RESUMO
Bazedoxifene (BZA), a chemically distinct selective estrogen receptor modulator, has demonstrated efficacy and long-term safety in phase 3 placebo-controlled studies for prevention and treatment of osteoporosis. Here, we assessed the potential effects of age and renal function on BZA pharmacokinetics in healthy postmenopausal women (aged 55-84 years; CLcr, 32-109 mL/min). This was an open-label, single-dose, parallel, nonrandomized inpatient study conducted in healthy postmenopausal women and postmenopausal women with impaired renal function. Each subject received a single oral dose of BZA in a 20-mg tablet. Twenty-six subjects were enrolled: 8 in each of 3 age groups (55-64 years, 65-74 years, ≥75 years) and 2 (aged 71 and 75 years) with mild renal impairment; all subjects received treatment and completed the study. Age-related changes in pharmacokinetics were apparent. Although the correlation was modest (R2 = 0.28), BZA CL/F decreased steadily with age, such that the oldest group (>75 years) had a mean CL/F 60% less than the youngest group (55-64 years). Over the observed range of CLcr, there was a weak positive correlation (R2 = 0.19) between BZA CL/F and CLcr.
Assuntos
Envelhecimento/fisiologia , Indóis/farmacocinética , Rim/fisiologia , Rim/fisiopatologia , Pós-Menopausa , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/sangue , Feminino , Humanos , Indóis/sangue , Pessoa de Meia-Idade , Pós-Menopausa/sangue , Insuficiência Renal/sangue , Insuficiência Renal/fisiopatologia , Moduladores Seletivos de Receptor Estrogênico/farmacocinéticaRESUMO
A first of its kind, simple, rapid, and sensitive liquid chromatography mass spectrometry (LC-MS/MS) method was developed and validated for quantification of perindopril and perindoprilat in both human plasma and breast milk. The analytes and internal standards (phenazone and acetyl salicylic acid) were extracted from biological matrices by protein precipitation. A Phenomenex® C-18 column was used to provide an appropriate chromatographic separation of the analytes, followed by detection with tandem mass spectrometry. Gradient chromatographic and mass spectrometric detection conditions with mobile phases (A: 5% methanol + 0.1% formic acid in water v/v, and B: 95% methanol + 0.1% formic acid in water v/v) were developed to achieve a LOQ of 0.5 ng/mL in both human plasma and milk. The method was suitable of evaluating clinical samples. The mass transition was followed as m/z 369.10/172.00 for perindopril, m/z 339.00/168.10 for perindoprilat, m/z 188.90/55.95 for phenazone, and m/z 179.04/137.02 for acetyl salicylic acid. The developed method was optimized and validated with a linear range of 0.1-200 ng/mL (r 2 = better than 0.99 for both perindopril and perindoprilat). The precision and accuracy values were within 15% CV. The overall recovery of the analytes was 80-110%. The method has good specificity and repeatability. Stability studies were conducted in both human plasma and bovine milk for up to 3 months, at the storage conditions of 25, 4, and -80 °C.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/análise , Inibidores da Enzima Conversora de Angiotensina/sangue , Indóis/análise , Indóis/sangue , Leite Humano/química , Perindopril/análise , Perindopril/sangue , Aleitamento Materno , Cromatografia Líquida/economia , Cromatografia Líquida/métodos , Feminino , Humanos , Limite de Detecção , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/economia , Espectrometria de Massas em Tandem/métodosRESUMO
Mavoglurant (MVG) is an antagonist at the metabotropic glutamate receptor-5 currently under clinical development at Novartis Pharma AG for the treatment of central nervous system diseases. The aim of this study was to develop and optimise a population whole-body physiologically-based pharmacokinetic (WBPBPK) model for MVG, to predict the impact of drug-drug interaction (DDI) and age on its pharmacokinetics. In a first step, the model was fitted to intravenous (IV) data from a clinical study in adults using a Bayesian approach. In a second step, the optimised model was used together with a mechanistic absorption model for exploratory Monte Carlo simulations. The ability of the model to predict MVG pharmacokinetics when orally co-administered with ketoconazole in adults or administered alone in 3-11 year-old children was evaluated using data from three other clinical studies. The population model provided a good description of both the median trend and variability in MVG plasma pharmacokinetics following IV administration in adults. The Bayesian approach offered a continuous flow of information from pre-clinical to clinical studies. Prediction of the DDI with ketoconazole was consistent with the results of a non-compartmental analysis of the clinical data (threefold increase in systemic exposure). Scaling of the WBPBPK model allowed reasonable extrapolation of MVG pharmacokinetics from adults to children. The model can be used to predict plasma and brain (target site) concentration-time profiles following oral administration of various immediate-release formulations of MVG alone or when co-administered with other drugs, in adults as well as in children.