Misconceptions and issues regarding allometric scaling during the drug development process

ABSTRACT

Introduction: Allometry is the study of size and its consequences. The simple hypothesis of allometric scaling is that all physiological parameters are proportional to body size or body mass. This review examines the development of theory-based allometry or fixed exponents (0.75 and 1.0 for basal metabolic rate and volume, respectively) and the evidence for or against the theory. The main focus of this report is to show the readers that there is enough evidence from experimental data that negate the concept of theory-based allometry in biology, physiology, and pharmacokinetics.

Areas covered: In this review, the history of the development of theoretical allometry and the strong evidence against theory-based allometry demonstrated by experimental data is provided. During drug development, allometry is applied to both inter-species (from animals to humans) and intra-species (adults to children) scaling. These two forms of allometric scaling in the context of theory-based allometry are discussed and provide insight on scientific progress that refute theory-based allometry.

Expert opinion: Theory-based allometry is a mere theory and experimental data and real-life observations strongly negate the existence of such a theory. Pharmacostatistical and physiological models based on theory-based allometry can be misleading and incorrect because the theory-based allometric exponent 0.75 is not universal. The exponents of allometry are data dependent and are not fixed in the universe.

KEYWORDS:

• Allometric models
• basal metabolic rate
• inter-species scaling
• drug clearance
• pediatrics
• pharmacokinetics
• theory-based allometry

Article highlights

• Allometric scaling can be described as the relationship between size and a physiological parameter and is a useful tool during both pre-clinical and clinical drug development.

• The exponents of allometry widely vary and the experimental data in biology, physiology, and PK negate the concept of theoretical allometry or power law (0.75, 1.0, and 0.25 for BMR, volume, and time, respectively).

• During pediatric drug development, the evidence of nonlinear allometry across the age groups is very strong as noted by the ADE and BDE models.

• Application of incorrect allometric exponents in PK modeling and simulation will lead to incorrect conclusions leading to wrong dose selection to both adult and pediatric patients.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.