Publications by authors named "Irene A Retmana"

5 Publications

  • Page 1 of 1

Quantification of KRAS inhibitor sotorasib in mouse plasma and tissue homogenates using liquid chromatography-tandem mass spectrometry.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Jun 20;1174:122718. Epub 2021 Apr 20.

Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, the Netherlands. Electronic address:

Sotorasib is a KRAS inhibitor with promising anticancer activity in phase I clinical studies. This compound is currently under further clinical evaluation as monotherapy and combination therapy against solid tumors. In this study, a liquid chromatography-tandem mass spectrometric method to quantify sotorasib in mouse plasma and eight tissue-related matrices (brain, liver, spleen, kidney, small intestine, small intestine content, lung, and testis homogenates) was developed and validated. Protein precipitation using acetonitrile was utilized in 96-well format to extract sotorasib and erlotinib (internal standard) from mouse plasma and tissue homogenates. Separation of the analytes was performed on an Acquity UPLC® BEH C18 column by gradient elution of methanol and 0.1% formic acid in water at a flow rate of 0.6 ml/min. Sotorasib was detected by a triple quadrupole mass spectrometer with positive electrospray ionization in selected reaction monitoring mode. A linear calibration range of 2-2,000 ng/ml of sotorasib was achieved during the validation. Accuracy values were in the range of 90.7-111.4%, and precision values (intra- and interday) were between 1.7% and 9.2% for all tested levels in all investigated matrices. The method was successfully applied to investigate the plasma pharmacokinetics and tissue accumulation of sotorasib in female wild-type mice.
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http://dx.doi.org/10.1016/j.jchromb.2021.122718DOI Listing
June 2021

Variability of in vivo potency tests of Diphtheria, Tetanus and acellular Pertussis (DTaP) vaccines.

Vaccine 2021 04 3;39(18):2506-2516. Epub 2021 Apr 3.

CBG-MEB, Graadt van Roggenweg 500, 3531 AH Utrecht, the Netherlands. Electronic address:

For batch release of legacy vaccines such as DTaP, in vivo potency release assays are required. We quantified the variability of in vivo potency release assays for four DTaP (Diphtheria, Tetanus, acellular Pertussis) products of different manufacturers. With their large CV (Coefficients of Variance) ranging from 16% to 132%, these in vivo assays are of limited value to ensure their potency is consistent and similar to the clinical batches used for the marketing authorisation. Our data show that, although individual potency test results show high variability, the DTaP batches are manufactured with great consistency, because repeated potency testing yields similar averages for the different batches. The economic impact of variability of in vivo tests is significant since it may result in the need for greater amount of antigen than may be required or for repeating a test. For monitoring the consistency of potency, in vitro assays are superior to in vivo assays. Animal-free potency determination is common practice for newly developed vaccines under modern GMP quality systems. However, replacement of in vivo potency tests for legacy vaccines like DTaP is challenging and would require a 'reverse characterisation' strategy in which the antigens are further characterised at the level of drug substance and drug product to identify critical quality attributes (CQA) that can be tested with in vitro assays. Based on these an updated set of release tests without animal tests can be proposed. Our data can serve as benchmark for the innovative methods.
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http://dx.doi.org/10.1016/j.vaccine.2021.03.078DOI Listing
April 2021

Chromatographic bioanalytical assays for targeted covalent kinase inhibitors and their metabolites.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Jan 30;1162:122466. Epub 2020 Nov 30.

Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacology, Universiteitsweg 99, 3584 CG, Utrecht, the Netherlands. Electronic address:

Deriving from targeted kinase inhibitors (TKIs), targeted covalent kinase inhibitors (TCKIs) are a new class of TKIs that are covalently bound to their target residue of kinase receptors. Currently, there are many new TCKIs under clinical development besides afatinib, ibrutinib, osimertinib, neratinib, acalabrutinib, dacomitinib, and zanubrutinib that are already approved by the FDA. Subsequently, there is an increasing demand for bioanalytical methods to qualitatively and quantitively investigate those compounds, leading to a number of papers reporting the development, validation, and use of bioanalytical methods for TCKIs. Most publications describe the technological set up of analytical methods that allow quantification of TCKIs in various biomatrices such as plasma, cerebrospinal fluid, urine, tissue, and liver microsomes. In addition, the identification of metabolites and biotransformation pathways of new TCKIs has gained more interest in recent years. We provide an overview of bioanalytical methods of this new class of TCKIs. The included issues are sample pretreatment, chromatographic separation, detection, and method validation. In the scope of bioanalysis of TCKIs, protein precipitation is mostly applied to treat the biological matrices sample. Liquid chromatographic in reversed-phase mode (RPLC) and mass detection with triple quadrupole (QqQ) are the most often utilized separation and quantitative detection modes, respectively. There may be a possibility of increased use of the high-resolution mass spectrometry (HRMS) for qualitative investigation purposes in the future. We also found that US FDA and EMA guidelines are the most common guidelines employed as validation framework for the bioanalytical methods of TCKIs.
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http://dx.doi.org/10.1016/j.jchromb.2020.122466DOI Listing
January 2021

P-glycoprotein (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) limit brain accumulation of the FLT3 inhibitor quizartinib in mice.

Int J Pharm 2019 Feb 12;556:172-180. Epub 2018 Dec 12.

The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Electronic address:

Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mAbcg2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mAbcg2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b and Abcb1a/1b;Abcg2 mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mAbcg2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33-51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug. Our results provide a possible rationale for using pharmacological ABCB1/ABCG2 inhibitors together with quizartinib when treating malignant lesions situated in part or in whole behind the blood-brain barrier.
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http://dx.doi.org/10.1016/j.ijpharm.2018.12.014DOI Listing
February 2019

Liquid chromatography-tandem mass spectrometric assay for the quantitative determination of the tyrosine kinase inhibitor quizartinib in mouse plasma using salting-out liquid-liquid extraction.

J Chromatogr B Analyt Technol Biomed Life Sci 2017 Sep 23;1061-1062:300-305. Epub 2017 Jul 23.

Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Chemical Biology & Drug Development, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands. Electronic address:

A bioanalytical assay for quizartinib -a potent, and selective FLT3 tyrosine kinase inhibitor- in mouse plasma was developed and validated. Salting-out assisted liquid-liquid extraction (SALLE), using acetonitrile and magnesium sulfate, was selected as sample pretreatment with deuterated quizartinib as internal standard. Separation was performed with reversed-phase liquid chromatography followed by detection with positive electrospray-triple quadrupole mass spectrometry in the selected reaction monitoring mode. The assay was successfully validated for mouse plasma in a 2-2000ng/ml calibration range with r=0.9958±0.0028 (n=7) for linear regression with the inverse square of the concentration as a weighting factor. The within-run precision (n=18), between-run precision and accuracy were 2.9-6.0%, 4.5-8.9% and 91.7-109.4% respectively. The drug was stable under all relevant conditions. Finally, the assay was successfully applied in a pharmacokinetic pilot study in plasma of FVB/NRj mice treated with quizartinb orally.
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http://dx.doi.org/10.1016/j.jchromb.2017.07.034DOI Listing
September 2017