A population pharmacokinetic (PPK) model for creatinine was successfully developed using creatinine concentration data from 6 healthy male volunteers with and without ingestion of 225 g boiled beef as an exogenous creatinine source. A model with first-order absorption, zero-order creatinine generation, and first-order elimination was used to describe the pharmacokinetic (PK) data. Creatinine parameters, estimated from the final model were: apparent absorption rate constant (Ka, 1.71 1/h), lag time (0.343 h), renal clearance (equal to systemic clearance) (CL, 7.57 L/h), apparent volume of distribution (Vd, 52.8 L), and creatinine generation rate (CGR, 67.8 mg/h). The CL and CGR estimates were in agreement with the reported values, whereas the Vd estimates were slightly higher than the reported values. The model is a useful starting point for further experimental approaches to improve the understanding of creatinine kinetics, which may involve creatinine “dosing” accompanied by independent methods to assess the glomerular filtration rate.

The minipig has become an animal of considerable interest in preclinical drug development. It has been used in toxicology research and in examining/establishing regulatory guidelines as a nonrodent animal model. We have reviewed some basic issues that one would want to consider in the development and testing of any animal model for humans. The pig is a reasonable alternative to the dog, but there are some clear limitations and unexplained disparities in the literature, which require further study; primary among these is the need for standardization in choice of breed and sex and routine protocols. The minipig offers numerous advantages over other established animal models, and it has similarities to the human with regard to anatomy, physiology, and biochemistry. The gastrointestinal tract is structurally and functionally similar to humans. This appears to be true for enzymes and transporters in the gut as well, but more study is needed. One major concern is assessment of oral drug absorption, especially with regard to potential food effects due to gastric emptying differences, yet this does not appear to be a consistent observation. Hepatic metabolism seems to reflect enzymatic patterns in humans, with some differences. Kidney function seems similar to humans but requires further study. We have analyzed literature data that suggest the pig would offer a reasonable model for human oral bioavailability and for allometric predictions of clearance. The minipig appears to be the model for dermal absorption in humans, and we discuss this in terms of literature data and our own in-house experience.

Should estimates of glomerular filtration rate and creatinine clearance be indexed to body surface area for drug dosing? David E. Nix, Pharm.D., David E. Nix, Pharm.D. Department of Pharmacy Practice & Science, College of Pharmacy, University of Arizona, Tucson, AZ Address correspondence to Dr. Nix (nix@pharmacy.arizona.edu). Search for other works by this author on: Oxford Academic Google Scholar Michael Mayersohn, Ph.D., Michael Mayersohn, Ph.D. Department of Pharmacy Practice & Science, College of Pharmacy, University of Arizona, Tucson, AZ Search for other works by this author on: Oxford Academic Google Scholar Brian L. Erstad, Pharm.D. Brian L. Erstad, Pharm.D. Department of Pharmacy Practice & Science, College of Pharmacy, University of Arizona, Tucson, AZ Search for other works by this author on: Oxford Academic Google Scholar American Journal of Health-System Pharmacy, Volume 74, Issue 21, 1 November 2017, Pages 1814–1819, https://doi.org/10.2146/ajhp160467 Published: 01 November 2017

This review focuses on a discussion of the controversies in allometric scaling (AS) for predicting human clearance from a mathematical and statistical perspective. First, a history of allometric scaling in comparative biology and its use in pharmacokinetics are reviewed. It is shown that the application of AS in predicting human clearance values based on a limited number of animal species (typically, 3 or 4) contains fundamental statistical errors from when AS was first introduced from comparative biology._Second, the mathematical nature of various allometrically-based methods is revealed and the soundness of these methods is assessed. It is demonstrated that any of these methods, which incorporate a correction factor in a traditional allometric approach (varying-exponent allometry), not only reduces the statistical power of the allometric analysis, but are also incorrect with regard to aspects of biology. Finally, it is concluded that allometry remains a valuable tool for predicting human clearance, and should be applied in the context of a fixed exponent. However, fixed-exponent allometry does not provide satisfactory accuracy in predicting human clearance, since it is not able to capture the biological differences among species. Therefore, it is recommended that the overall effort in predicting human pharmacokinetics should be directed to the collection and generation of reliable data (both in vitro and in vivo) along with a better understanding of the DMPK properties of the chemical entity.

