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Birsfelden, Switzerland

Buscher B.,TNO | Laakso S.,Orion Corporation | Mascher H.,Pharm Analyt | Pusecker K.,Grunenthal GmbH | And 6 more authors.

Plasma protein binding (PPB) is an important parameter for a drug's efficacy and safety that needs to be investigated during each drug-development program. Even though regulatory guidance exists to study the extent of PPB before initiating clinical studies, there are no detailed instructions on how to perform and validate such studies. To explore how PPB studies involving bioanalysis are currently executed in the industry, the European Bioanalysis Forum (EBF) has conducted three surveys among their member companies: PPB studies in drug discovery (Part I); in vitro PPB studies in drug development (Part II); and in vivo PPB studies in drug development. This paper reflects the outcome of the three surveys, which, together with the team discussions, formed the basis of the EBF recommendation. The EBF recommends a tiered approach to the design of PPB studies and the bioanalysis of PPB samples: 'PPB screening' experiments in (early) drug discovery versus qualified/validated procedures in drug development. © 2014 Future Science Ltd. Source

Spieker E.,Swiss BioAnalytics AG | Wagner-Redeker W.,Swiss BioAnalytics AG | Dingemanse J.,Actelion Pharmaceuticals
Journal of Pharmaceutical and Biomedical Analysis

A sensitive liquid chromatography-tandem mass spectrometry method has been developed to quantify miglustat in mouse plasma and in human plasma. The method involved simple protein precipitation with methanol. N-(n-nonyl)deoxynojirimycin was used as internal standard. Separation was performed on a Gemini C 18 column (2.1mm×50mm, particle size 5μm) with a binary gradient at a flow rate of 600μl/min. The mobile phases were methanol and water both containing 0.01% of a 25% ammonium hydroxide solution. The triple stage quadrupole mass spectrometer was operated in APCI mode using the transitions m/z 220.1≥158.0 for miglustat and m/z 290.1≥228.0 for the internal standard. The method was linear over a range of 10-10,000ng/ml. The intra-day coefficients of variation for mouse plasma were equal to or smaller than 14.1%. The intra- and inter-day accuracies were 84.5-107.2% and 90.9-104.0%, respectively. For human plasma the intra-day coefficients of variation were equal to or smaller than 13.5%, while accuracies ranged between 93.6% and 100.0%. The validated method offered increased sensitivity (10 times higher) and decreased cycle times compared to other methods. It was successfully applied to the pharmacokinetic assessment of miglustat during treatment of patients with cystic fibrosis. © 2011 Elsevier B.V. Source

Wagner-Redeker W.,Swiss BioAnalytics AG | Finsterwald I.,Swiss BioAnalytics AG | Dingemanse J.,Actelion Pharmaceuticals
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences

A sensitive and selective LC-MS/MS method has been developed to quantify almorexant and its four primary metabolites M3, M5, M6, and M8 in human plasma samples. The method involved protein precipitation with acetonitrile in the high calibration range and liquid/liquid extraction with ethyl acetate in the low calibration range. Labeled internal standards were available for four analytes. Separation was performed with an Eclipse XDB-C18 (2.1mm×150mm, particle size 3.5μm) and a XBridge C18 column (2.1mm×50mm, particle size 3.5μm). The mobile phases were mixtures of acetonitrile, methanol, and water containing 1% formic acid; flow rate was 400μL/min. The triple stage quadrupole mass spectrometer was operated in ESI mode and the methods were linear over a range of 0.400-100ng/mL (almorexant, M5, M6), 1.00-100ng/mL (M3, M8), and 50.0-1000ng/mL (all analytes). The inter-day coefficients of variation were equal to or smaller than 10.5%. The inter-day accuracies were between 92.1% and 105.2%. The validated method was successfully applied to the pharmacokinetic assessment of almorexant and its metabolites in several phase I studies. © 2014 Elsevier B.V. Source

Bruderer S.,Actelion Pharmaceuticals | Hopfgartner G.,Swiss BioAnalytics AG | Seiberling M.,Covance | Wank J.,Swiss BioAnalytics AG | And 3 more authors.

Macitentan is a tissue-targeting, dual endothelin receptor antagonist, currently under phase 3 investigation in pulmonary arterial hypertension. In this study the disposition and metabolism of macitentan were investigated following administration of a single oral 10mg dose of 14C-macitentan to six healthy male subjects. The total radioactivity in matrices was determined using liquid scintillation counting. The proposed structure of metabolites was based on mass spectrometry characteristics and, when available, confirmed by comparison with reference compounds. Mean (± SD) cumulative recovery of radioactivity from faeces and urine was 73.6% (±6.2%) of the administered radioactive dose, with 49.7% (±3.9%) cumulative recovery from urine, and 23.9% (±4.8%) from faeces. In plasma, in addition to parent macitentan, ACT-132577, a pharmacologically active metabolite elicited by oxidative depropylation and the carboxylic acid metabolite ACT-373898 were identified. In urine, four entities were identified, with the hydrolysis product of ACT-373898 as the most abundant one. In faeces, five entities were identified, with the hydrolysis product of macitentan and ACT-132577 as the most abundant one. Concentrations of total radioactivity in whole blood were lower compared to plasma, which indicates that macitentan and its metabolites poorly bind to or penetrate into erythrocytes. © 2012 Informa UK, Ltd. Source

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