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  1. Article: Knowledge Gaps in the Pharmacokinetics of Therapeutic Proteins in Pediatric Patients.

    Meibohm, Bernd

    Frontiers in pharmacology

    2022  Volume 13, Page(s) 847021

    Abstract: Therapeutic proteins such as monoclonal antibodies and their derivatives, fusions proteins, hormone analogs and enzymes for replacement therapy are an ever-growing mainstay in our pharmacopoeia. While a growing number of these medications are developed ... ...

    Abstract Therapeutic proteins such as monoclonal antibodies and their derivatives, fusions proteins, hormone analogs and enzymes for replacement therapy are an ever-growing mainstay in our pharmacopoeia. While a growing number of these medications are developed for and used in younger and younger pediatric patients, knowledge gaps in the basic understanding of the molecular and physiologic processes governing the disposition of these compounds in the human body and their modulation by age and childhood development are a hindrance to the effective and timely development and clinical use of these compounds, especially in very young pediatric patient populations. This is particularly the case for the widespread lack of information on the ontogeny and age-associated expression and function of receptor systems that are involved in the molecular processes driving the pharmacokinetics of these compounds. This article briefly highlights three receptor systems as examples, the neonatal Fc receptor, the asialoglycoprotein receptor, and the mannose receptor. It furthermore provides suggestions on how these gaps should be addressed and prioritized to provide the field of pediatric clinical pharmacology the urgently needed tools for a more effective development and clinical utilization of this important class of drugs with rapidly evolving importance as cornerstone in pediatric pharmacotherapy.
    Language English
    Publishing date 2022-02-10
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2022.847021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Book: Pharmacokinetics and pharmacodynamics of biotech drugs

    Meibohm, Bernd

    principles and case studies in drug development

    2006  

    Author's details ed. by Bernd Meibohm
    Keywords Pharmazeutische Technologie ; Biotechnologie ; Pharmakokinetik ; Pharmakodynamik
    Subject Technische Biochemie ; Technische Biologie ; Biotechnik ; Biotech ; Arzneimittelherstellung ; Galenische Pharmazie ; Arzneiformenlehre ; Galenik ; Klinische Pharmakokinetik ; Toxikokinetik
    Language English
    Size XXI, 403 S. : Ill., graph. Darst., 240 mm x 170 mm
    Publisher WILEY-VCH
    Publishing place Weinheim
    Publishing country Germany
    Document type Book
    HBZ-ID HT014780781
    ISBN 978-3-527-31408-9 ; 3-527-31408-3
    Database Catalogue ZB MED Medicine, Health

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  3. Article ; Online: Clinical and Translational Pharmacology Considerations for Anti-infectives Approved Under the FDA Animal Rule.

    Temrikar, Zaid H / Golden, Jennifer E / Jonsson, Colleen B / Meibohm, Bernd

    Clinical pharmacokinetics

    2023  Volume 62, Issue 7, Page(s) 943–953

    Abstract: The US Food and Drug Administration's Animal Rule provides a pathway for approval of drugs and biologics aimed to treat serious or life-threatening conditions wherein traditional clinical trials are either not ethical or feasible. In such a scenario, ... ...

    Abstract The US Food and Drug Administration's Animal Rule provides a pathway for approval of drugs and biologics aimed to treat serious or life-threatening conditions wherein traditional clinical trials are either not ethical or feasible. In such a scenario, determination of safety and efficacy are based on integration of data on drug disposition and drug action collected from in vitro models, infected animals, and healthy volunteer human studies. The demonstration of clinical efficacy and safety in humans based on robust, well-controlled animal studies is filled with challenges. This review elaborates on the challenges in the translation of data from in vitro and animal models to human dosing for antimicrobials. In this context, it discusses precedents of drugs approved under the Animal Rule, along with the approaches and guidance undertaken by sponsors.
    MeSH term(s) Animals ; United States ; Humans ; Drug Approval ; United States Food and Drug Administration ; Pharmaceutical Preparations ; Anti-Infective Agents/pharmacology ; Anti-Infective Agents/therapeutic use ; Biological Factors
    Chemical Substances Pharmaceutical Preparations ; Anti-Infective Agents ; Biological Factors
    Language English
    Publishing date 2023-06-16
    Publishing country Switzerland
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 197627-8
    ISSN 1179-1926 ; 0312-5963
    ISSN (online) 1179-1926
    ISSN 0312-5963
    DOI 10.1007/s40262-023-01267-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Protein engineering for improved pharmacologic characteristics of established monoclonal antibody-based therapeutics.

