Publications by authors named "Dieter Zimmer"

18 Publications

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Metabolism of the Dual Orexin Receptor Antagonist ACT-541468, Based on Microtracer/ Accelerator Mass Spectrometry.

Curr Drug Metab 2019 ;20(4):254-265

Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123 Allschwil, Switzerland.

Background: As part of an integrated and innovative approach to accelerate the clinical development of the dual receptor antagonist ACT-541468, 6 healthy subjects in one cohort in a first-in-humans (FIH) study received an oral dose of 50 mg non-labeled ACT-541468 together with a microtracer amount of 250 nCi of 14C-labeled ACT- 541468 to investigate its absorption, distribution, metabolism, and excretion (ADME).

Methods: Using accelerator mass spectrometry (AMS), radiochromatograms were constructed for fractionated plasma, urine, and feces samples. Subsequently, the structures of the metabolites were elucidated using high performance liquid chromatography (HPLC) coupled with high resolution mass spectrometry.

Results: In total 77 metabolites have been identified of which 30, 28, and 60 were present in plasma, urine, and feces, respectively. In plasma, the major metabolites were the mono-oxidized benzylic alcohol M3, the ACT-541468 aldehyde M1, formed by further oxidation of M3 in the benzylic position, and the doubly oxidized M10, formed by (1) benzylic oxidation of M3 (loss of one molecule of water and one molecule of ammonia) and (2) additional loss of water from the oxidized pyrrolidine ring of M5. Transformation of the pyrrolidine to a 6-membered ring was detected. Metabolites that accounted for more than 5% of total radioactivity in excreta were M2, which is also formed by oxidation at the benzylic position, M4, formed by demethylation of the methoxy-group, M7 and A6, both formed by oxidation of M4, and M10, the only major metabolite detected in urine.

Conclusion: In conclusion, ACT-541468 is extensively metabolized predominantly by oxidative transformations.
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http://dx.doi.org/10.2174/1389200220666190206141814DOI Listing
November 2019

Bioanalytical outsourcing models in pharmaceutical companies.

Authors:
Dieter Zimmer

Bioanalysis 2017 Aug 1;9(15):1145-1148. Epub 2017 Aug 1.

Zimmer BioAnalytics & More, 4052 Basel, Switzerland.

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http://dx.doi.org/10.4155/bio-2017-4995DOI Listing
August 2017

Drugs in control samples in nonclinical safety studies: a reconsideration.

Authors:
Dieter Zimmer

Bioanalysis 2016 May 15;8(10):1003-7. Epub 2016 Apr 15.

Zimmer BioAnalytics & More, 4052 Basel, Switzerland.

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http://dx.doi.org/10.4155/bio-2016-0066DOI Listing
May 2016

New US FDA draft guidance on bioanalytical method validation versus current FDA and EMA guidelines: chromatographic methods and ISR.

Authors:
Dieter Zimmer

Bioanalysis 2014 Jan 20;6(1):13-9. Epub 2013 Nov 20.

Zimmer BioAnalytics & More, St. Alban-Ring 282, CH-4052, Basel, Switzerland.

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http://dx.doi.org/10.4155/bio.13.298DOI Listing
January 2014

Bioanalytical outsourcing: the two sides of the medal.

Authors:
Dieter Zimmer

Bioanalysis 2013 Sep;5(17):2095-9

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http://dx.doi.org/10.4155/bio.13.185DOI Listing
September 2013

Internal standard application to dried blood spots by spraying: investigation of the internal standard distribution.

Bioanalysis 2013 Mar;5(6):711-9

Harlan Laboratories Ltd., Itingen, Switzerland.

Background: The scientifically and logistically best way of application of the internal standard (IS) in the analysis of dried blood spots (DBS) analysis is still a matter of debate and investigation. Most commonly the IS is added in the solvent used for extraction of the discs punched from DBS. In this case, the recovery of the non-extracted IS is complete while the recovery of the analyte extracted from DBS is different from the IS.

Results: An alternative way for addition of the IS was investigated. A homogeneous distribution and absorption of the test compound across the spots was demonstrated by spraying a solution of a radiolabeled test compound (mimicking an IS solution) onto DBS.

Conclusion: This spray-on technique is convenient and easily automatable. Spraying of the solution was rapid, precise and reproducible, and therefore seems to be suitable for routine analysis of DBS by offline and online extraction.
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http://dx.doi.org/10.4155/bio.13.21DOI Listing
March 2013

Recommendations on bioanalytical method stability implications of co-administered and co-formulated drugs by Global CRO Council for Bioanalysis (GCC).

