First-in-human dose: current status review for better future perspectives

Mishra, Archana; Sarangi, Sudhir Chandra; Reeta, K.H.

doi:10.1007/s00228-020-02924-x

Cited by 6 publications

(11 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…124 It can also be used for deriving receptor occupancy. 126 The MABEL approach was suggested to help prevent future tragic events (as occurred with the first administration of TGN1412), 127,128 and should be used especially for high-risk medicinal products. 127 It may also be helpful when mAb toxicology studies do not provide useful information, for example, when the species used in the toxicology studies are not pharmacologically relevant.…”

Section: Selection Of Starting and Therapeutic Human Dosementioning

confidence: 99%

“…129 These approaches can be used separately or in combination to determine the optimal starting dose. 35,126 There is no consensus on the best approach; often it depends on the mAb mechanism of action and the available preclinical toxicology, pharmacology, and PK data. 35,123 Several guidance documents from the Food and Drug Administration and European Medicines Agency also exist on this topic.…”

Section: Selection Of Starting and Therapeutic Human Dosementioning

confidence: 99%

See 1 more Smart Citation

Allometric scaling of therapeutic monoclonal antibodies in preclinical and clinical settings

Germovsek

Jin

Giragossian

2021

mAbs

View full text Add to dashboard Cite

Constant technological advancement enabled the production of therapeutic monoclonal antibodies (mAbs) and will continue to contribute to their rapid expansion. Compared to small-molecule drugs, mAbs have favorable characteristics, but also more complex pharmacokinetics (PK), e.g., target-mediated nonlinear elimination and recycling by neonatal Fc-receptor. This review briefly discusses mAb biology, similarities and differences in PK processes across species and within human, and provides a detailed overview of allometric scaling approaches for translating mAb PK from preclinical species to human and extrapolating from adults to children. The approaches described here will remain vital in mAb drug development, although more data are needed, for example, from very young patients and mAbs with nonlinear PK, to allow for more confident conclusions and contribute to further growth of this field. Improving mAb PK predictions will facilitate better planning of (pediatric) clinical studies and enable progression toward the ultimate goal of expediting drug development.

show abstract

Section: Selection Of Starting and Therapeutic Human Dosementioning

confidence: 99%

Section: Selection Of Starting and Therapeutic Human Dosementioning

confidence: 99%

Allometric scaling of therapeutic monoclonal antibodies in preclinical and clinical settings

Germovsek

Jin

Giragossian

2021

mAbs

View full text Add to dashboard Cite

show abstract

“…AUC values provide insight into the total exposure to a drug and its clearance rate from the body [ 26 ]. No observed adverse effect level (NOAEL): The maximum dose in animal species that does not produce a significant increase in adverse events when compared to those in the control group [ 28 ]. Minimal anticipated biological effect level (MABEL): Exposure level in humans at which biological effect is anticipated.…”

Section: Discussionmentioning

confidence: 99%

“…The MABEL is based on PD effects in non-clinical studies. To establish the MABEL, receptor occupancy and target binding studies comparing animal and human cell lines should be taken into account [ 28 ]. Pharmacologically active dose (PAD): The lowest dose tested in animal species with intended pharmacological activity [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…To establish the MABEL, receptor occupancy and target binding studies comparing animal and human cell lines should be taken into account [ 28 ]. Pharmacologically active dose (PAD): The lowest dose tested in animal species with intended pharmacological activity [ 28 ]. Anticipated therapeutic dose (ATD): Dose range at which an exposure level leading to therapeutic efficacy is expected [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system active drugs

et al. 2023

View full text Add to dashboard Cite

The primary purpose of this study was to assess the translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system (CNS) active drugs. As a part of this, IBs were reviewed on reporting quality. Investigator’s Brochures (IBs) of studies performed at the Centre for Human Drug Research (CHDR) reporting statistically significant results of CNS activity related to the drug’s mechanism of action were included. The quality of IBs was assessed based on the presence of a rationale for the chosen animal model, completeness of pharmacokinetic (PK) results in reporting and internal validity information of the preclinical evidence. The IB-derisk tool was used to generate preclinical and early clinical data overviews data. For each compound, the overlap between pharmacologically active dose ranges and well-tolerated levels was calculated for three pharmacokinetic (PK) parameters: human equivalent dose (HED), maximum plasma concentration (Cmax) and area under the curve (AUC). Twenty-five IBs were included. In general, the quality of reporting in IBs was assessed as poor. About a third of studies did not explore the entire concentration-effect curve (pre)clinically. Single dose tolerability ranges were most accurately predicted by Cmax. Human equivalent dose and AUC were the best predictors of pharmacologically active ranges. Tolerable and pharmacologically active dose ranges in healthy volunteers can be reasonably well predicted from preclinical data with the IB-derisk tool. The translatability of preclinical studies can be improved by applying a higher reporting standard in IBs including comparable PK measurements across all preclinical and clinical studies.

show abstract

New Approaches Targeting Immuno-oncology and Tumor Microenvironment

Zhu

He²

2022

Interdisciplinary Cancer Research

View full text Add to dashboard Cite

First-in-human dose: current status review for better future perspectives

Cited by 6 publications

References 20 publications

Allometric scaling of therapeutic monoclonal antibodies in preclinical and clinical settings

Allometric scaling of therapeutic monoclonal antibodies in preclinical and clinical settings

Translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system active drugs

New Approaches Targeting Immuno-oncology and Tumor Microenvironment

Contact Info

Product

Resources

About