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Flint A.,Novo Nordisk AS | Nazzal K.,Medical University of Warsaw | Jagielski P.,PRA Early Development Services | Hindsberger C.,Novo Nordisk AS | Zdravkovic M.,Novo Nordisk AS
British Journal of Clinical Pharmacology | Year: 2010

AIMS: To compare the pharmacokinetics (PK) of a single-dose of liraglutide in subjects with hepatic impairment. METHODS: This parallel group, open label trial involved four groups of six subjects with healthy, mild, moderate and severe hepatic impairment, respectively. Each subject received 0.75 mg of liraglutide (s.c., thigh), and blood samples were taken over 72 h for PK assessment. Standard laboratory and safety data were collected. The primary endpoint was area under the plasma liraglutide concentration-time curve from time zero to infinity (AUC(0,∞)). RESULTS: Exposure to liraglutide was not increased by hepatic impairment. On the contrary, mean AUC(0,∞) was highest for healthy subjects and lowest for subjects with severe hepatic impairment (severe/healthy: 0.56, with 90% CI 0.39, 0.81) and equivalence in this parameter across groups was not demonstrated. Cmax also tended to decrease with hepatic impairment (severe/healthy: 0.71, with 90% CI 0.52, 0.97), but tmax was similar across groups (11.3-13.2 h). There were no serious adverse events, hypoglycaemic episodes or clinically significant changes in laboratory parameters and liraglutide was considered well tolerated. CONCLUSIONS: This study indicated no safety concerns regarding use of liraglutide in patients with hepatic impairment. Exposure to liraglutide was not increased by impaired liver function; rather, the results suggest a decreased exposure with increasing degree of hepatic impairment. However, data are not conclusive to suggest a dose increase of liraglutide. Thus, the results indicate that patients with type 2 diabetes mellitus and hepatic impairment can use standard treatment regimens of liraglutide. There is, however, currently limited clinical experience with liraglutide in patients with hepatic impairment. © 2010 Novo Nordisk A/S. British Journal of Clinical Pharmacology © 2010 The British Pharmacological Society. Source

Van De Merbel N.C.,PRA Early Development Services | Van De Merbel N.C.,University of Groningen | Walland P.,PRA Early Development Services | Tiensuu M.,Active Biotech AB | Sennbro C.J.,Active Biotech AB
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2014

Tasquinimod is an anti-tumor drug that is currently in clinical development for the treatment of solid cancers. After oral administration, tasquinimod and a number of its metabolites are excreted in the urine. The quantitative determination of tasquinimod in urine is challenging because of the required sensitivity (down to 0.1. nM or 40. pg/mL), the highly variable nature of this biological matrix and the presence of potentially unstable metabolites, which may convert back to the parent drug. In this article, an LC-MS/MS method is described for the determination of tasquinimod in human urine in the concentration range 0.1-200. nM. Liquid-liquid extraction with n-chlorobutane was used to extract tasquinimod from 100. μL human urine and to remove interfering endogenous urinary constituents. Reversed-phase liquid chromatography coupled to a triple quadrupole mass spectrometer equipped with an ESI source was used for quantification of tasquinimod in a 2.5-min run. A stable-isotope labeled internal standard was used for response normalization. The intra- and inter-day coefficients of variation (precision) as well as the bias (accuracy) of the method were below 7%. Although considerable conversion of conjugated tasquinimod metabolites back to parent drug was observed when incurred samples were stored at 37. °C for a prolonged time, tasquinimod as well as its metabolites were sufficiently stable under all relevant sampling, storage and analysis conditions. The method was successfully applied to determine the urinary excretion of tasquinimod in healthy volunteers and patients with renal impairment after a 0.5-mg oral dose. © 2014 Elsevier B.V. Source

Hilhorst M.J.,PRA Early Development Services | Hendriks G.,PRA Early Development Services | de Vries R.,Janssen Pharmaceutical | Hillewaert V.,Janssen Pharmaceutical | And 3 more authors.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2014

A liquid chromatography-tandem mass spectrometry method is described for the quantitative determination of artemether (ART) and its metabolite dihydroartimisinin (DHA) in human plasma samples. Quantitation of ART and DHA in plasma is challenging due to the presence of malaria related hemolytic products in patient plasma causing degradation of the compounds when organic solvents are used during sample processing. Furthermore, both compounds consist of two epimeric forms that can interconvert both in solution and during chromatographic separation, an effect that is dependent on temperature and solvent properties and needs to be taken into account. This method utilizes micro-elution solid-phase extraction as sample preparation technique to minimize the need for organic solvents. Reversed-phase HPLC using a C18 50. ×. 2.1. mm column with 3.5. μm particles and a mobile phase of acetonitrile:water (30:70, v/v), followed by a step gradient at 90% acetonitrile, is applied to separate ART from DHA and matrix interferences within a run time of 4. min. Chromatographic conditions were optimized to allow analyte quantitation independent of the (unknown) ratio of the epimers in the injected sample. A triple quadruple mass spectrometer equipped with an atmospheric pressure chemical ionization interface in positive mode was used for detection in order to detect all epimeric forms. The method proved to be linear over a concentration range of 1.00-1000. ng/mL using 50. μL of plasma. Accuracy and precision were within 15% for bias and CV (20% at the lower limit of quantification). ART and DHA were stable (bias <15%) in plasma for 211 days after storage at -20. °C and -70. °C, 17. h on melting ice and 2. h at room temperature. Furthermore, both compounds were stable in whole blood after storage for 2. h on melting ice and at room temperature and after five freeze/thaw cycles. The method was successfully used for the analysis of pharmacokinetic samples originating from a drug-drug interaction study in which the antimalarial drugs artemether/lumefantrine were coadministrated etravirine or darunavir/ritonavir in healthy human immunodeficiency virus (HIV)-negative subjects. © 2014. Source

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