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  • 1
    Online Resource
    Online Resource
    Software‐aided cytochrome P450 reaction phenotyping and kinetic analysis in early drug discovery
    Wiley ; 2016
    In:  Rapid Communications in Mass Spectrometry Vol. 30, No. 2 ( 2016-01-30), p. 301-310
    Details
    In: Rapid Communications in Mass Spectrometry, Wiley, Vol. 30, No. 2 ( 2016-01-30), p. 301-310
    Abstract: Cytochrome P450 (CYP450) reaction phenotyping (CRP) and kinetic studies are essential in early drug discovery to determine which metabolic enzymes react with new drug entities. A new semi‐automated computer‐assisted workflow for CRP is introduced in this work. This workflow provides not only information regarding parent disappearance, but also metabolite identification and relative metabolite formation rates for kinetic analysis. Methods Time‐course experiments based on incubating six probe substrates (dextromethorphan, imipramine, buspirone, midazolam, ethoxyresorufin and diclofenac) with recombinant human enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) and human liver microsomes (HLM) were performed. Liquid chromatography/high‐resolution mass spectrometry (LC/HRMS) analysis was conducted with an internal standard to obtain high‐resolution full‐scan and MS/MS data. Data were analyzed using Mass‐MetaSite software. A server application (WebMetabase) was used for data visualization and review. Results CRP experiments were performed, and the data were analyzed using a software‐aided approach. This automated‐evaluation approach led to (1) the detection of the CYP450 enzymes responsible for both substrate depletion and metabolite formation, (2) the identification of specific biotransformations, (3) the elucidation of metabolite structures based on MS/MS fragment analysis, and (4) the determination of the initial relative formation rates of major metabolites by CYP450 enzymes. Conclusions This largely automated workflow enabled the efficient analysis of HRMS data, allowing rapid evaluation of the involvement of the main CYP450 enzymes in the metabolism of new molecules during drug discovery. Copyright © 2015 John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0951-4198 , 1097-0231
    URL: Issue
    URL: Article
    DOI: 10.1002/rcm.v30.2
    DOI: 10.1002/rcm.7429
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 2002158-6
    detail.hit.zdb_id: 58731-X
    SSG: 11
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  • 2
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    Evaluation of the drug disposition of RO7049389 with in vitro data and human mass balance supported by physiologically based pharmacokinetic modelling
    Wiley ; 2023
    In:  British Journal of Clinical Pharmacology Vol. 89, No. 10 ( 2023-10), p. 3079-3091
    Details
    In: British Journal of Clinical Pharmacology, Wiley, Vol. 89, No. 10 ( 2023-10), p. 3079-3091
    Abstract: RO7049389 (linvencorvir) is a developmental oral treatment for chronic hepatitis B virus infection. The aim of this work was to conduct mass balance (MB) and absolute bioavailability (BA) analyses in healthy volunteers, alongside in vitro evaluations of the metabolism of RO7049389 and a major circulating active metabolite M5 in human hepatocytes, and physiologically based pharmacokinetic (PBPK) modelling to refine the underlying drug disposition paradigm. Methods Participants in the clinical study (MB: Caucasian, male, n  = 6; BA: Caucasian and Asian, male and female, n  = 16, 8 in each ethnic groups) received oral [ 14 C] or unlabelled RO7049389 (600/1000 mg) followed by 100 μg intravenous [ 13 C]RO7049389. Metabolic pathways with fractions metabolized—obtained from the in vitro incubation results of 10 μM [ 14 C]RO7049389 and 1 μM M5 with (long‐term cocultured) human hepatocytes in the absence and presence of the cytochrome P450 3A4 (CYP3A4) inhibitor itraconazole—were used to complement the PBPK models, alongside the clinical MB and BA data. Results The model performance in predicting the pharmacokinetic profiles of RO7049389 and M5 aligned with clinical observations in Caucasians and was also successfully applied to Asians. Accordingly, the drug disposition pathways for RO7049389 were postulated with newly characterized estimates of the fractions: biliary excretion by P‐glycoprotein (~41%), direct glucuronidation via uridine 5′‐diphosphoglucuronosyltransferase 1A3 (~11%), hexose conjugation (~6%), oxidation by CYP3A4 (~28%) and other oxidation reactions (~9%). Conclusion These results support the ongoing clinical development program for RO7049389 and highlight the broader value of PBPK and MB analyses in drug development.