    Meibohm, Bernd

    Clinical pharmacokinetics

    2014  Volume 53, Issue 10, Page(s) 863–864

    MeSH term(s) Antibodies, Monoclonal/genetics ; Antibodies, Monoclonal/pharmacokinetics ; Antibodies, Monoclonal/pharmacology ; Humans ; Protein Engineering
    Chemical Substances Antibodies, Monoclonal
    Language English
    Publishing date 2014-08-29
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 197627-8
    ISSN 1179-1926 ; 0312-5963
    ISSN (online) 1179-1926
    ISSN 0312-5963
    DOI 10.1007/s40262-014-0186-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Time to 'Mind the Gap' in novel small molecule drug discovery for direct-acting antivirals for SARS-CoV-2.

    Jonsson, Colleen B / Golden, Jennifer E / Meibohm, Bernd

    Current opinion in virology

    2021  Volume 50, Page(s) 1–7

    Abstract: A pipeline of effective direct-acting antivirals (DAAs) remains a critical gap in addressing the current pandemic given vaccination hesitancy, the emergence of viral variants of concern, susceptible populations for which vaccination is ineffective or ... ...

    Abstract A pipeline of effective direct-acting antivirals (DAAs) remains a critical gap in addressing the current pandemic given vaccination hesitancy, the emergence of viral variants of concern, susceptible populations for which vaccination is ineffective or unavailable, and the possibility that coronavirus disease 2019 (COVID-19) is here to stay. Since the start of the pandemic, global efforts in small molecule drug discovery have focused largely on testing of FDA-approved drugs to accelerate evaluation in clinical trials in hospitalized patients. With 80% of the population who test positive for SARS-CoV-2 having asymptomatic to mild COVID-19, early stage, DAAs would be of enormous benefit to reduce spread, duration of symptoms and quarantine length. We highlight a few of the most promising DAAs in clinical trials and discuss considerations in how to navigate the challenges and pitfalls of novel small molecule discovery and thereby accelerate the advancement of new, safe, and oral DAAs.
    MeSH term(s) Antiviral Agents/pharmacology ; Clinical Trials as Topic ; Critical Pathways ; Drug Discovery ; Humans ; SARS-CoV-2/drug effects
    Chemical Substances Antiviral Agents
    Language English
    Publishing date 2021-06-29
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2611378-8
    ISSN 1879-6265 ; 1879-6257
    ISSN (online) 1879-6265
    ISSN 1879-6257
    DOI 10.1016/j.coviro.2021.06.008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Pharmacometric Applications and Challenges in the Development of Therapeutic Antibodies in Immuno-Oncology.

    Diao, Lei / Meibohm, Bernd

    Current pharmacology reports

    2018  Volume 4, Issue 4, Page(s) 285–291

    Abstract: Purpose of review: Monoclonal antibodies targeting key checkpoints in immune stimulatory pathways have over the last years become the mainstay of cancer immunotherapy. This article provides a brief review of the application and key impact of ... ...

