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

Aim The aim of this article is to understand the pros and cons of various methods involved in first-in-human (FIH) dose calculation and act decisively in dose escalations when calculating the maximum tolerated dose. Subjects and methods We reviewed early phase clinical trials for methods of FIH dose...

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Veröffentlicht in:European journal of clinical pharmacology Jg. 76; H. 9; S. 1237 - 1243
Hauptverfasser: Mishra, Archana, Sarangi, Sudhir Chandra, Reeta, Kh
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2020
Springer Nature B.V
Schlagworte:
Antibodies, Monoclonal, Humanized - administration & dosage
Antibodies, Monoclonal, Humanized - adverse effects
Biomedical and Life Sciences
Biomedicine
Clinical Trial
Clinical trials
Clinical Trials, Phase I as Topic - methods
Clinical Trials, Phase I as Topic - standards
Cyclic N-Oxides - administration & dosage
Cyclic N-Oxides - adverse effects
Developmental stages
Dose-Response Relationship, Drug
Drug development
Drug dosages
Humans
Maximum Tolerated Dose
Pharmaceutical Preparations - administration & dosage
Pharmacodynamics
Pharmacokinetics
Pharmacology/Toxicology
Pyridines - administration & dosage
Pyridines - adverse effects
Research Design
Reviews
PK/PD modelling
Phase 1
Dose escalation
First-in-human dose
MABEL
NOAEL
ISSN:0031-6970, 1432-1041, 1432-1041
Online-Zugang:Volltext
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Zusammenfassung:Aim The aim of this article is to understand the pros and cons of various methods involved in first-in-human (FIH) dose calculation and act decisively in dose escalations when calculating the maximum tolerated dose. Subjects and methods We reviewed early phase clinical trials for methods of FIH dose and dose-escalation steps and discuss them in line with existing guidelines. We also reviewed the clinical trial registry to recognize trends in trial registration in recent years and after a massive failure in a few trials. Results Phase 1 trials of TGN 1412 and BIA10-2474 would always be remembered as catastrophes for pharmaceutical development plans. Quite often than not, healthy human volunteers are the guinea pigs in this stage of drug development. And, the most important aspect of designing an early phase study is deciding upon the dose to be started with, apart from the selection of cohort and escalation steps. The common principles used for FIH dose calculation include no observed adverse effect level, minimum anticipated biological effect level, pharmacologically active dose, pharmacokinetic/pharmacodynamic approach, and similar drug comparison approach. Conclusion Early phase clinical trials are basically foundation stones on which lies the entire onus of the later stages of development. Deciding FIH dose is a crucial step that necessitates the incorporation of detailed data from the preclinical stages and application of the most conservative approach for the safety/benefit of the volunteers in these studies.
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ISSN:0031-6970
1432-1041
1432-1041
DOI:10.1007/s00228-020-02924-x