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacocinética , Indóis/farmacocinética , Modelos Biológicos , Modelos Estatísticos , Administração Intravenosa , Administração Oral , Adulto , Fatores Etários , Teorema de Bayes , Encéfalo/metabolismo , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Simulação por Computador , Esquema de Medicação , Interações Medicamentosas , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/sangue , Feminino , Humanos , Indóis/administração & dosagem , Indóis/sangue , Cetoconazol/administração & dosagem , Masculino , Cadeias de Markov , Método de Monte Carlo , Distribuição TecidualRESUMO
The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of 6-hydroxyindole, which functions as an oxidative hair dye ingredient. The Panel considered relevant animal and human data provided in this safety assessment and concluded that 6-hydroxyindole is safe for use in oxidative hair dye formulations.
Assuntos
Qualidade de Produtos para o Consumidor , Cosméticos/química , Indóis/toxicidade , Animais , Testes de Carcinogenicidade , Relação Dose-Resposta a Droga , Feminino , Tinturas para Cabelo/química , Humanos , Indóis/sangue , Indóis/química , Masculino , Ratos , Ratos Wistar , Testes de Toxicidade AgudaRESUMO
A sensitive high-performance liquid chromatography-positive ion electrospray tandem mass spectrometry method was developed and validated for the quantification of dimebon in rat plasma and brain tissue. Following liquid-liquid extraction, the analyte was separated using a gradient mobile phase on a reversed phase column and analyzed by MS/MS in the multiple reaction monitoring mode using the respective [M+H](+) ions, m/z 320-277 for dimebon and m/z 407-100 for the internal standard. The assay exhibited a linear dynamic range of 0.25-250 ng/mL for dimebon in rat plasma and brain tissue. Acceptable precision (<11%) and accuracy (100+/-7%) were obtained for concentrations over the standard curve range. A run time of 2.5 min for each sample made it possible to analyze more than 250 samples per day. The method was successfully applied to quantify dimebon concentrations in a rodent pharmacokinetic study. Moreover, it can be believed that the assay method in rat plasma would facilitate the ease of adaptability of dimebon quantification in human plasma for clinical trials.
Assuntos
Encéfalo/metabolismo , Indóis/sangue , Indóis/metabolismo , Espectrometria de Massas em Tandem/métodos , Animais , Cromatografia Líquida , Indóis/química , Estrutura Molecular , RatosRESUMO
A sensitive and rapid high-performance liquid chromatography-positive ion electrospray tandem mass spectrometry method is developed and validated for the quantitation of tegaserod in human plasma. Following liquid-liquid extraction, the analytes are separated using an isocratic mobile phase on a reversed-phase column and analyzed by tandem mass spectrometry in the multiple reaction monitoring mode using the respective (M+H)+ ions, m/z 302 to 173 for tegaserod and m/z 409 to 228 for the internal standard. The assay exhibits a linear dynamic range of 100-10000 pg/mL for tegaserod in human plasma. The lower limit of quantitation is 100 pg/mL with a relative standard deviation of less than 7%. Acceptable precision and accuracy are obtained for concentrations over the standard curve range. A run time of 2.0 min for each sample makes it possible to analyze more than 250 human plasma samples per day. The validated method is successfully used to analyze human plasma samples for application in pharmacokinetic, bioavailability, or bioequivalence studies.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Indóis/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Fracionamento Químico/métodos , Estabilidade de Medicamentos , Humanos , Reprodutibilidade dos TestesRESUMO
