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First-time-in-human dose selection: allometric thoughts and perspectives
1Wyeth-Ayerst Research, Philadelphia, Pennsylvania 19101, USA.
Journal of Clinical Pharmacology
|October 1, 1995
Summary
Determining the first dose in human studies involves complex preclinical factors like toxicology and pharmacokinetics. Current methods lack a definitive algorithm, relying on established rules of thumb due to inherent uncertainties.
Area of Science:
- Pharmacology and Toxicology
- Clinical Trial Design
Background:
- First-time-in-human (FTIH) studies require careful dose selection to ensure safety.
- Preclinical data is crucial but presents challenges in predicting human response.
Purpose of the Study:
- To examine factors influencing dose selection in early-phase clinical trials.
- To discuss the limitations of current methods for determining initial human doses.
Main Methods:
- Review of factors including animal toxicology, toxicokinetics, and allometric scaling.
- Integration of preclinical pharmacologic and toxicologic data.
- Discussion of pharmacokinetic and body surface area correlations.
Main Results:
- Preclinical evaluation can mitigate risks in Phase I trials.
- Significant uncertainties remain in predicting safe starting doses.
- A definitive algorithm for dose selection is currently not feasible.
Conclusions:
- While preclinical data is vital, precise dose determination for FTIH studies remains challenging.
- Existing rules of thumb are valuable but insufficient for a comprehensive decision tree.
- Ongoing research is needed to improve the predictability of human dose selection.
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