Interspecies scaling and prediction of human clearance: comparison of small- and macro-molecule drugs

Huh, Yeamin; Smith, David Eugene; Feng, Mingchen

doi:10.3109/00498254.2011.598582

Cited by 74 publications

(65 citation statements)

References 120 publications

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“…The value of scaling coefficient used for clearance was 0.75 (6). The body weight used for scaling the clearance were 0.028, 0.28, 1.2, 6.2, and 70 kg for mouse, rat, rabbit, monkey, and human, respectively.…”

Section: Methodsmentioning

confidence: 99%

Influence of Molecular size on the clearance of antibody fragments

Krippendorff

Shah

2017

Pharm Res

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Purpose To establish a continuous relationship between the size of various antibody fragments and their systemic clearance (CL) in mice. Methods Two different orthogonal approaches have been used to establish the relationship. First approach uses CL values estimated by non-compartmental analysis (NCA) to establish a correlation with protein size. The second approach simultaneously characterizes the PK data for all the proteins using a 2-compartment model to establish a relationship between protein size and pharmacokinetic (PK) parameters. Results Simple mathematical functions (e.g. sigmoidal, power law) were able to characterize the CL vs. protein size relationship generated using the investigated proteins. The relationship established in mouse was used to predict rat, rabbit, monkey, and human relationships using allometric scaling. The predicted relationships were found to capture the available spares data from each species reasonably well. Conclusions The CL vs. protein size relationship is important for establishing a robust quantitative structure-PK relationship (QSPKR) for protein therapeutics. The relationship presented here can help in a priori predicting plasma exposure of therapeutic proteins, and together with our previously established relationship between plasma and tissue concentrations of proteins, it can predict the tissue exposure of non-binding proteins simply based on molecular weight/radius and dose.

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Section: Methodsmentioning

confidence: 99%

Influence of Molecular size on the clearance of antibody fragments

Krippendorff

Shah

2017

Pharm Res

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“…The large difference in body size between miniature horses and standard-sized horses suggests the need to take body size into account when dosing miniature horses. When there is considerable variation in body size among animals of the same (Maxwell & Jacobson, 2008;Martinez et al, 2009) or different species (Mahmood et al, 2006;Huh et al, 2011), pharmacokinetic parameters such as clearance and elimination half-life relate to body weight in a nonproportional manner (Mordenti, 1986;Ritschel et al, 1992). In general, smaller individuals have a higher surface area to volume ratio and a higher mass-specific metabolic rate.…”

Section: Introductionmentioning

confidence: 99%

Effect of body weight on the pharmacokinetics of flunixin meglumine in miniature horses and quarter horses

Lee

Maxwell

2013

Vet Pharm & Therapeutics

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In most species, large variations in body size necessitate dose adjustments based on an allometric function of body weight. Despite the substantial disparity in body size between miniature horses and light-breed horses, there are no studies investigating appropriate dosing of any veterinary drug in miniature horses. The purpose of this study was to determine whether miniature horses should receive a different dosage of flunixin meglumine than that used typically in light-breed horses. A standard dose of flunixin meglumine was administered intravenously to eight horses of each breed, and three-compartmental analysis was used to compare pharmacokinetic parameters between breed groups. The total body clearance of flunixin was 0.97 ± 0.30 mL/min/kg in miniature horses and 1.04 ± 0.27 mL/min/kg in quarter horses. There were no significant differences between miniature horses and quarter horses in total body clearance, the terminal elimination rate, area under the plasma concentration versus time curve, apparent volume of distribution at steady-state or the volume of the central compartment for flunixin (P > 0.05). Therefore, flunixin meglumine may be administered to miniature horses at the same dosage as is used in light-breed horses.

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“…There are hardly any reports in the literature on the relationship between the exponent and the prediction accuracy in the allometric concept, and only a report by Huh et al (2011) illustrated that accuracy was high with an exponent of 0.65 to 0.7 for small molecular drugs. However, please note that this result was obtained from single species scaling.…”

Section: Discussionmentioning

confidence: 99%

Application of Hybrid Approach Based on Empirical and Physiological Concept for Predicting Pharmacokinetics in Humans—Usefulness of Exponent on Prospective Evaluation of Predictability

2012

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We developed a hybrid method for predicting plasma concentration-time curves in humans by integrating species differences in in vitro intrinsic clearance (CL int ) into the Dedrick approach based on the allometry concept. With prediction of clearance (CL) by allometric scaling, taking in vitro CL int into consideration improved the accuracy and reduced the average fold error from 2.72 to 1.99. With the hybrid approach of applying the same concept to the Dedrick approach, the predictability of plasma concentration profiles was compared with the results of the conventional Dedrick approach and the physiologically based pharmacokinetic model using 15 compounds with widely ranging physicochemical and pharmacokinetic profiles. The hybrid approach showed the highest predictability among the examined methods. For CL and the apparent volume of distribution at the steady state (V ss ), the relationship between the exponent of allometric equation and fold error was also evaluated with the hybrid approach. The relationship appeared to be a horseshoe curve. Six compounds with exponents ranging from 0.7 to 1.1 for both CL and V ss [antipyrine, caffeine, epiroprim, propafenone, theophylline, and verapamil] displayed higher predictability. Three compounds with an exponent ranging from 0.7 to 1.1 for CL showed better predictability for CL, and the other four compounds appeared to display similar relationship between the exponent and predictability for V ss . These findings indicated that the exponent becomes a preliminary index to speculate on predictability. Combination of the hybrid approach and exponent allows us to prospectively draw human plasma concentration-time curves, with the implication of possible prediction accuracy prior to clinical studies.

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Interspecies scaling and prediction of human clearance: comparison of small- and macro-molecule drugs

Cited by 74 publications

References 120 publications

Influence of Molecular size on the clearance of antibody fragments

Influence of Molecular size on the clearance of antibody fragments

Effect of body weight on the pharmacokinetics of flunixin meglumine in miniature horses and quarter horses

Application of Hybrid Approach Based on Empirical and Physiological Concept for Predicting Pharmacokinetics in Humans—Usefulness of Exponent on Prospective Evaluation of Predictability

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