RESUMO
Following a decision to require label warnings for concurrent use of opioids and benzodiazepines and increased risk of respiratory depression and death, the US Food and Drug Administratioin (FDA) recognized that other sedative psychotropic drugs may be substituted for benzodiazepines and be used concurrently with opioids. In some cases, data on the ability of these alternatives to depress respiration alone or in conjunction with an opioid are lacking. A nonclinical in vivo model was developed that could detect worsening respiratory depression when a benzodiazepine (diazepam) was used in combination with an opioid (oxycodone) compared to the opioid alone based on an increased arterial partial pressure of carbon dioxide (pCO2 ). The current study used that model to assess the impact on respiration of non-benzodiazepine sedative psychotropic drugs representative of different drug classes (clozapine, quetiapine, risperidone, zolpidem, trazodone, carisoprodol, cyclobenzaprine, mirtazapine, topiramate, paroxetine, duloxetine, ramelteon, and suvorexant) administered alone and with oxycodone. At clinically relevant exposures, paroxetine, trazodone, and quetiapine given with oxycodone significantly increased pCO2 above the oxycodone effect. Analyses indicated that most pCO2 interaction effects were due to pharmacokinetic interactions resulting in increased oxycodone exposure. Increased pCO2 recorded with oxycodone-paroxetine co-administration exceeded expected effects from only drug exposure suggesting another mechanism for the increased pharmacodynamic response. This study identified drug-drug interaction effects depressing respiration in an animal model when quetiapine or paroxetine were co-administered with oxycodone. Clinical pharmacodynamic drug interaction studies are being conducted with these drugs to assess translatability of these findings.
Assuntos
Quimioterapia Combinada/efeitos adversos , Hipnóticos e Sedativos/efeitos adversos , Oxicodona/efeitos adversos , Psicotrópicos/efeitos adversos , Insuficiência Respiratória/induzido quimicamente , Animais , Oxicodona/administração & dosagem , Psicotrópicos/administração & dosagem , Ratos , Ratos Sprague-DawleyRESUMO
Application of sunscreen is one of many ways to protect skin from the harmful effects of UV radiation. Sunscreen products are widely used and regulated as over-the-counter drug products in the United States. The U.S. Food and Drug Administration recommends an assessment of human systemic absorption of sunscreen active ingredients with a Maximal Usage Trial. The FDA conducted a clinical study to determine the systemic exposure of sunscreen active ingredients present in 4 commercially available sunscreen products of different formulation types under maximal usage conditions. To support this clinical study, a sensitive and specific LC-MS/MS method for the simultaneous determination of the two sunscreens avobenzone and oxybenzone in human plasma was developed. Phospholipid removal 96-well protein precipitation plates were used for sample clean-up and the extracted samples were chromatographed on an Ethylene-Bridged Hybrid (BEH) C18 column in isocratic flow using 10 mM ammonium formate in 0.1% formic acid and methanol (24:76, v/v) as a mobile phase. A triple quadrupole mass spectrometer in multiple reaction monitoring (MRM) mode was used to acquire data. The method was validated as per current FDA bioanalytical method validation guidance, in the ranges 0.20-12.00 ng/mL for avobenzone and 0.40-300.00 ng/mL for oxybenzone. The validated method was used toanalyzethese active ingredients in human clinical study samples.
Assuntos
Benzofenonas/sangue , Cromatografia Líquida de Alta Pressão/métodos , Propiofenonas/sangue , Protetores Solares/administração & dosagem , Espectrometria de Massas em Tandem/métodos , Administração Cutânea , Benzofenonas/farmacocinética , Feminino , Humanos , Modelos Lineares , Masculino , Propiofenonas/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Protetores Solares/farmacocinéticaRESUMO
Opioids and benzodiazepines were frequently co-prescribed to patients with pain and psychiatric or neurological disorders; however, co-prescription of these drugs increased the risk for severe respiratory depression and death. Consequently, the U.S. Food and Drug Administration added boxed label warnings describing this risk for all opioids and benzodiazepines. Sedating psychotropic drugs with differing mechanisms of action (e.g., antipsychotics, antidepressants, non-benzodiazepine sedative-hypnotics, etc.) may be increasingly prescribed in place of benzodiazepines. Despite being marketed for years, many sedating psychotropic drugs have neither human nor animal data that quantify or qualify the potential for causing respiratory depression, either alone or in combination with an opioid. In this study, diazepam was selected as the benzodiazepine to detect any additive or synergistic effects on respiratory depression caused by the opioid, oxycodone. Pharmacokinetic studies were conducted at three doses with oxycodone (6.75, 60, 150â¯mg/kg) and with diazepam (2, 20, 200â¯mg/kg). Dose dependent decrease in arterial partial pressure of oxygen and increase in arterial partial pressure of carbon dioxide were observed with oxycodone. Diazepam caused similar partial pressure changes only at the highest dose. Further decreases in arterial partial pressure of oxygen and increases in arterial partial pressure of carbon dioxide consistent with exacerbated respiratory depression were observed in rats co-administered oxycodone 150â¯mg/kg and diazepam 20â¯mg/kg. These findings confirm previous literature reports of exacerbated opioid-induced respiratory depression with benzodiazepine and opioid co-administration and support the utility of this animal model for assessing opioid-induced respiratory depression and its potential exacerbation by co-administered drugs.
