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Groningen, Netherlands

Heijboer A.C.,VU University Amsterdam | Zimmerman Y.,Pantarhei Bioscience B.V. | de Boer T.,QPS Netherlands BV | Coelingh Bennink H.,Pantarhei Bioscience B.V. | Blankenstein M.A.,VU University Amsterdam
Clinica Chimica Acta

Total testosterone is considered to be decreased during the use of combined oral contraceptives. There is, however, considerable concern about the quality of testosterone assays, especially at low levels. We aimed to confirm testosterone levels measured by direct radioimmunoassay in a recent clinical trial with a state-of-the-art LC-MSMS method.Surplus specimens with known testosterone levels collected during the study (Clinical Trial Registration number ISRCTN06414473) were reanalyzed with an LC-MSMS method. This method was compared to another LC-MSMS method that had shown to concur excellently to a reference method. Follow-up experiments were designed to explain the results.In contrast to our expectation, LC-MSMS measurements did not corroborate the data obtained by radioimmunoassay. Subsequent experiments showed that this could be attributed to a strong dependency of the radioimmunoassay on SHBG. Testosterone results (n=198) obtained by direct radioimmunoassay showed a negative correlation to SHBG levels (r=0.676; p. <. 0.001). By contrast, testosterone results obtained by LC-MSMS were not related to SHBG (r=0.100; NS).In conclusion, our results indicate that total testosterone measurements during oral contraceptive use are unreliable when performed with assays sensitive to the SHBG concentration. The discrepancy with the literature can most likely be explained by the sensitivity of the immunoassay used to SHBG. Given the sharp increase in SHBG during the use of many oral contraceptives, total testosterone may not decrease, whereas its bioavailability, estimated by free testosterone levels, will be diminished. Studies aiming at restoration of testosterone homeostasis during oral contraception need to take this into account. © 2014 Elsevier B.V. Source

De Vries R.,Janssen R and D NV | Barfield M.,Glaxosmithkline | Van De Merbel N.,PRA | Schmid B.,Nuvisan GmbH | And 7 more authors.

Background: The European Bioanalysis Forum dried blood spots (DBS)/microsampling consortium is reporting back from the experiments they performed on further documenting the potential hurdles of the DBS technology. This paper is focused on the impact of hematocrit changes on DBS analyses. Results: The hematocrit can have an effect on the size of the blood spot, on spot homogeneity and on extraction recovery in a compound-dependent manner. The extraction recovery can change upon aging in an hematocrit-dependent way. Different card materials can give different outcomes. Conclusions: The results from the conducted experiments show that the issues of DBS in regulated bioanalysis are real and that the technology will need improvements to be ready for use as a general tool for regulated bioanalysis. © 2013 Future Science Ltd. Source

Jager U.,Medical University of Vienna | Fridrik M.,Center for Hematology and Medical Oncology | Zeitlinger M.,Medical University of Vienna | Heintel D.,Center for Oncology and Hematology | And 13 more authors.

Background Treatment of follicular lymphoma with rituximab is currently recommended at a dose of 375 mg/m2. We aimed to provide a rationale for optimal dosing and scheduling of this anti-CD20 antibody based on pharmacokinetics. Design and Methods Clinical efficacy of immuno-chemotherapy with rituximab, fludarabine and mitoxantrone followed by 2-monthly rituximab maintenance was evaluated in 29 patients with previously untreated follicular lymphoma in a prospective phase II trial (AGMT-NHL9). Pharmacokinetic analysis was assessed in 17 patients. Results Induction treatment resulted in high clinical response rates (complete remission 66%; ORR 100%). Significantly higher complete remission rates were observed in female patients (86 vs. 47%; Odds Ratio 6.8, 95% CI: 1.12; 41.82; P=0.05). Rituximab pharmacokinetic analysis showed a high variability ranging over almost 1 order of magnitude at maintenance cycle 1 (area under the curve 1,540-12,025 g/L*days). Median area under the curve was lower in men (81%) and in patients with initial bone marrow infiltration (76%). Higher rituximab serum concentrations before next therapy (Ctrough) were associated with female sex (P=0.04) as well as with absence of initial bone marrow infiltration (P=0.001). Ctrough correlated with remission quality (complete vs. partial remission; P=0.005) and progression-free survival (P=0.03). A decline in rituximab Ctrough below 25,000 ng/mL was observed 9.5 to 62 months before clinical relapse (P=0.008). Conclusions The results of this pilot trial suggest that more differentiated dosing schedules based on gender and bone marrow infiltration should be explored for rituximab therapy for lymphoma. This study was registered in ClinicalTrials.gov (Identifier: NCT01560117). ©2012 Ferrata Storti Foundation. Source

Van Baar B.L.M.,QPS Netherlands BV | Verhaeghe T.,Janssen R and D | Heudi O.,Novartis | Rohde M.,Lundbeck | And 6 more authors.

Background: In the framework of wider exploration of the application of dried blood spots (DBS) in bioanalysis, by the DBS consortium of the European Bioanalytical Forum, one team of five laboratories investigated the merits of the various ways of IS addition prior to LC-MS/MS analysis. A set of 22 pharmaceutical compounds with log P in the range of 0-10 was selected for this purpose. Assessments were made of precision, recovery, and of the effects of prolonged storage. Results: Assay precision was not significantly different for 3 month-aged samples as compared with 'fresh" samples stored for 7-22 days. Extraction recovery from 3 month-aged spots decreased for some of the analytes; the most widely employed addition of IS in the extraction solvent does not compensate for recovery in such cases. Conclusion: From the overall results, it is clear that there is no 'one size fits all" approach to IS addition in DBS bioanalysis. © 2013 Future Science Ltd. Source

Cobb Z.,Quotient Bio Analytical science Part of the LGC Group | De Vries R.,Janssen R and D | Spooner N.,Glaxosmithkline | Williams S.,Charles River Laboratories | And 12 more authors.

Background: At the start of their work, the European Bioanalysis Forum dried blood spots microsampling consortium did not form a dedicated team to investigate the spot homogeneity. However, two teams performed experiments that produced results relating to sample homogeneity. Results: The data, which were produced via two different approaches (a radiolabeled and a nonradiolabeled approach), are highly complementary and demonstrate clear effects on sample inhomogeneity due to the substrate type, compound and hematocrit levels. Conclusion: The results demonstrate that sample inhomogeneity is a significant hurdle to the use of dried blood spots for regulated bioanalysis that should be investigated further in the method establishment phase if the whole spot is not sampled. © 2013 Future Science Ltd. Source

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