Bioanalysis 2012 Sep;4(17):2117-26

Advion Bioanalytical Laboratories, Quintiles, NY, USA.

An open letter written by the Global CRO Council for Bioanalysis (GCC) describing the GCC survey results on stability data from co-administered and co-formulated drugs was sent to multiple regulatory authorities on 14 December 2011. This letter and further discussions at different GCC meetings led to subsequent recommendations on this topic of widespread interest within the bioanalytical community over the past 2 years.
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http://dx.doi.org/10.4155/bio.12.192DOI Listing
September 2012

STORC safety initiative: a multicentre survey on preparedness & confidence in obstetric emergencies.

Qual Saf Health Care 2010 Dec;19(6):e41

Department of Emergency Medicine, Oregon Health & Science University, Portland, Oregon 97239, USA.

Background: Patient safety is a national and international priority. The purpose of this study was to understand clinicians' perceptions of teamwork during obstetric emergencies in clinical practice, to examine factors associated with confidence in responding to obstetric emergencies and to evaluate perceptions about the value of team training to improve preparedness.

Methods: An anonymous survey was administered to all clinical staff members who respond to obstetric emergencies in seven Oregon hospitals from June 2006 to August 2006.

Results: 614 clinical staff (74.5%) responded. While over 90% felt confident that the appropriate clinical staff would respond to emergencies, more than half reported that other clinical staff members were confused about their role during emergencies. Over 84% were confident that emergency drills or simulation-based team training would improve performance.

Conclusions: Clinical staff who respond to obstetric emergencies in their practice reported feeling confident that the qualified personnel would respond to an emergency; however, they were less confident that the responders would perform well as a team. They reported that simulation and team training may improve their preparedness and confidence in responding to emergencies.
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http://dx.doi.org/10.1136/qshc.2008.030890DOI Listing
December 2010

Towards absolute quantification of therapeutic monoclonal antibody in serum by LC-MS/MS using isotope-labeled antibody standard and protein cleavage isotope dilution mass spectrometry.

Anal Chem 2008 Jun 9;80(11):4200-7. Epub 2008 May 9.

DMPK/Bioanalytics, and Biotechnology Development, Novartis Pharma AG, CH-4002 Basel, Switzerland.

Although LC-MS methods are increasingly used for the absolute quantification of proteins, the lack of appropriate internal standard (IS) hinders the development of rapid and standardized analytical methods for both in vitro and in vivo studies. Here, we have developed a novel method for the absolute quantification of a therapeutic protein, which is monoclonal antibody (mAb). The method combines liquid chromatography tandem mass spectrometry (LC-MS/MS) and protein cleavage isotope dilution mass spectrometry with the isotope-labeled mAb as IS. The latter was identical to the analyzed mAb with the exception that each threonine contains four (13)C atoms and one (15)N atom. Serum samples were spiked with IS prior to the overnight trypsin digestion and subsequent sample cleanup. Sample extracts were analyzed on a C18 ACE column (150 mm x 4.6 mm) using an LC gradient time of 11 min. Endogenous mAb concentrations were determined by calculating the peak height ratio of its signature peptide to the corresponding isotope-labeled peptide. The linear dynamic range was established between 5.00 and 1000 microg/mL mAb with accuracy and precision within +/-15% at all concentrations and below +/-20% at the LLOQ (lower limit of quantification). The overall method recovery in terms of mAb was 14%. The losses due to sample preparation (digestion and purification) were 72% from which about 32% was due to the first step of the method, the sample digestion. This huge loss during sample preparation strongly emphasizes the necessity to employ an IS right from the beginning. Our method was successfully applied to the mAb quantification in marmoset serum study samples, and the precision obtained on duplicate samples was, in most cases, below 20%. The comparison with enzyme-linked immunosorbent assay (ELISA) showed higher exposure in terms of AUC and Cmax with the LC-MS/MS method. Possible reasons for this discrepancy are discussed in this study. The results of this study indicate that our LC-MS/MS method is a simple, rapid, and precise approach for the therapeutic mAb quantification to support preclinical and clinical studies.
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http://dx.doi.org/10.1021/ac800205sDOI Listing
June 2008

Detection of photogenotoxicity in skin and eye in rat with the photo comet assay.