RESUMO
The authors developed a novel, sensitive high-throughput ultra-performance liquid chromatography-tandem mass spectrometric method for the determination of dofetilide in human plasma. To compensate for the matrix effect, a deuterated internal standard was used. The method employed a very low sample volume (50 µL) of plasma for sample processing by using simple protein precipitation extraction in a 96-well plate. The extracted samples were chromatographed on an Acquity BEH C18 column (2.1 × 100 mm, 1.7 µm) and eluted in a gradient manner at a flow rate of 0.5 mL/min for 2 min using 5 mM ammonium formate (0.1% formic acid) and methanol. The calibration curve was linear from 25 to 2,500 pg/mL with a correlation coefficient (r2) ≥ 0.99 (0.9969-0.9980; n = 3). The developed method was validated as per the current United States Food and Drug Administration's guidance for industry on 'Bioanalytical Method Validation'. The multiple reaction-monitoring mode was employed for quantitation of dofetilide with m/z 442.2/198.2 and dofetilide d4 with m/z 446.2/198.2. The validated method was used for evaluation of dofetilide concentration in the Comprehensive in vitro Proarrhythmia Assay phase 1 electrocardiogramic biomarker validation study.
Assuntos
Fenetilaminas/análise , Bloqueadores dos Canais de Potássio/análise , Sulfonamidas/análise , Biomarcadores/química , Calibragem , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Eletrocardiografia , Formiatos , Humanos , Limite de Detecção , Fenetilaminas/química , Plasma , Bloqueadores dos Canais de Potássio/química , Reprodutibilidade dos Testes , Sulfonamidas/química , Espectrometria de Massas em TandemRESUMO
Benzodiazepines potentiate respiratory depression when combined with an opioid leading the U.S Food and Drug Administration (FDA) to recommend updating the labels of these products with a boxed warning for respiratory depression with co-use. Potential respiratory depression upon co-administration of opioids with some psychotropic drugs is not well understood. The FDA is currently investigating various psychotropic drug interactions with the commonly used opioid, oxycodone, in a rat model assessing respiratory depression. Pharmacokinetic and/or pharmacodynamic (PK/PD) interaction between oxycodone and diazepam was evaluated in a positive control arm of these experiments. Understanding the systemic exposure of these drugs alone and in combination exposures was used to identify PK/PD interactions. The authors developed a simple, high throughput liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay for the simultaneous determination of oxycodone and diazepam in rat plasma. Sample preparation was performed in 96-well protein precipitation plates using acetonitrile. Processed samples were analyzed using a C18 column with a gradient mobile phase composed of 2 mM aqueous ammonium formate with 0.1% formic acid and acetonitrile. A Thermo TSQ Quantum Ultra AM triple quadrupole mass spectrometer with multiple reaction monitoring (MRM) mode was used to acquire data. The method was validated for selectivity, specificity, linearity, precision and accuracy, dilution integrity and stability. The validated LC-MS/MS assay was utilized for quantifying oxycodone and diazepam in concomitantly treated Sprague Dawley (SD) rats.
RESUMO
Developing mathematical models to predict changes in ocular bioavailability and pharmacokinetics due to differences in the physicochemical properties of complex topical ophthalmic suspension formulations is important in drug product development and regulatory assessment. Herein, we used published FDA clinical pharmacology review data, in-house, and literature rabbit pharmacokinetic data generated for dexamethasone ophthalmic suspensions to demonstrate how the mechanistic Ocular Compartmental Absorption and Transit model by GastroPlus™ can be used to characterize ocular drug pharmacokinetic performance in rabbits for suspension formulations. This model was used to describe the dose-dependent (0.01 to 0.1%) non-linear pharmacokinetic in ocular tissues and characterize the impact of viscosity (1.67 to 72.9 cP) and particle size (5.5 to 22 µm) on in vivo ocular drug absorption and disposition. Parameter sensitivity analysis (hypothetical suspension particle size: 1 to 10 µm, viscosity: 1 to 100 cP) demonstrated that the interplay between formulation properties and physiological clearance through drainage and tear turnover rates in the pre-corneal compartment drives the ocular drug bioavailability. The quick removal of drug suspended particles from the pre-corneal compartment renders the impact of particle size inconsequential relative to viscosity modification. The in vivo ocular absorption is (1) viscosity non-sensitive when the viscosity is high and the impact of viscosity on the pre-corneal residence time reaches the maximum physiological system capacity or (2) viscosity sensitive when the viscosity is below a certain limit. This study reinforces our understanding of the interplay between physiological factors and ophthalmic formulation physicochemical properties and their impact on in vivo ocular drug PK performance in rabbits.