A highly sensitive, rapid assay method has been developed and validated for the estimation of ropinirole (RPR) in human plasma with liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive-ion mode. A solid-phase process was used to extract RPR and citalopram (internal standard, IS) from human plasma. Chromatographic separation was operated with 0.2% ammonia solution:acetonitrile (20:80, v/v) at a flow rate of 0.50 mL/min on a Hypurity C(18) column with a total run time of 3.2 min. The MS/MS ion transitions monitored were 261.2 --> 114.2 for RPR and 325.1 --> 209.0 for IS. Method validation and clinical sample analysis were performed as per FDA guidelines and the results met the acceptance criteria. The lower limit of quantitation achieved was 3.45 pg/mL and the linearity was observed from 3.45 to 1200 pg/mL. The intra-day and inter-day precisions were in the range of 4.71-7.98 and 6.56-8.31%, respectively. This novel method has been applied to a pharmacokinetic study of RPR in humans.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Agonistas de Dopamina/sangue , Agonistas de Dopamina/farmacocinética , Indóis/sangue , Indóis/farmacocinética , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/economia , Humanos , Masculino , Sensibilidade e Especificidade , Extração em Fase Sólida , Espectrometria de Massas por Ionização por Electrospray/economia , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/economia , Fatores de TempoRESUMO
Perospirone is a novel atypical antipsychotic with a unique combination of 5-HT(1A) receptor agonism as well as 5-HT(2A) and D(2) receptor antagonism. A simple rapid and selective LC-MS method utilizing a single quadrupole mass spectrometer was developed and validated for the determination of perospirone hydrochloride in human plasma. N-hexane was used to extract perospirone hydrochloride and amlodipine benzenesulfonate (internal standard (IS)) from an alkaline plasma sample. LC separation was performed on a XTerra MS C(18) column (100mmx2.1mm, i.d. 3.5microm) using methanol -10mM ammonium acetate (84:16, v/v) as a mobile phase. The quantification of target compounds was obtained by using a selected ion monitoring (SIM) at m/z 427.5 [M+H](+) for perospirone hydrochloride, and at m/z 431.4 [M+Na](+) for IS (amlodipine benzenesulfonate). Perospirone and IS eluted as sharp, symmetrical peaks with retention times of 3.11+/-0.01min and 4.15+/-0.2min, respectively. Calibration curves of perospirone hydrochloride in human plasma at concentrations ranging from 0.10 to 21.1ng/mL exhibited excellent linearity (r(2)=0.9997). The mean absolute recovery of the drug from plasma was more than 85%. Intra- and inter-day relative standard deviations were less than 6.43% and 11.9% for perospirone hydrochloride at the range from 0.32 to 10.6ng/mL. Stability characteristics of the drug-containing plasma were thoroughly evaluated to establish appropriate conditions to process, store and prepare for chromatographic analysis without inducing significant chemical degradation. The following pharmacokinetic parameters were elucidated after administering a single dose of 8mg perospirone hydrochloride. The area under the plasma concentration versus time curve from time 0 to 24h (AUC(0-24)) was 15.48+/-4.23microg/Lh; peak plasma concentration (C(max)) was 2.79+/-0.78microg/L; time to C(max) (T(max)) was 1.79+/-0.45h; and elimination half-life (t(1/2)) 6.78+/-1.38h. The described assay method showed acceptable precision, accuracy, linearity, stability, and specificity and can be used for pharmacokinetic studies, therapeutic drug monitoring, and drug abuse screening.
Assuntos
Cromatografia Líquida/métodos , Indóis/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Tiazóis/sangue , Adulto , Antipsicóticos/sangue , Antipsicóticos/química , Antipsicóticos/farmacocinética , Povo Asiático , China , Feminino , Humanos , Indóis/química , Indóis/farmacocinética , Isoindóis , Masculino , Estrutura Molecular , Reprodutibilidade dos Testes , Tiazóis/química , Tiazóis/farmacocinéticaRESUMO
A sensitive high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (MS/MS) method was developed and validated for the simultaneous quantification of trandolapril and its metabolite trandolaprilat in human plasma using ramipril as an internal standard. Following solid-phase extraction, the analytes were separated using an isocratic mobile phase on a reversed-phase column and analyzed by MS/MS in the multiple reaction monitoring mode using the respective [M-H]- ions, m/z 429/168 for trandolapril, m/z 401/168 for trandolaprilat and m/z 415/166 for the internal standard. The method exhibited a linear dynamic range of 20-10,000 pg/mL for both trandolapril and trandolaprilat in human plasma. The lower limit of quantification was 20 pg/mL for both trandolapril and its metabolite. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. A run time of 2.0 min for each sample made it possible to analyze more than 400 human plasma samples per day. The validated method has been successfully used to analyze human plasma samples for application in pharmacokinetic, bioavailability or bioequivalence studies.
