Considerations of Design and Data When Developing Physiologically Based Pharmacokinetic Models
John C. Lipscomb, Edward V. Ohanian in Toxicokinetics and Risk Assessment, 2016
To account for the difference in parameter values due to variations in body weight (BW) across species, allometric scaling is commonly employed. Allometry takes the form of power-law equations relating parameter values to body mass. The usual allometric scaling relationship relating metabolic rate (B) to body mass (M) is where B0 is the normalization parameter or coefficient (36,37). This formula has been extended to a wide range of organisms from the microbes to large vertebrates and plants. Hence, in pharmacokinetics, values for blood flows, clearance rates, and maximum velocities are most commonly scaled by multiplication with BW3/4. It should be noted that body weight in these formulas assumes “normal” body composition. Further adjustments for the prediction of body size differences clearance and volume in obese or very lean people will usually require the use of other covariate information (e.g., height and skin thickness) to predict the weight with “normal” body composition. Allometric scaling within a species is not appropriate. Additional adjustments may be required to account for developmental changes (refer to Chapter 11, by G. Ginsberg) (38).
The brain
Francesco E. Marino in Human Fatigue, 2019
However, regardless of what the exponent might be (noting that previous research has suggested exponents ranging from 0.3 to 3.0; Stevens 1957), it is worthwhile understanding (1) what purpose the exponent plays in psychophysical relations beyond its quantification, and (2) what advantage this relationship provided during our evolutionary past and how it relates to fatigue. The answers to these questions are not particularly apparent, but we are able to infer from previous work that has established an allometric law that pervades biological diversity (Porter & Brand 1993; West et al. 1997). Although allometry specifically describes relations of size of different organs or parts of an organism, it is now accepted that a 3/4 scaling law has been established by nature as a way of placing constraints on body size relative to the rates at which resources are used from the environment, transported and transformed within the body (West et al. 1997). Similarly, an exponent related to apparent and perceived exertion based on the accelerating growth of sensation would also constrain the organism within its biological limitations.
Interspecies Extrapolation of Toxicological Data
Rhoda G. M. Wang, James B. Knaak, Howard I. Maibach in Health Risk Assessment, 2017
The above conclusions are based on a series of assumptions outlined in the text of this paper. The most debatable assumption involves the allometric scaling of physiological parameters with the 3/4 power of body weight. It might be argued that if these physiological parameters scaled with the 0.7 power of body weight, then our conclusion would be that interspecies scaling should be on the basis of mg/kg0.7/day, a result more consistent with the currently accepted surface area scaling law. The scaling of physiological parameters such as cardiac output and alveolar ventilation rate is only necessary to obtain a closed form analytical proof of our results (Appendix B). If one is willing to accept a computer verification of the result, then it is not necessary to scale the physiological parameters. One can set up three pharmacokinetic models (one each for mice, rats, and human) using actiual physiological parameters. It still must be assumed that (1) partition coefficients are approximately constant across species; (2) Vmax scales with the 3/4 power of body weight; and (3) Km is approximately constant across species. We have performed such computer calculations and found that the body weight per unit of physiological time scaling law still holds. Thus our conclusion is, in reality, based only on the above three assumptions plus the assumption concerning the appropriateness of the pharmacokinetic model. The debate (Section IV.F) over the appropriate scaling law for physiological parameters becomes irrelevant.
Allometric scaling of therapeutic monoclonal antibodies in preclinical and clinical settings
Published in mAbs, 2021
Eva Germovsek, Ming Cheng, Craig Giragossian
With the constant advancement in mAb engineering and manufacturing technologies, mAb-based therapeutics will continue to grow and remain one of the most prevalent drug classes. The allometric scaling approaches discussed herein will remain critically important in the mAb drug development, specifically for designing and conducting FIH and pediatric clinical studies. The direct comparison of the use of allometry in preclinical and clinical settings presented here highlights the current status in both, enables identification of knowledge gaps and can enable the field to advance faster. In particular, more data from very young patients and mAbs with nonlinear elimination are needed to be able to make more confident conclusions. With more and more data becoming available, these approaches will continue to evolve, and we will likely see a growing recognition and expanding use of pharmacometric modeling approaches in both settings, especially in the preclinical research. This would help incorporate and increase knowledge regarding e.g., the TMDD, ADA effects, and age-related effects, and lead to better mAb PK predictions thereby improving FIH/pediatric dose determination, which will facilitate and ultimately accelerate drug development.
Tooth dimensions and body size in a Pygmy population
Published in Annals of Human Biology, 2019
Fernando V. Ramirez-Rozzi, Alejandro Romero
Many studies (e.g. Wood 1979), especially the only previous work on Pygmies (Shea and Gomez 1988), use the term “allometry” to refer to correlations. These studies, based on the concept developed by Huxley (1932) and Jolicoeur (1963), see allometry when a change in one trait is greater or less than a change in body size; generally stature. This concept is different to that suggested by Gould (1966) and Mosimann (1970), who consider that the terms “allometry” and “isometry” should be used when size is compared with shape. Godfrey and Sutherland (1995, 1996; Ramírez Rozzi 2000) have clearly explained the different interpretations of a result that can be given depending on the theoretical framework applied. Shea and Gomez (1988) reported some “allometries” for Pygmies but they compare some traits against size (Huxley–Jolicoeur framework), use cranial measurements as proxies for body size and do not use any proxy for shape. In other words, their method did not allow the assessment of allometry. Further, they did not distinguish between sexes and thus the few relationships they found between stature and tooth diameters probably result from analysing the sexes pooled together. The few significant correlations between tooth diameters and stature and the lack of any significant correlation of area or geometric mean with stature in our analysis, mean that changes in body size are accompanied by a random variation in tooth dimensions in the Baka Pygmies.
Minocycline improves cognition and molecular measures of inflammation and neurodegeneration following repetitive mTBI
Published in Brain Injury, 2021
Matthew I. Hiskens, Rebecca K. Vella, Anthony G. Schneiders, Andrew S. Fenning
There were two separate arms for this study, an acute branch where animals were sacrificed 48 hours following final impact, and a chronic branch where animals were sacrificed 90 days following final impact (Figure 1a). Using the random number generator function of Excel, mice were randomized to 1 of 4 treatment groups: control with vehicle (VEH + CON, n = 8), control with minocycline (MIN + CON, n = 8), impacts with minocycline (MIN + IMP, n = 8), or impacts with vehicle (VEH + IMP, n = 8). Allometric scaling informs equivalent animal dosing based on body surface area, which reflects the differences in human and mouse metabolic rates. Minocycline was delivered at a dose of 50 mg kg−1 day−1, which was calculated using FDA allometric scaling factor of 0.081 (18) and is equivalent to previous murine studies (19). Minocycline was dissolved in saline, while the vehicle groups received saline only. Vehicle and minocycline were administered via subcutaneous injection and were given for 14 days prior to the first impact and throughout the impact and testing schedule until the time of sacrifice of the acute groups. Bodyweight of each mouse was assessed before the commencement of minocycline administration, weekly during mTBI administration, and at time of euthanasia. There were no significant differences in weight between impacted and non-impacted groups at all time-points (data not shown).
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