Interspecies allometric scaling. Part I: prediction of clearance in large animals

Interspecies scaling is a useful tool for the prediction of pharmacokinetic parameters from animals to humans, and it is often used for estimating a first-time in human dose. The knowledge of pharmacokinetics in veterinary species is important for dosage selection, particularly in the treatment of large zoo animal species, such as elephants, giant cats and camels, for which pharmacokinetic data are scant. Therefore, the accuracy in clearance predictions in large animal species, with and without the use of correction factors (rule of exponents), and the impact of species selection in the prediction of clearance in large animal species was examined. Based upon this analysis, it was determined that there is a much larger risk of inaccuracies in the clearance estimates in large animal species when compared with that observed for humans. Unlike in humans, for large animal species, correction factors could not be applied because there was no trend between the exponents of simple allometry and the appropriate correction factor for improving our predictions. Nevertheless, we did see an indication that the exponents of simple allometry may alert us as to when the predicted clearance in the large animal may be underestimated or overpredicted. For example, if a large animal is included in the scaling, the predicted clearance in a large animal should be considered overestimated if the exponent of simple allometry is >1.3. Despite the potential for extrapolation error, the reality is that allometric scaling is needed across many veterinary practice situations, and therefore will be used. For this reason, it is important to consider mechanisms for reducing the risk of extrapolation errors that can seriously affect target animal safety, therapeutic response, or the accuracy of withdrawal time predictions.     

Interspecies allometric analysis of the comparative pharmacokinetics of 44 drugs across veterinary and laboratory animal species

The purpose of this study was to apply the method of allometric analysis to a study of the comparative disposition of veterinary drugs using the Food Animal Residue Avoidance Databank (FARAD) as a source of the comparative pharmacokinetic data. An initial filtration of the FARAD data was performed in order to exclude drugs for which no pharmacokinetic data were available, in at least four species the route of administration was other than intravenous, and the matrix was different from blood, plasma or serum. This process restricted the study to a total of 44 candidate drugs. The primary pharmacokinetic parameter selected for study was half-life (t_1/2). As this parameter is a composite of clearance (Cl) and volume of distribution (Vd), it was considered to be the most robust for interspecies scaling. Volume of distribution at steady state (Vd_ss) and clearance showed weak allometric correlations with weight across species. The relationships between body weight and elimination half-life (t_1/2β) were determined for this selected group of drugs by using the empirically determined function Y=a W^b. The function Y represents the parameter of concern (half-life), a is a coefficient typical of every drug (intercept), W is the species average body weight, and b is the scaling exponent. A total of 11 drugs (tetracycline, oxytetracycline, chlortetracycline, erythromycin, diazepam, prednisolone, cephapirin, ampicillin, gentamicin, apramycin and carbenicillin) showed statistically significant correlations and consequently are excellent candidates for interspecies extrapolation of pharmacokinetic parameters (half-life) in species of relevance to veterinary medicine. The remaining 33 drugs were divided into two groups which showed various degrees of lack of correlation. Many of the drugs that showed no allometric correlation were low hepatic extraction drugs. However, some other drugs demonstrated equivocal results which could either be due to a true lack of allometric correlation, or be inconclusive due to the lack of quality data or excessive variability due to the multi-laboratory origin of the FARAD data. The results of this study show that interspecies scaling is applicable to certain veterinary drugs. The experimental determination of the coefficients of the allometric equation for relevant pharmacokinetic parameters (clearance and volume of distribution) could be an important tool in estimating dose in species where the drug has never been studied. This could have important consequences in terms of avoiding the use of dose-titration studies in Phase I of drug development, for drugs that are experimentally ‘well behaved’.     

