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Br J Clin Pharmacol. 2009 Feb;67(2):153-60. doi: 10.1111/j.1365-2125.2008.03297.x. Epub 2008 Dec 11.

Use of pharmacokinetic/ pharmacodynamic modelling for starting dose selection in first-in-human trials of high-risk biologics.

Author information

1
Department of Clinical Pharmacology, Pfizer Inc., Ramsgate Road, Sandwich, UK. balaji.agoram@pfizer.com

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT:

Recent regulatory guidance has highlighted the importance of using pharmacokinetic-pharmacodynamic (PK-PD) modelling in the selection of starting doses in first-in-human trials of high-risk biologics. However, limited examples exist in literature illustrating this procedure.

WHAT THIS STUDY ADDS:

An interpretation of the recommended dose-selection methodology and the minimum anticipated biological effect level (MABEL) principle, contained in the updated European Medicines Agency guidance on risk-mitigation strategies for first-in-human studies, is presented. Some literature and simulation-based examples of the application of PK-PD modelling principles to starting dose selection using in vitro and in vivo data under the MABEL paradigm are highlighted, along with the advantages and limitations of this approach.

AIMS:

To illustrate the use of pharmacokinetic-pharmacodynamic (PK-PD) models to select rational starting doses in clinical trials within the minimum anticipated biological effect level (MABEL) principle using literature data and through simulations.

METHODS:

The new European Medicines Agency guidance on starting dose selection of high-risk biologics was analysed considering the basic pharmacological properties and preclinical testing limitations of many biologics. The MABEL approach to dose selection was illustrated through simulations and through literature-reported examples on the selection of starting doses for biologics such as antibodies based on in vitro biomarker data, in vivo PK and PK-PD data.

RESULTS:

Literature reports indicating the use of preclinical pharmacological and toxicological data to select successfully safe starting doses in line with the MABEL principle are summarized. PK-PD model-based simulations of receptor occupancy for an anti-IgE antibody system indicate that the relative abundance of IgE in animal models and patients and the turnover rate of the IgE-antibody complex relative to the off-rate of the antibody from IgE are important determinants of in vivo receptor occupancy.

CONCLUSIONS:

Mechanistic PK-PD models are capable of integrating preclinical in vitro and in vivo data to select starting doses rationally in first-in-human trials. Biological drug-receptor interaction dynamics is complex and multiple factors affect the dose-receptor occupancy relationship. Thus, these factors should be taken into account when selecting starting doses.

PMID:
19076987
PMCID:
PMC2670372
DOI:
10.1111/j.1365-2125.2008.03297.x
[Indexed for MEDLINE]
Free PMC Article

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