Assuntos
Análise Química do Sangue/métodos , Cromatografia Líquida de Alta Pressão/métodos , Indóis/sangue , Extração em Fase Sólida/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Anti-Hipertensivos/sangue , Humanos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
A simple, sensitive and rapid high-performance liquid chromatography/negative ion electrospray tandem mass spectrometry method was developed and validated for the assay of fluvastatin in human plasma. Following solid-phase extraction, the analytes were separated using an isocratic mobile phase on a reversed-phase column and analyzed by mass spectrometry in the multiple reaction monitoring mode using the respective [M-H]- ions, m/z 410/348 for fluvastatin and m/z 480/418 for the internal standard. The assay exhibited a linear dynamic range of 2-500 ng/mL for fluvastatin in human plasma. The lower limit of quantification was 2 ng/mL with a relative standard deviation of less than 5%. Acceptable precision and accuracy were obtained for concentrations over the standard curve range. A run time of 1.5 min for each sample made it possible to analyze more than 400 human plasma samples per day. The validated method has been successfully used to analyze human plasma samples for application in pharmacokinetic, bioavailability or bioequivalence studies.
Assuntos
Ácidos Graxos Monoinsaturados/sangue , Ácidos Graxos Monoinsaturados/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Indóis/sangue , Indóis/farmacocinética , Disponibilidade Biológica , Calibragem , Cromatografia Líquida de Alta Pressão , Fluorbenzenos/sangue , Fluvastatina , Humanos , Pirimidinas/sangue , Padrões de Referência , Reprodutibilidade dos Testes , Rosuvastatina Cálcica , Espectrometria de Massas por Ionização por Electrospray , Sulfonamidas/sangue , Equivalência TerapêuticaAssuntos
Bactérias Anaeróbias , Infecções Bacterianas/diagnóstico , Infecções dos Tecidos Moles/diagnóstico , Aminas/sangue , Infecções Bacterianas/sangue , Infecções Bacterianas/metabolismo , Infecções Bacterianas/terapia , Cromatografia Gasosa , Cresóis/sangue , Ácidos Graxos/sangue , Ácidos Graxos Voláteis/sangue , Hemoperfusão , Humanos , Indóis/sangue , Cetonas/sangue , Espectrometria de Massas , Fenóis/sangue , Plasmaferese , Infecções dos Tecidos Moles/sangue , Infecções dos Tecidos Moles/metabolismo , Infecções dos Tecidos Moles/terapia , Fatores de TempoRESUMO
The objective of this study was to assess the effect on serum lipid levels of the substitution of simvastatin for fluvastatin at a dose ratio of 8:1 (fluvastatin to simvastatin). A secondary objective was to determine the number of patients at goal lipid levels before and after this substitution. The study included 60 outpatients with hyperlipidemia who had received a constant dose of fluvastatin for at least 6 weeks. After a baseline 12-hour lipid profile (total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein [LDL]) was obtained, patients were switched from fluvastatin to simvastatin at an 8:1 dose ratio. Patients were instructed to split the simvastatin tablets in half with a pill splitter and to take one half-tablet at bedtime. A repeat lipid profile and liver function testing were performed after 6 to 8 weeks of simvastatin therapy. Lipid components were compared before and during simvastatin therapy using a paired t test. Target LDL levels were based on guidelines issued by the National Cholesterol Education Program. Fifty-six patients completed the study. No change in lipid components was observed, except for a statistically significant decrease in LDL. The majority of patients had a decrease in LDL levels, rather than an increase, after the conversion to simvastatin. Six patients required a dose increase of simvastatin in response to increased LDL levels. Forty-one percent of patients achieved goal LDL levels with simvastatin, compared with 30% with fluvastatin. Four patients withdrew from the study, two because of troublesome side effects and two for failure to complete the protocol. The results show that simvastatin can be substituted for fluvastatin at a dose ratio of 8:1 without loss of lipid control in the majority of patients and that by using this ratio and splitting tablets, significant cost savings can be realized.