    Abstract Purpose of review: Monoclonal antibodies targeting key checkpoints in immune stimulatory pathways have over the last years become the mainstay of cancer immunotherapy. This article provides a brief review of the application and key impact of pharmacometrics and quantitative clinical pharmacology approaches in the development of these novel biologics.
    Recent findings: The clinical development and selection of optimal dosing regimens for monoclonal antibodies used in immune-oncology has been facilitated by an extensive application of pharmacometric approaches to characterize the exposure-response relationship for major efficacy and safety endpoints. These analysis techniques were applied for the anti CTLA-4 antibody ipilimumab, as well as the anti PD1/PD-L1 antibodies nivolumab, pembrolizumab, avelumab, atezolizumab and durvalumab. The utilization of quantitative clinical pharmacology, including model-based analyses, did not only support the identification of efficacious doses with acceptable safety limits, but was also able to address complicating challenges such as time- and response-dependent changes in antibody clearance as observed for most compounds.
    Summary: A widespread and systematic application of pharmacometric approaches has provided key aspects in elucidating, interpreting and integrating preclinical, biochemical and clinical data in support of the development of safe and efficacious dosing regimens of monoclonal antibodies used in immuno-oncology, thereby facilitating the clinical use of this promising new class of biologics in cancer patients with unmet medical needs.
    Language English
    Publishing date 2018-05-03
    Publishing country Switzerland
    Document type Journal Article
    ISSN 2198-641X
    ISSN 2198-641X
    DOI 10.1007/s40495-018-0142-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Population pharmacokinetic/pharmacodynamic analyses as the basis for dosing of therapeutic monoclonal antibodies.

    Meibohm, Bernd

    Clinical pharmacokinetics

    2011  Volume 50, Issue 12, Page(s) 823–824

    MeSH term(s) Antibodies, Monoclonal/pharmacokinetics ; Antibodies, Monoclonal, Humanized ; Bone Density Conservation Agents/pharmacokinetics ; Bone Diseases, Metabolic/blood ; Denosumab ; Female ; Humans ; Models, Biological ; Osteoporosis/blood ; RANK Ligand/antagonists & inhibitors
    Chemical Substances Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Bone Density Conservation Agents ; RANK Ligand ; Denosumab (4EQZ6YO2HI)
    Language English
    Publishing date 2011-11-16
    Publishing country Switzerland
    Document type Journal Article ; Comment
    ZDB-ID 197627-8
    ISSN 1179-1926 ; 0312-5963
    ISSN (online) 1179-1926
    ISSN 0312-5963
    DOI 10.2165/11597950-000000000-00000
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Pharmacokinetics and Clinical Pharmacology of Monoclonal Antibodies in Pediatric Patients.

    Temrikar, Zaid H / Suryawanshi, Satyendra / Meibohm, Bernd

    Paediatric drugs

    2020  Volume 22, Issue 2, Page(s) 199–216

    Abstract: Monoclonal antibodies (mAbs) and their derivatives are increasingly used in pediatric pharmacotherapy, and the number of antibody-based drug products with approved pediatric indications is continuously growing. In most instances, pediatric use is being ... ...

    Abstract Monoclonal antibodies (mAbs) and their derivatives are increasingly used in pediatric pharmacotherapy, and the number of antibody-based drug products with approved pediatric indications is continuously growing. In most instances, pediatric use is being pursued after the efficacy and safety of novel antibody medications have been established in adult indications. The pediatric extrapolation exercise that is frequently used in this context to bridge efficacy and safety from adults to children is oftentimes challenged through uncertainties and knowledge gaps in how to reliably extrapolate pharmacokinetics and clinical pharmacology of mAbs to different pediatric age groups, and how to derive age-appropriate dosing regimens that strike a balance between precision dosing and practicability. The article highlights some of the pharmacokinetic and clinical pharmacology challenges with regard to therapeutic use of mAbs and antibody derivatives in children, including immunogenicity events. Although considering body size-based differences in drug disposition can account for many of the perceived and actual differences in the distribution and elimination of antibody-based therapeutics between children and adults, increasing evidence suggests potential or actual age-associated differences beyond size differences, especially for young pediatric patients such as newborns and infants. To overcome age-associated differences in antibody disposition, various different dosing approaches have been applied to ensure safe and efficacious antibody exposure for pediatric populations of different ages. The development of such dosing regimens and the associated pathway to pediatric indication approval is illustrated in more detail for two antibody-based biologics, the fusion protein abatacept and the mAb tocilizumab.
    MeSH term(s) Adolescent ; Antibodies, Monoclonal/pharmacokinetics ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal/therapeutic use ; Child ; Child, Preschool ; Humans ; Infant ; Infant, Newborn ; Neoplasms/drug therapy
    Chemical Substances Antibodies, Monoclonal
    Language English
    Publishing date 2020-02-12
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 1492748-2
    ISSN 1179-2019 ; 1174-5878
    ISSN (online) 1179-2019
    ISSN 1174-5878
    DOI 10.1007/s40272-020-00382-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: The atypical antipsychotic aripiprazole alters the outcome of disseminated

