizolid phosphate is a novel antibacterial prodrug that is rapidly and extensively converted to its active moiety, tedizolid. We developed a population pharmacokinetics (PK) model for tedizolid using pooled data from seven densely and sparsely sampled clinical trials evaluating oral and intravenous tedizolid. Model-derived exposure estimates were evaluated for relationships to select efficacy and safety outcomes. A two-compartment model with sigmoidal absorption, absolute bioavailability, and linear elimination described the PK data well. Variability was small (clearance, 31% coefficient of variation; volume, 13.4% coefficient of variation), and absolute bioavailability was high (86%). No clinically significant covariate effects on tedizolid PK were found. Based on phase 3 data evaluating 200-mg once-daily tedizolid for acute bacterial skin and skin structure infections (ABSSSI), no relationships were seen between various efficacy outcomes and estimated tedizolid exposure; the estimated exposure range (free-drug area under the concentration-time curve over 24 h at steady state [AUCss(0-24)], 7 to 50 µg · h/ml) in these patients was modest. Safety data modeling, using once-daily doses of up to 400 mg, showed a small increase in the probability of an adverse event with increasing model-estimated tedizolid exposure; no such relationship was observed when specifically evaluating the 200-mg dose. There were no trends in neutrophil or platelet counts with increasing tedizolid exposure. Target attainment simulations for 200-mg tedizolid indicated a 98.31% probability of attaining the target measure (AUC for the free, unbound fraction of a drug [fAUC]/MIC = 3) against a Staphylococcus aureus strain for which the MIC was ≤0.5 µg/ml. These findings support 200-mg tedizolid once daily as the optimum dose for treatment of ABSSSI.


Assuntos
Antibacterianos/farmacocinética , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Oxazolidinonas/farmacocinética , Infecções Estafilocócicas/tratamento farmacológico , Tetrazóis/farmacocinética , Adolescente , Adulto , Idoso , Antibacterianos/efeitos adversos , Antibacterianos/sangue , Área Sob a Curva , Disponibilidade Biológica , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Organofosfatos/efeitos adversos , Organofosfatos/sangue , Oxazóis/efeitos adversos , Oxazóis/sangue , Oxazolidinonas/efeitos adversos , Oxazolidinonas/sangue , Contagem de Plaquetas , Pró-Fármacos/farmacocinética , Dermatopatias Bacterianas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Tetrazóis/efeitos adversos , Tetrazóis/sangue , Adulto Jovem
20.
Int J Pharm ; 475(1-2): 97-109, 2014 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-25171976

RESUMO

The aim of the present work was to design a pH-modified solid dispersion (pH(M)-SD) that can improve the dissolution and bioavailability of poorly water-soluble weakly basic GT0918, a developing anti-prostate cancer drug. To select the appropriate acidifiers, a solubility test was carried out first. Solid dispersions (SDs) containing GT0918 and polyvinylpyrrolidone (PVP) were prepared using a solvent evaporation method and were characterized using dissolution studies in different media. The solid states of the SDs were investigated using scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and Fourier transformed infrared spectroscopy (FTIR). The in vivo pharmacokinetics of the pH(M)-SDs tablets were also studied in beagle dogs compared to the conventional tablets. The optimized pH(M)-SD (GT0918/PVP/citric acid, 1:2:2 weight ratio) exhibited a significant improvement in the dissolution behavior compared to both the physical mixture and the binary SDs. Solid-state characterization revealed that the amorphous formation of GT0918 in the SDs and the strong H-bonding were only found in the pH(M)-SDs containing citric acid. Furthermore, the GT0918-loaded pH(M)-SD tablets showed a higher AUC and a lower tmax compared to the conventional tablets. Accordingly, the pH(M)-SD might be an efficient route for enhancing the dissolution and bioavailability of poorly water-soluble GT0918.


Assuntos
Antineoplásicos/farmacocinética , Drogas em Investigação/farmacocinética , Excipientes/química , Imidazóis/farmacocinética , Nitrilos/farmacocinética , Oxazóis/farmacocinética , Tioidantoínas/farmacocinética , Animais , Animais Endogâmicos , Antineoplásicos/administração & dosagem , Antineoplásicos/análise , Antineoplásicos/sangue , Disponibilidade Biológica , Cinamatos/química , Ácido Cítrico/química , Cães , Composição de Medicamentos , Drogas em Investigação/administração & dosagem , Drogas em Investigação/análise , Fumaratos/química , Concentração de Íons de Hidrogênio , Imidazóis/administração & dosagem , Imidazóis/análise , Imidazóis/sangue , Masculino , Nitrilos/administração & dosagem , Nitrilos/análise , Nitrilos/sangue , Oxazóis/administração & dosagem , Oxazóis/análise , Oxazóis/sangue , Povidona/química , Neoplasias da Próstata/tratamento farmacológico , Distribuição Aleatória , Solubilidade , Ácido Succínico/química , Suspensões , Comprimidos , Tioidantoínas/administração & dosagem , Tioidantoínas/análise , Tioidantoínas/sangue
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