This commentary is a reply to a recent article by Mahmood commenting on the authors' article on the use of fixed-exponent allometry in predicting human clearance. The commentary discusses eight issues that are related to criticisms made in Mahmood's article and examines the controversies (fixed-exponent vs. varying-exponent allometry) from the perspective of statistics and mathematics. The key conclusion is that any allometric method, which is to establish a power function based on a limited number of animal species and to extrapolate the resulting power function to human values (varying-exponent allometry), is infused with fundamental statistical errors.

The objective of these studies was to examine the in vivo performance of oral formulations of chlorpropham (CIPC). In order to develop a new oral formulation several different solubilization techniques were evaluated, namely: cosolvents, surfactants, and complexing agents. The solubilization data indicated that a conventional solution formulation was not plausible. Two self-emulsifying drug delivery systems (SEDDS) were developed and evaluated for stability. Both SEDDS formulations were found to be chemically stable. In vivo analysis of a SEDDS formulation, a suspension formulation and an intravenous bolus dose was conducted in F344 rats. Pharmacokinetic analysis of the formulation data indicated that the SEDDS formulation provided only marginally better oral bioavailability compared to a suspension formulation. While SEDDS formulations often result in greater bioavailability this was not observed for CIPC. In vivo analysis indicate that CIPC results in a situation where the dissolution rate of CIPC from the suspension is not rate limiting, rather the absorption rate in the GI tract is rate-limiting. This paradigm is the result of CIPCs low melting point and the relatively small particle size of the suspension which facilitate the dissolution in the GI tract. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5222–5228, 2008

A data-driven approach was adopted to derive new one- and two-species-based methods for predicting human drug clearance (CL) using CL data from rat, dog, or monkey (n = 102). The new one-species methods were developed as CL(human)/kg = 0.152 x CL(rat)/kg, CL(human)/kg = 0.410 x CL(dog)/kg, and CL(human)/kg = 0.407 x CL(monkey)/kg, referred to as the rat, dog, and monkey methods, respectively. The coefficient of the monkey method (0.407) was similar to that of the monkey liver blood flow (LBF) method (0.467), whereas the coefficients of the rat method (0.152) and dog method (0.410) were considerably different from those of the LBF methods (rat, 0.247; dog, 0.700). The new rat and dog methods appeared to perform better than the corresponding LBF methods, whereas the monkey method and the monkey LBF method showed improved predictability compared with the rat and dog one-species-based methods and the allometrically based "rule of exponents" (ROE). The new two-species methods were developed as CL(human) = a(rat-dog) . W (human)(0.628) (referred to as rat-dog method) and CL(human) = a(rat-monkey) . W (human)(0.650) (referred to as rat-monkey method), where a(rat-dog) and a(rat-monkey) are the coefficients obtained allometrically from the corresponding two species. The predictive performance of the two-species methods was comparable with that of the three-species-based ROE. Twenty-six Wyeth compounds having data from mouse, rat, dog, monkey, and human were used to test these methods. The results showed that the rat, dog, monkey, rat-dog, and rat-monkey methods provided improved predictions for the majority of the compounds compared with those for the ROE, suggesting that the use of three or more species in an allometrically based approach may not be necessary for the prediction of human exposure.

The appropriateness of relying on the coefficient of determination (r(2)) as a statistical metric for judging the predictability of human clearance (CL) based on interspecies animal data was assessed. An explicit mathematical expression was derived for r(2) as a function of species body weight and the corresponding measured value of CL. The derived mathematical function demonstrated that r(2) is numerically large in most instances. Simulations using random CL generated from a common combination of species of mouse, rat, and monkey resulted in an r(2) of 0.75 as the minimum, and 0.95 and 0.98 at 50th and 75th percentiles, respectively, given that total CL values increase with increasing species body weight. Analysis of literature data also indicated that the prediction accuracy of human CL was not correlated with values of r(2). Therefore, it is concluded that r(2) is a limited statistical measure when assessing allometric scaling for the purpose of predicting human CL.