    Type of Medium: Online Resource
    ISSN: 0306-5251 , 1365-2125
    URL: Issue
    URL: Article
    DOI: 10.1111/bcp.v89.10
    DOI: 10.1111/bcp.15809
    RVK:
    XA 33650
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 1498142-7
    SSG: 15,3
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  • 3
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    Online Resource
    Preclinical Reproductive and Developmental Toxicity Profile of a Glycine Transporter Type 1 (Glyt1) Inhibitor
    Wiley ; 2016
    In:  Birth Defects Research Part B: Developmental and Reproductive Toxicology Vol. 107, No. 3 ( 2016-06), p. 148-156
    Details
    In: Birth Defects Research Part B: Developmental and Reproductive Toxicology, Wiley, Vol. 107, No. 3 ( 2016-06), p. 148-156
    Abstract: Bitopertin is a glycine type 1 (GlyT1) inhibitor intended for the treatment of psychiatric disorders. The principle adverse effect in the regulatory reproductive toxicity studies was peri‐natal pup death when rat dams were treated during parturition at a dose resulting in five‐times the human therapeutic exposure (AUC). Cessation of dosing two days before parturition prevented the pup deaths. Investigatory experiments and pharmacokinetic modelling suggested that the neonatal mortality was related to transplacental passage of bitopertin leading to high systemic levels in the newborn pups. Brain levels of bitopertin in the rat fetus and neonate were two‐fold higher than in the mother. As illustrated by knock‐out mice models, GlyT1 function is essential for neonatal pup survival in rodents, but is not necessary for normal prenatal morphological development. The glycine transport systems are immature at birth in the rat, but are functionally well‐developed in the human newborn. While the relevance to humans of the neonatal mortality seen in rats following late gestational exposure is unknown, bitopertin would not be recommended for use during late pregnancy unless the anticipated benefit for the mother outweighs the potential risk to the newborn.
    Type of Medium: Online Resource
    ISSN: 1542-9733 , 1542-9741
    URL: Issue
    URL: Article
    DOI: 10.1002/bdrb.2016.107.issue-3
    DOI: 10.1002/bdrb.21179
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 2108625-4
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  • 4
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    Online Resource
    How Semiphysiological Population Pharmacokinetic Modeling Incorporating Active Hepatic Uptake Supports Phase II Dose Selection of RO7049389, A Novel Anti–Hepatitis B Virus Drug
    Wiley ; 2021
    In:  Clinical Pharmacology & Therapeutics Vol. 109, No. 4 ( 2021-04), p. 1081-1091
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    In: Clinical Pharmacology & Therapeutics, Wiley, Vol. 109, No. 4 ( 2021-04), p. 1081-1091
    Abstract: The pharmacokinetics (PK) of RO7049389, a new hepatitis B virus (HBV) core protein allosteric modulator of class I, and of its active metabolite M5 were studied in fasted and fed conditions after single and multiple once‐a‐day and twice‐a‐day doses in healthy subjects and patients with HBV. The nonlinearity of the pharmacokinetics, the large variability, the small sample size per dose arms, the higher plasma exposure in Asians, and the heterogeneity in patient baseline characteristics seen in phase I studies made the ethnic sensitivity assessment and the selection of the recommended phase II dose difficult. A population PK model, simultaneously modeling RO7049389 and M5, was developed to characterize the complex PK, quantify ethnicity (i.e., Asian vs. non‐Asian) and gender effects on the PK of RO7049389 and M5, and infer the quantity of RO7049389 in liver relative to plasma. Exposures in the liver are of particular importance for dose selection since the liver is the site of action of the compound. The model described and reproduced the population PK profiles as well as the between‐subject variability of RO7049389 and its metabolite. It could show that the PK is similar between healthy subjects and in HBV patients, once the ethnicity and gender effects are accounted for. The model predicts that, despite a large difference in the plasma exposure of RO7049389 between Asians and non‐Asians, the exposure in the liver is comparable, allowing the use of the same dose to treat Asian and non‐Asian patients. This model provides a valuable basis to develop this new anti‐HBV drug and to define optimal dosing.