Photochem Photobiol Sci 2008 Feb 9;7(2):240-9. Epub 2008 Jan 9.

Novartis Pharma AG, 4002, Basel, Switzerland.

Photosensitizing drugs increase the sensitivity of the skin and the eye toward normally harmless sunlight conditions and are known to enhance the induction of skin tumors or severe injuries to the eye. The photogenotoxicity of five common drugs (sparfloxacin, dacarbazine, chlorpromazine and 8-methoxypsoralen, promazine) was investigated in the skin as well as in the retina and cornea of Wistar rats. The compounds were administered once orally by gavage and the resulting DNA damage was analyzed in the newly developed in vivo photo comet assay. All drugs except of promazine were clearly photogenotoxic in the skin. In the cornea sparfloxacin and dacarbazine induced an increased DNA damage following irradiation. A photogenotoxic effect in the retina was observed by sparfloxacin, which is the only compound tested that absorbs wavelengths reaching the retina. The drug concentration analysis revealed that the compounds were distributed into plasma, skin and eye at concentrations, which were photogenotoxic in vitro. Additionally, histopathological analysis showed no relevant alterations or inductions of necrosis, apoptosis or inflammation in the skin or eye. In conclusion, we confirmed the photogenotoxic potential of compounds from different chemical classes in the skin. Moreover, it is the first time that photogenotoxicity has been detected in the retina and cornea in an in vivo study. Based on our results it is concluded that the photo comet assay in rat is an easy and reliable method to elucidate drug induced photogenotoxicity under conditions, which are relevant to human exposure.
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http://dx.doi.org/10.1039/b715756hDOI Listing
February 2008

Determination of deltamethrin residues in plant materials by liquid chromatography/tandem mass spectrometry with electrospray ionization.

J AOAC Int 2006 May-Jun;89(3):786-96

Bayer CropScience AG, Alfred-Nobel-Str. 50, D-40789 Monheim, Germany.

This paper describes a selective and sensitive method that uses liquid chromatography/tandem mass spectrometry with positive electrospray ionization (ESI+) for the determination of deltamethrin in a variety of crops. Samples were extracted by conventional high-speed blending. Some samples required no further cleanup; others were cleaned up by gel permeation chromatography, strong cation-exchange cartridges, or partitioning with n-hexane. In the determinative step, the buffered neutral mobile phase, consisting of 10 mM ammonium acetate (pH 6.8) and methanol, and ESI+ provided strong ammonium adduct formation to [M+NH4]+ at m/z 523, and the multiple-reaction monitoring (MRM) transition at m/z 523/281 was used for the quantitation of deltamethrin. A second MRM transition at m/z 525/283 was used for confirmation. The limit of quantitation (LOQ) values were 0.01 mg/kg for edible materials and 0.05 mg/kg for nonedible materials. Mean overall recoveries at the LOQ and the 10-fold LOQ ranged from 73 to 96%, and the relative standard deviations were <10% for all samples materials analyzed.
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November 2006

Matrix effects during analysis of plasma samples by electrospray and atmospheric pressure chemical ionization mass spectrometry: practical approaches to their elimination.

Rapid Commun Mass Spectrom 2003 ;17(17):1950-7

Preclinical Pharmacokinetics, Pharma Research Center, Bayer AG, 42096 Wuppertal, Germany.

Some cases of occurrence of matrix effects (mostly ion suppression) in protein-precipitated plasma samples, and their influence on the validity of plasma concentrations and pharmacokinetic parameters, are discussed. The comparison of matrix effects using either electrospray (TurboIonspray, TISP) or atmospheric pressure chemical ionization (APCI) indicated that APCI is less prone to matrix effects. Nevertheless, TISP is usually the first choice of ionization technique since unknown thermally labile metabolites might be present in the plasma samples causing erroneous results. A high impact of ion suppression on the plasma concentrations after intravenous (i.v.) administration was found, depending on the drug formulation (vehicle). Since ion suppression caused significantly lower plasma concentrations (by a factor of up to 5.5) after i.v. dosing, the area under the curve (AUC) was underestimated and the plasma clearance was consequently erroneously high, with an impact on drug candidate selection. By simple stepwise dilution (e.g. 10-fold and 50-fold) of the supernatant of protein-precipitated plasma samples, including all calibration and quality control samples, the matrix effects were recognized and eliminated.
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http://dx.doi.org/10.1002/rcm.1139DOI Listing
September 2003