Allometrically scaled data sets (138 compounds) used for predicting human clearance were obtained from the literature. Our analyses of these data have led to four observations. (1) The current data do not provide strong evidence that systemic clearance (CLs; n=102) is more predictable than apparent oral clearance (CLpo; n=24), but caution needs to be applied because of potential CLpo prediction error caused by differences in bioavailability across species. (2) CLs of proteins (n=10) can be more accurately predicted than that of non-protein chemicals (n=102). (3) CLs is more predictable for compounds eliminated by renal or biliary excretion (n=33) than by metabolism (n=57). (4) CLs predictability for hepatically eliminated compounds followed the order: high CL (n=11)>intermediate CL (n=17)>low CL (n=29). All examples of large vertical allometry (% error of prediction greater than 1000%) occurred only when predicting human CLs of drugs having very low CLs. A qualitative analysis revealed the application of two potential rules for predicting the occurrence of large vertical allometry: (1) ratio of unbound fraction of drug in plasma (fu) between rats and humans greater than 5; (2) C logP greater than 2. Metabolic elimination could also serve as an additional indicator for expecting large vertical allometry.

The prediction of a human clearance (CL) value for UCN-01, an extreme example of vertical allometry (a large overprediction by allometric scaling), was examined using commonly used simple allometry and the "rule of exponents," as well as a newly proposed model, which quantitatively incorporates plasma protein-binding information from rats and humans. Simple allometry and the rule of exponents were shown to overpredict the human CL value of UCN-01 by about 5000- and 1750-fold, respectively. The new model incorporating the ratio of fraction unbound between rats and humans improved the prediction by about 20-fold compared to the rule of exponents. The model is expected to improve if a more accurate measurement of the unbound fraction in human plasma is obtained. The prediction of volume distribution for UCN-01 by allometric scaling was also shown to be dependent on the difference of fraction unbound between animal species and humans. In summary, plasma protein binding has been demonstrated to be an important measure for interspecies scaling of pharmacokinetics.

The functionality of the correction factors, maximum life-span potential (MLP), and brain weight (BrW) used in allometry is mathematically described. Correction by MLP or BrW is equivalent to a multiplication of some constants by the predicted values in humans from simple allometry, but they have no relationship to measured pharmacokinetic parameters in the animal species. The values of these constants (F-MLP or F-BrW) were calculated for some commonly used combinations of animal species. For all combinations of animal species, the value of F-BrW is always greater than that of F-MLP with a fold-increase of about 1.3 to 1.9. Different combinations of species give different values of F-BrW and F-MLP. In addition, the role of correction factors (MLP and BrW) or the "rule of exponents" (ROE) was evaluated. An intrinsic defect in using correction factors or ROE was revealed; different study designs will produce significantly different prediction results. However, ROE may still serve as a useful practical approach in predicting human CL since it was derived from real observations and has been applied to many examples.

Sixty-one sets of clearance ( CL) values in animal species were allometrically scaled for predicting human clearance. Unbound fractions (f(u)) of drug in plasma in rats and humans were obtained from the literature. A model was developed to predict human CL: CL = 33.35 ml/min x (a/Rf(u))(0.770), where Rf(u) is the f(u) ratio between rats and humans and a is the coefficient obtained from allometric scaling. The new model was compared with simple allometric scaling and the "rule of exponents" (ROE). Results indicated that the new model provided better predictability for human values of CL than did ROE. It is especially significant that for the first time the proposed model improves the prediction of CL for drugs illustrating large vertical allometry.

A general equation was derived, which directly describes the mathematical relationship between the allometrically predicted pharmacokinetic (PK) parameters in humans and the body weights of animal species (along with their corresponding measured PK parameters). It was shown, with use of the derived equation, that the predicted values in humans, based on combinations of animal species commonly used in allometry, are heavily dependent on certain species, for example, the dog. In contrast, parameter values from the rat made no contribution to the predicted human values, as long as the rat was not the smallest species used. Monte Carlo simulations were further performed to examine the species or weight dependence. The cost-effective combinations of animal species, in terms of number and species type, were theoretically examined through simulations. Finally, literature data demonstrated the species or weight dependence predicted from the equation and as illustrated through the Monte Carlo simulations. Appreciation of this species or weight dependence should guide researchers in selecting animal species and designing optimal experiments in the application of allometric scaling.