Interspecies allometric meta‐analysis of the comparative pharmacokinetics of 85 drugs across veterinary and laboratory animal species

Allometric scaling is widely used for the determination of first dosage regimen and the interpolation or extrapolation of pharmacokinetic parameters across many animal species during drug development. In this article, 85 drugs used in veterinary medicine obtained from the Food Animal Residue Avoidance Databank database were selected for allometric scaling analysis. Outlier species were identified by statistical methods. The results showed that 77% and 88% of drugs displayed significant correlations between total systemic clearance (CL) and volume of distribution at steady status (Vss) vs. body weight (P < 0.05) on a log‐log scale, respectively. The distribution of the allometric exponent b for CL and Vss displays approximate normal distribution, with means (0.87 and 0.99) and standard deviations (0.143 and 0.157) for CL and Vss, respectively. Twelve drugs were identified to have at least one outlier species for CL and ten drugs for Vss. The human CL and Vss were predicted for selected drugs by the obtained allometric equations. The predicted CL and Vss were within a threefold error compared to observed values, except the predicted CL values for antipyrine, warfarin and diazepam. The results can be used to estimate cross‐species pharmacokinetic profiles for predicting drug dosages in veterinary species, and to identify those species for which interpolation or extrapolation of pharmacokinetics properties may be problematic.     

Anatomical and physiological basis for the allometric scaling of cisplatin clearance in dogs

Cisplatin is a platinum‐containing cytotoxic drug indicated for the treatment of solid tumors in veterinary and human patients. Several of the algorithms used to standardize the doses of cytotoxic drugs utilize allometry, or the nonproportional relationships between anatomical and physiological variables, but the underlying basis for these relationships is poorly understood. The objective of this proof of concept study was to determine whether allometric equations explain the relationships between body weight, kidney weight, renal physiology, and clearance of a model, renally cleared anticancer agent in dogs. Postmortem body, kidney, and heart weights were collected from 364 dogs (127 juveniles and 237 adults, including 51 dogs ≥ 8 years of age). Renal physiological and cisplatin pharmacokinetic studies were conducted in ten intact male dogs including two juvenile and eight adult dogs (4–55 kg). Glomerular filtration rate (GFR), effective renal plasma flow, effective renal blood flow, renal cisplatin clearance, and total cisplatin clearance were allometrically related to body weight with powers of 0.75, 0.59, 0.61, 0.71, and 0.70, respectively. The similar values of these diverse mass exponents suggest a common underlying basis for the allometry of kidney size, renal physiology, and renal drug handling.     

Modeling and allometric scaling of s(+)-ketoprofen pharmacokinetics and pharmacodynamics: a retrospective analysis

Interspecies scaling of pharmacokinetic (PK) parameters is commonplace in drug development. However, information about proportionality of pharmacodynamic (PD) parameters in different species is scarce. We investigated the feasibility of allometric scaling of PK and PD parameters of s(+)-ketoprofen (sKTP) using the literature data from several animal species. Two different indirect response models were proposed to characterize sKTP inhibitory effects on synthesis of thromboxane B(2) (TXB(2)) and prostaglandin E(2) (PGE(2)). Using the traditional allometric approach, the obtained PK and PD parameters were plotted against body weights (BW) on a log-log scale. For all species, values of systemic clearance (Cl), distribution clearance (Cl(D)), central volume of distribution (V(c)), and volume of distribution at steady-state (V(ss)) were highly correlated (r(2) = 0.89-0.99) with BW. The PD parameters for inhibition of TXB(2) synthesis were poorly correlated with BW (r(2) = 0.25-0.54) while most of the parameters for inhibition of PGE(2) synthesis lacked any correlation (r(2) approximately 0.05). In conclusion, indirect response models adequately described the time course of sKTP inhibitory effects on synthesis of TXB(2) and PGE(2). Allometrical scaling showed PK parameters to change proportionally to BW, whereas PD parameters had limited ranges and were essentially weight independent.     

Antibiotic susceptibilities of Salmonella species isolated at a large animal veterinary medical center: a three year study.

The antibiograms of 408 Salmonella species isolated from large animals were collected during a three year study from 1981 through 1983. The predominant Salmonella serogroup among these isolates was group B. A consistently high percentage of all isolates were resistant to ampicillin and tetracycline. A pattern of increasing resistance to chloramphenicol and gentamicin was documented for serogroup B isolates while the susceptibility of the isolates to neomycin increased. There was a decrease in the incidence of susceptibility to sulfamethoxazole-trimethoprim among the group E isolates. These changes were not as remarkable, nor as alarming, as the overall decreased susceptibility to chloramphenicol and gentamicin. An evaluation of the principles concerning use of antimicrobial agents in veterinary medicine for treatment of Salmonella infections is recommended.     