    Reitler, Parker / Regan, Jessica / DeJarnette, Christian / Srivastava, Ashish / Carnahan, Jen / Tucker, Katie M / Meibohm, Bernd / Peters, Brian M / Palmer, Glen E

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Invasive fungal infections (IFIs) impose an enormous clinical, social, and economic burden on humankind. For many IFIs, ≥ 30% of patients fail therapy with existing antifungal drugs, including the widely used azole class. We previously identified a ... ...

    Abstract Invasive fungal infections (IFIs) impose an enormous clinical, social, and economic burden on humankind. For many IFIs, ≥ 30% of patients fail therapy with existing antifungal drugs, including the widely used azole class. We previously identified a collection of 13 approved medications that antagonize azole activity. While gain-of-function mutants resulting in antifungal resistance are often associated with reduced fitness and virulence, it is currently unknown how exposure to azole antagonistic drugs impact
    Language English
    Publishing date 2024-02-14
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.02.13.580133
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Alcohol inhibits the metabolism of dimethyl fumarate to the active metabolite responsible for decreasing relapse frequency in the treatment of multiple sclerosis.

    Yang, Bing / Parker, Robert B / Meibohm, Bernd / Temrikar, Zaid H / Srivastava, Ashish / Laizure, S Casey

    PloS one

    2022  Volume 17, Issue 11, Page(s) e0278111

    Abstract: Dimethyl fumarate (DMF) is a first-line prodrug for the treatment of relapsing-remitting multiple sclerosis (RRMS) that is completely metabolized to monomethyl fumarate (MMF), the active metabolite, before reaching the systemic circulation. Its ... ...

    Abstract Dimethyl fumarate (DMF) is a first-line prodrug for the treatment of relapsing-remitting multiple sclerosis (RRMS) that is completely metabolized to monomethyl fumarate (MMF), the active metabolite, before reaching the systemic circulation. Its metabolism has been proposed to be due to ubiquitous esterases in the intestines and other tissues, but the specific enzymes involved are unknown. We hypothesized based on its structure and extensive presystemic metabolism that DMF would be a carboxylesterase substrate subject to interaction with alcohol. We sought to determine the enzymes(s) responsible for the extensive presystemic metabolism of DMF to MMF and the effect of alcohol on its disposition by conducting metabolic incubation studies in human recombinant carboxylesterase-1 (CES1), carboxylesterase-2 (CES2) and human intestinal microsomes (HIM), and by performing a follow-up study in an in vivo mouse model. The in vitro incubation studies demonstrated that DMF was only metabolized to MMF by CES1. Consistent with the incubation studies, the mouse pharmacokinetic study demonstrated that alcohol decreased the maximum concentration and area-under-the-curve of MMF in the plasma and the brain after dosing with DMF. We conclude that alcohol may markedly decrease exposure to the active MMF metabolite in the plasma and brain potentially decreasing the effectiveness of DMF in the treatment of RRMS.
    MeSH term(s) Humans ; Animals ; Mice ; Dimethyl Fumarate/pharmacology ; Dimethyl Fumarate/therapeutic use ; Multiple Sclerosis/drug therapy ; Follow-Up Studies ; Ethanol ; Multiple Sclerosis, Relapsing-Remitting/drug therapy ; Chronic Disease ; Carboxylic Ester Hydrolases ; Recurrence
    Chemical Substances Dimethyl Fumarate (FO2303MNI2) ; Ethanol (3K9958V90M) ; monomethyl fumarate (45IUB1PX8R) ; Carboxylic Ester Hydrolases (EC 3.1.1.-)
    Language English
    Publishing date 2022-11-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0278111
    Database MEDical Literature Analysis and Retrieval System OnLINE

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