The purpose of this study is to characterize the distribution pattern of P–gp protein levels along the entire GI tract in the Yucatan micropig, which is being developed as a model for human drug bioavailability. Small and large intestines were freshly obtained and divided into about 37 segments and 10 segments, respectively (ca., 1 foot/segment). Epithelial cells from the small intestine were obtained by an elution method; whereas, a scraping method was applied to the large intestine. Total cellular protein was isolated from the epithelial cells. Western blot analysis using P–gp antibody showed that the amount of P–gp protein increased distally from the duodenum to the ileum over approximately a 10–fold range. P–gp protein in the large intestine was present at a higher level in the central portion, but the absolute amount was much less than what was found in the small intestine. © 2004 Wiley Periodicals, Inc. J Biochem Mol Toxicol 18:18–22, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20001

Camphor, menthol, and methyl salicylate occur in numerous over‐the‐counter products. Although extensively used, there have been no estimates of human exposure following administration via dermal application. Furthermore, there is little information about the pharmacokinetics of those compounds. The authors report the plasma concentrations of the intact compounds as a function of dose following dermal patch application. Three groups of 8 subjects (4 male, 4 female) applied a different number of commercial patches (2, 4, or 8) to the skin for 8 hours. Plasma samples were assayed using sensitive and selective gas‐chromatographic methods. For the 8‐patch group, the average maximum plasma concentrations (C max ± SD) were 41.0 ± 5.8 ng/mL, 31.9 ± 8.8 ng/mL, and 29.5 ± 10.5 ng/mL for camphor, menthol, and methyl salicylate, respectively. The corresponding values for the 4‐patch group were 26.8 ± 7.2 ng/mL, 19.0 ± 5.4 ng/mL, and 16.8 ± 6.8 ng/mL. The harmonic mean terminal half‐lives were 5.6 ± 1.3 hours, 4.7 ± 1.6 hours, and 3.0 ± 1.2 hours for camphor, menthol, and methyl salicylate, respectively. The 2‐patch group had measurable but low plasma concentrations of each compound. Low‐dose dermal application for an extended time results in low plasma concentrations of all 3 compounds. Four and 8 patches, when applied for 8 hours, gave measurable and nearly proportional plasma concentrations. Although unable to determine the absolute dermal bioavailability of these compounds, there appears to be relatively low systemic exposure to these potentially toxic compounds, even when an unrealistically large number of patches are applied for an unusually long time.

A model is proposed for the prediction of either high or low fraction absorbed for an orally administered, passively transported drug on the basis of a new absorption parameter, Pi The model includes only two inputs: the octanol-water partition coefficient (K-ow) and the dimensionless oversaturation number (O-Lumen). The latter is the ratio of the concentration of drug delivered to the gastrointestinal (GI) fluid to the solubility of the drug in that environment. Thus, O-Lumen is equal to the dose-normalized solubility for suspensions and unity for solutions. The value of Pi increases with an increase in K-ow and a decrease in O-Lumen for suspensions, and is equal to K-ow for solutions. The effectiveness of the model is validated using experimental human gastrointestinal absorption data for 98 compounds. About 88% of these drugs are correctly predicted to be either well absorbed or poorly absorbed based solely upon whether their Pi value is greater than or less than unity. Thus, the use of a single absorption parameter, Pi provides a simple means to estimate whether or not an orally administered drug undergoing passive transport will be absorbed efficiently. The advantage of this parameter is that it is based upon simple, easily measured (or calculated) physical chemical data. It is especially noteworthy that experimental measurement of in vitro membrane transport is not required. The model based on the new absorption parameter is shown to have wider applicability than current available models for predicting the fraction absorbed.

An HPLC assay was developed using three methods of plasma sample preparation in order to quantitate curcumin, the main constituent in the herbal dietary supplement turmeric. Each method involves simple and rapid processing of samples (either an ethyl acetate or chloroform extraction) with resulting different quantitation limits for curcumin. The assay was developed in an effort to quantify extremely low curcumin plasma concentrations observed in preliminary in vivo studies. The most sensitive assay can reliably detect concentrations down to 2.5ng/ml. Plasma quantitation was precise and accurate based on both intra- and inter-day validations as indicated by low values for coefficients of variation and bias, respectively (≤15%). The analytical validation was reproducible between different analysts. The resulting analytical method couples desired sensitivity with the ease of an isocratic system.