Allometric scaling of orbifloxacin disposition in nine mammal species: a retrospective analysis

The objective of this study was to analyze the relationship between pharmacokinetic parameters and body weight (W) for orbifloxacin using reported pharmacokinetic data. The parameters of interest: clearance (Cl), volume of distribution at steady state (Vss) and elimination half-life were correlated across nine mammal species, including cattle, dog, rat, rabbit, goat, camel, horse, cat and sheep as a function of W using the conventional allometric equation Y = aW(b), where Y is the pharmacokinetic parameter, W is the body weight, a is the allometric coefficient (intercept) and b is the exponent that describes the relationship between the pharmacokinetic parameter and W. Our estimates (Cl=4.40 W(1.03); Vss=1.10W(1.05)) indicated that the increase in these parameters with W approximates a linear power relationship with slopes being very close to one. Overall, the results of this study indicated that it is possible to use allometry to predict pharmacokinetic variables of orbifloxacin based on W of mammal species.     

Beyond BSE: Transmissible spongiform encephalopathies in other animal species

There are several other diseases besides BSE which belong to the group of transmissible spongiform encephalopathies (TSE). Although most mammals can be experimentally infected with the agent of these diseases, generally only single representatives of the orders Artiodactyla (cloven-hoofed animals), Carnivora (carnivores) and Primates (humans and monkeys) are naturally infected in the field. An overview of the current state of knowledge on TSE in several species like exotic ruminants, deer, mink and cats is presented. Etiological, clinical, anatomic-pathological and epidemiological aspects are described.     

Procedural and mathematical considerations in urea dilution estimation of body composition in lambs

Two experiments (n = 46 and 56, respectively) were conducted to evaluate urea dilution as an estimator of body composition in lambs and to address certain procedural and mathematical considerations in this technique. In Exp. 1, 14 blood samples were taken over 240 min after urea infusion. The equation describing the urea clearance curve was: delta PUN = 9.7e-.1727(min) + 10.4e-.0021(min), pools 1 and 2, respectively (r2 = .99, P less than .001; individual lamb effects removed). In the combined experiments, urea space (US) was related to percentage of empty body water (PEBH2O) by the equation 31.7 + .471 US (empty body weight basis; r2 = .56, P less than .001). The regression equation indicates that the US-PEBH2O relationship in lambs is different from that reported in cattle, even though urea clearance kinetics are similar. Although the prediction equations appeared to be biologically valid, considerable error was associated with the composition estimates. The PEBH2O was predicted as well by live weight (r2 = .69; SEy.x = 3.0) as by US in these experiments. The two-sample method (T12 minus T0) to determine the change in marker concentration was shown to be related more closely (r2 = .56) to PEBH2O than the standard multisample extrapolation to T0 method (r2 = .0 and .38 for pools 1 and 2, respectively). An equilibration time of 9 to 12 min provided the best estimate of body composition in lambs.(ABSTRACT TRUNCATED AT 250 WORDS)     

准噶尔荒漠6种类短命植物生物量分配与异速生长关系

类短命植物是我国荒漠植物区系中重要而独特的组成部分。准噶尔荒漠是类短命植物在中亚干旱区分布的最东端。目前关于类短命植物生物量分配及异速生长关系的研究较少。选择了百合科的小山蒜、棱叶韭、粗柄独尾草、黑鳞顶冰花、伊犁郁金香以及菊科的细叶鸦葱共6种植物作为研究对象,对比研究了其生物量分配及异速生长关系的异同。结果表明,6种类短命植物单株总生物量在0.628～21.144 g之间,根冠比在0.355～3.066之间,叶片生物量比例在0.092～0.289之间,繁殖分配比例在0.111～0.649之间。6种植物用于繁殖器官和光合器官的生物量分配各不相同,表明不同科、不同属及同属不同种之间的生物量大小及器官分配比例无一致规律。大部分物种根冠比随个体增大而显著下降,而繁殖分配则呈显著的异速增加的趋势。6种植物器官生物量间(共45对)大部分(40对)表现为等速生长关系(即异速生长指数为1),而且地上与地下生物量间及叶片与地下生物量间还各自具有共同的异速生长指数(分别为0.8764和0.8585),表现出强烈的功能趋同性。但6个物种间没有出现完全一致的相关生长关系,这可能归因于由系统分类地位决定的遗传特性的差异。