J Clin Pharmacol
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Sign In to gain access to subscriptions and/or personal tools.
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Citing Articles
Right arrow Citing Articles via ISI Web of Science (5)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mahmood, I.
Right arrow Articles by Fisher, J. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mahmood, I.
Right arrow Articles by Fisher, J. E.

DRUG DEVELOPMENT

Selection of the First-Time Dose in Humans: Comparison of Different Approaches Based on Interspecies Scaling of Clearance

Iftekhar Mahmood, PhD, Martin David Green, PhD and J. Edward Fisher, PhD

From the Division of Clinical Trial Design and Analysis, Center for Biologics Evaluation and Research (I. Mahmood, M. D. Green) and the Division of Neuropharmacological Drug Products, Center for Drug Evaluation and Research (J.E. Fisher), Food and Drug Administration (FDA), Rockville, Maryland.

The authors describe four approaches to selecting a safe starting dose for humans in clinical drug trials based on interspecies scaling of clearance. Human clearance was predicted by scaling for 10 example drugs for which animal clearance values were available in the literature. The predicted human clearance values were then used to select the estimated starting dose in humans. These doses were then compared with the actual doses given to humans during clinical trials. All four approaches used to estimate the first-time dose in humans provided values that were within the dose range given to humans from Phases I to III. This work demonstrates that animal pharmacokinetic data can be used to estimate a suitable human starting dose, provided the data have been obtained from a dose that produces no adverse effects.

Key Words: Interspecies scaling • first-time dose • drug development • allometric scaling • predicted human clearance • toxicity

Address for reprints: Iftekhar Mahmood, Division of Clinical Trial Design and Analysis, Office of Therapeutic Research and Review, Clinical Pharmacology and Toxicology Branch (HFD-579), Center for Biologics Evaluation and Research, Food and Drug Administration, Woodmont Office Center I, Suite 200N, 1401 Rockville Pike, Rockville, MD 20852.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2003 by the American College of Clinical Pharmacology