    Type of Medium: Online Resource
    ISSN: 0009-9236 , 1532-6535
    URL: Issue
    URL: Article
    DOI: 10.1002/cpt.v109.4
    DOI: 10.1002/cpt.2184
    RVK:
    XA 36900
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2040184-X
    SSG: 15,3
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  • 5
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    RO6807936 as a novel positron emission tomography (PET) radiotracer for in vitro and in vivo visualization and quantification of beta‐site amyloid precursor protein cleaving enzyme (BACE1) in the rodent and baboon brain
    Wiley ; 2023
    In:  Journal of Labelled Compounds and Radiopharmaceuticals Vol. 66, No. 9 ( 2023-07), p. 222-236
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    In: Journal of Labelled Compounds and Radiopharmaceuticals, Wiley, Vol. 66, No. 9 ( 2023-07), p. 222-236
    Abstract: The beta‐site amyloid precursor protein cleaving enzyme (BACE1) is responsible for initiating the generation of beta‐amyloid, the major constituent of amyloid plaques in Alzheimer's disease (AD). The purpose of this study was to develop a specific BACE1 radioligand for visualization of the distribution pattern and quantification of the BACE1 protein in the rodent and monkey brain both in vitro by autoradiography and in vivo by positron emission tomography (PET). The BACE1 inhibitor RO6807936 originating from an in‐house chemical drug optimization program was selected based on its PET tracer‐like physicochemical properties and a favorable pharmacokinetic profile. Saturation binding analysis of [ 3 H]RO6807936 revealed specific and high‐affinity binding ( K D  = 2.9 nM) and a low B max value (4.3 nM) of the BACE1 protein in native rat brain membranes. [ 3 H]RO6807936 binding showed a ubiquitous distribution on rat brain slices in vitro with higher levels in the CA3 pyramidal cell layer and the granule cell layer of the hippocampus. In a next step, RO6807936 was successfully radiolabeled with carbon‐11 and showed acceptable uptake in the baboon brain as well as a widespread and rather homogeneous distribution con sistent with rodent data. In vivo blockade studies with a specific BACE1 inhibitor reduced uptake of the tracer to homogenous levels across brain regions and demonstrated specificity of the signal. Our data warrant further profiling of this PET tracer candidate in humans to investigate BACE1 expression in normal individuals and those with AD and as an imaging biomarker for target occupancy studies in clinical drug trials.
    Type of Medium: Online Resource
    ISSN: 0362-4803 , 1099-1344
    URL: Issue
    URL: Article
    DOI: 10.1002/jlcr.v66.9
    DOI: 10.1002/jlcr.4025
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 1491841-9
    SSG: 15,3
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  • 6
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    Post‐acquisition analysis of untargeted accurate mass quadrupole time‐of‐flight MS E data for multiple collision‐induced neutral losses and fragment ions of glutathione conjugates
    Wiley ; 2014
    In:  Rapid Communications in Mass Spectrometry Vol. 28, No. 24 ( 2014-12-30), p. 2695-2703
    Details
    In: Rapid Communications in Mass Spectrometry, Wiley, Vol. 28, No. 24 ( 2014-12-30), p. 2695-2703
    Abstract: Analytical methods to assess glutathione (GSH) conjugate formation based on mass spectrometry usually take advantage of the specific fragmentation behavior of the glutathione moiety. However, most methods used for GSH adduct screening monitor only one specific neutral loss or one fragment ion, even though the peptide moiety of GSH adducts shows a number of other specific neutral fragments and fragment ions which can be used for identification. METHODS Nine reference drugs well known to form GSH adducts were incubated with human liver microsomes. Mass spectrometric analysis was performed with a quadrupole time‐of‐flight mass spectrometer in untargeted accurate mass MS E mode. The data analysis and evaluation was achieved in an automated approach with software to extract and identify GSH conjugates based on the presence of multiple collision‐induced neutral losses and fragment ions specific for glutathione conjugates in the high‐energy MS spectra. RESULTS In total 42 GSH adducts were identified. Eight (18%) adducts did not show the neutral loss of 129 but were identified based on the appearance of other GSH‐specific neutral losses or fragment ions. In high‐energy MS E spectra the GSH‐specific fragment ions of m/z 308 and 179 as well as the neutral loss of 275 Da were complementary to the commonly used neutral loss of 129 Da. Further, one abundant (yet unpublished) GSH conjugate of troglitazone formed in human liver microsomes was found. CONCLUSIONS A software‐aided approach was developed to reliably retrieve GSH adduct formation data out of untargeted complex full scan QTOFMS E data in a fast and efficient way. The present approach to detect and analyze multiple collision‐induced neutral losses and fragment ions of glutathione conjugates in untargeted MS E data might be applicable to higher throughput to assess reactive metabolite formation in drug discovery. Copyright © 2014 John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0951-4198 , 1097-0231
    URL: Issue
    URL: Article
    DOI: 10.1002/rcm.v28.24
    DOI: 10.1002/rcm.7062
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 2002158-6
    detail.hit.zdb_id: 58731-X
    SSG: 11
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