Assuntos
Simulação por Computador , Dexametasona/farmacocinética , Olho/metabolismo , Modelos Biológicos , Absorção Ocular , Animais , Disponibilidade Biológica , Dexametasona/administração & dosagem , Dexametasona/sangue , Relação Dose-Resposta a Droga , Humanos , Soluções Oftálmicas , Coelhos , SuspensõesRESUMO
In mass spectrometry, compounds that have different ionization properties experience challenges in simultaneous analysis. In the present paper, the authors proposed a polarity switching (+ve and -ve) LC-MS/MS method to analyze oxycodone and topiramate in a single run. The developed method was validated in the range of 5-1000â¯ng/mL for oxycodone and 20-5000â¯ng/mL for topiramate as per the US FDA guidelines. The mass spectrometer was operated in multiple reaction monitoring (MRM) mode to analyze oxycodone and topiramate simultaneously using oxycodone-d6 and topiramate-d12 as internal standards, respectively. Sample preparation was performed in 96-well protein precipitation plates using acetonitrile. Processed samples were analyzed using a C18 column with a gradient mobile phase composed of 10â¯mm ammonium formate with 0.1% formic acid and acetonitrile. The method was validated for selectivity, specificity, linearity, precision and accuracy, dilution integrity and stability. After validation, this method was successfully applied to quantify oxycodone and topiramate in plasma of concomitantly treated Sprague Dawley (SD) rats.
Assuntos
Cromatografia Líquida/métodos , Oxicodona/sangue , Espectrometria de Massas em Tandem/métodos , Topiramato/sangue , Animais , Modelos Lineares , Masculino , Oxicodona/administração & dosagem , Oxicodona/química , Oxicodona/farmacocinética , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Topiramato/administração & dosagem , Topiramato/química , Topiramato/farmacocinéticaRESUMO
A rapid, sensitive and specific ultrafiltration inductively-coupled plasma mass spectrometry (UF-ICP-MSICP-MS) method was developed and validated for the quantification of non-transferrin bound iron (NTBI), transferrin bound iron (TBI), drug bound iron (DI) and total iron (TI) in the same rat serum sample after intravenous (IV) administration of iron gluconate nanoparticles in sucrose solution (Ferrlecit®). Ultrafiltration with a 30 kDa molecular cut-off filter was used for sample cleanup. Different elution solvents were used to separate each form of iron from sample serum. Isolated fractions were subjected to inductively-coupled mass spectrometric analysis after microwave digestion in 4% nitric acid. The reproducibility of the method was evaluated by precision and accuracy. The calibration curve demonstrated linearity from 5-500 ng/mL with a regression (r²) of more than 0.998. This method was effectively implemented to quantify rat pharmacokinetic study samples after intravenous administration of Ferrlecit®. The method was successfully applied to a pharmacokinetic (PK) study of Ferrlecit in rats. The colloidal iron followed first order kinetics with half-life of 2.2 h and reached background or pre-dose levels after 12 h post-dosing. The drug shown a clearance of 0.31 mL/min/kg and volume of distribution of 0.05 L/kg. 19.4 ± 2.4 mL/h/kg.
RESUMO
Exposure to Paraquat and RNA interference knockdown of mitochondrial superoxide dismutase (Sod2) are known to result in significant lifespan reduction, locomotor dysfunction, and mitochondrial degeneration in Drosophila melanogaster. Both perturbations increase the flux of the progenitor ROS, superoxide, but the molecular underpinnings of the resulting phenotypes are poorly understood. Improved understanding of such processes could lead to advances in the treatment of numerous age-related disorders. Superoxide toxicity can act through protein carbonylation. Analysis of carbonylated proteins is attractive since carbonyl groups are not present in the 20 canonical amino acids and are amenable to labeling and enrichment strategies. Here, carbonylated proteins were labeled with biotin hydrazide and enriched on streptavidin beads. On-bead digestion was used to release carbonylated protein peptides, with relative abundance ratios versus controls obtained using the iTRAQ MS-based proteomics approach. Western blotting and biotin quantitation assay approaches were also investigated. By both Western blotting and proteomics, Paraquat exposure, but not Sod2 knockdown, resulted in increased carbonylated protein relative abundance. For Paraquat exposure versus control, the median carbonylated protein relative abundance ratio (1.53) determined using MS-based proteomics was in good agreement with that obtained using a commercial biotin quantitation kit (1.36).