Allometric scaling of xenobiotic clearance: Uncertainty versus universality

Abstract

Statistical analysis and Monte Carlo simulation were used to characterize uncertainty in the allometric exponent (b) of xenobiotic clearance (CL). CL values for 115 xenobiotics were from published studies in which at least 3 species were used for the purpose of interspecies comparison of pharmacokinetics. The b value for each xenobiotic was calculated along with its confidence interval (CI). For 24 xenobiotics (21%), there was no correlation between log CL and log body weight.

Utility of the Coefficient of Determination (r2) in Assessing the Accuracy of Interspecies Allometric Predictions: Illumination or Illusion?

“…High r 2 values (ca. greater than 0.90) have been cited for most of the allometric relationships reported in the literature (Mahmood and Balian, 1996;Hu and Hayton, 2001). By definition, r 2 is the fraction of the total squared error explained by the model.…”

Interspecies Allometric Scaling of Antimalarial Drugs and Potential Application to Pediatric Dosing

“…Notwithstanding the limitations of interspecies scaling and the power law relationship debate, allometric scaling data indicate that fixed exponents of 2/3 or 3/4 may not be universally applicable in pharmacokinetics (24,28,29,31,33,38,44,47). Our analyses showed that the 95% CI encompassed both 2/3 and 3/4 for CL of artemether and artemisinin, whereas the upper limit of the 95% CIs for mefloquine, quinine, and chloroquine (0.63, based on reanalysis of a previous study [33]) were all Ͻ0.65 (Table 1).…”

“…where Y is the pharmacokinetic parameter (e.g., CL or V z ), W is the body weight of the species, a is the coefficient, and b is the allometric exponent (19,24,38).…”

“…Allometric scaling is a well-established technique for relating physiological or pharmacokinetic parameters to body weight (17)(18)(19)(20)(21)(22), and allometric relationships have been demonstrated for a wide range of drugs, including antimicrobial agents (23)(24)(25)(26)(27). The conventional applications of interspecies allometric scaling include prediction of human doses by extrapolation from preclinical animal studies and dose estimates for other mammalian species in veterinary medicine (18,23,26,28).…”

A two-tiered physiologically based model for dually labeled single-chain Fv-Fc antibody fragments

“…Some physiologic, species-specific model parameters (e.g., volume flow rates) can be translated across species using the allometric equation, an empirical power law that relates the biological parameter to body weight (25,26). Hence, the mathematical model can be parameterized using animal data and then ''scaled-up'' to human and used to predict the biodistribution of the same drug in the clinic (27).…”