Allometric Scaling Research Articles

Coupling Random Forest, Allometric Scaling, and Cellular Automata to Predict the Evolution of LULC under Various Shared Socioeconomic Pathways

Accurately estimating land-use demand is essential for urban models to predict the evolution of urban spatial morphology. Due to the uncertainties inherent in socioeconomic development, the accurate forecasting of urban land-use demand remains a daunting challenge. The present study proposes a modeling framework to determine the scaling relationship between the population and urban area and simulates the spatiotemporal dynamics of land use and land cover (LULC). An allometric scaling (AS) law and a Markov (MK) chain are used to predict variations in LULC. Random forest (RF) and cellular automata (CA) serve to calibrate the transition rules of change in LULC and realize its micro-spatial allocation (MKCARF-AS). Furthermore, this research uses several shared socioeconomic pathways (SSPs) as scenario storylines. The MKCARF-AS model is used to predict changes in LULC under various SSP scenarios in Jinjiang City, China, from 2020 to 2065. The results show that the figure of merit (FoM) and the urban FoM of the MKCARF-AS model improve by 3.72% and 4.06%, respectively, compared with the MKCAANN model during the 2005–2010 simulation period. For a 6.28% discrepancy between the predicted urban land-use demand and the actual urban land-use demand over the period 2005–2010, the urban FoM degrades by 21.42%. The growth of the permanent urban population and urban area in Jinjiang City follows an allometric scaling law with an exponent of 0.933 for the period 2005–2020, and the relative residual and R2 are 0.0076 and 0.9994, respectively. From 2020 to 2065, the urban land demand estimated by the Markov model is 19.4% greater than the urban area predicted under scenario SSP5. At the township scale, the different SSP scenarios produce significantly different spatial distributions of urban expansion rates. By coupling random forest and allometric scaling, the MKCARF-AS model substantially improves the simulation of urban land use.

Elevated developmental temperatures impact the size and allometry of morphological traits of the bumblebee Bombus terrestris.

The impact of global warming on wild bee decline threatens the pollination services they provide. Exposure to temperatures above optimal during development is known to reduce adult body size but how it affects the development and scaling of body parts remains unclear. In bees, a reduction in body size and/or a reduction in body parts, such as the antennae, tongue and wings, and how they scale with body size (i.e. their allometry) could severely affect their fitness. To date, it remains unclear how temperature affects body size and the scaling of morphological traits in bees. To address this knowledge gap, we exposed both males and workers of Bombus terrestris to elevated temperature during development and assessed the effects on (i) the size of morphological traits and (ii) the allometry between these traits. Colonies were exposed to optimal (25°C) or stressful (33°C) temperatures. We then measured the body size, wing size, antenna and tongue length, as well as the allometry between these traits. We found that workers were smaller and the antennae of both castes were reduced at the higher temperature. However, tongue length and wing size were not affected by developmental temperature. The allometric scaling of the tongue was also affected by developmental temperature. Smaller body size and antennae could impair both individual and colony fitness, by affecting foraging efficiency and, consequently, colony development. Our results encourage further exploration of how the temperature-induced changes in morphology affect functional traits and pollination efficiency.

Echocardiographic reference intervals and cut-off values to diagnose dilated cardiomyopathy in guinea pigs (Cavia porcellus)

The objective of this study was to establish reference intervals in healthy guinea pigs and to calculate optimal cut-off values for several M-Mode parameters to diagnose dilated cardiomyopathy (DCM) phenotype. This prospective study included 146 guinea pigs. The apparently healthy group included 92 animals and was used to create reference intervals for left ventricular internal diameter in diastole (LVIDd), left ventricular internal diameter in systole (LVIDS), E-point-to-septal separation (EPSS), diastolic wall thickness and left atrium and aorta. Allometric scaling was used to normalize LVIDd(-n) and LVIDs(-n) to body weight with a scaling exponent (BWexp). The DCM phenotype group included 54 subjects and was used to calculate optimal cut-off values of several M-mode parameters. Guinea pigs with DCM phenotype had significantly larger measurements of LVIDd, LVIDs and EPSS, as well as lower FS and wall thicknesses compared to apparently healthy guinea pigs. Allometric scaling exponents to normalize LVIDd and LVIDs to BW (g) were 0.336 and 0.346, respectively. The highest area under the curve (AUC) to diagnose DCM were found for LVIDs-n (cut-off value >0.74 mm, AUC 0.996), FS (cut-off value <29%, AUC 0.995), LVIDd-n (cut-off value >1.07 mm, AUC 0.980) and EPSS (cut-off value >1.4 mm, AUC 0.944). M-mode and 2D reference intervals for guinea pigs are presented, including lower and upper limits. Diagnosis of DCM phenotype in guinea pigs can be established using parameters known to be useful in other species, namely LVIDs, LVIDs-n, FS, LVIDd, LVIDd-n and EPSS.

Abstract 2793: Preclinical pharmacokinetics in cynomolgus monkeys and first in human dose prediction of DB-1303, a HER2-targeting antibody-drug conjugate

Abstract Background: DB-1303 is a novel antibody-drug conjugate comprised of trastuzumab biosimilar, enzymatically cleavable peptide-linker, and a proprietary topoisomerase I inhibitor P1003. It is designed to have high plasma stability, low free payload in circulation and wide therapeutic index. Herein, the preclinical pharmacokinetics (PK) characteristics of DB-1303 in cynomolgus monkeys is reported, and human PK exposure in a first in human study was predicted using population PK model with allometric scaling. Material and Methods: The PK parameters of DB-1303 were obtained from single PK and repeated TK studies in female and male cynomolgus monkeys. Concentrations of DB-1303 ADC, total antibody and released payload P1003 were measured using ELISA or LC-MS/MS. In a PK study, single dose of DB-1303 at 1, 3 and 10 mg/kg were determined in cynomolgus monkeys via IV infusion. In TK studies, cynomolgus monkeys were intravenously administered with DB-1303 at 50, 80 mg/kg once every 3 weeks for 2 repeated doses, or 10, 40, 80 mg/kg once every 3 weeks (Q3W) for 3 repeated doses followed by a 4-week recovery. A population PK model was developed based on the collective PK/TK data in monkeys. Results: The non-compartment analysis PK parameters of three analytes (DB-1303 ADC, total antibody and released payload P1003) are summarized following single and multiple doses of DB-1303 in cynomolgus monkeys. To predict the human PK for DB-1303, a target mediated drug disposition (TMDD) model was constructed, incorporating binding to serum HER2 and subsequent elimination of the complex into a standard 2-compartmental PK model. The 2-compartment linear parameters were scaled from cynomolgus monkey population PK parameters using allometric scaling exponents of 1 for volumes and 1 for clearance. The binding of DB-1303 to HER2 was incorporated into the model and assumed to be the same for HER2 ECD and transmembrane domain. The PK profiles for DB-1303 in human at the proposed doses in the first in human study are predicted. The safety margins from the monkey HNSTD for each proposed human dose are calculated. Conclusions: DB-1303 exhibited favorable PK characteristics of DB-1303 in cynomolgus monkeys, and is predicted to have large safety margins at the selected doses in the first in human study. At the time of presentation, the first-in-human phase 1/2 study in patients with advanced solid tumors is in progress (NCT05150691). Citation Format: Rong Shi, Shengchao Lin, Yu Zhang, Bing Li, Haiqing Hua, Yang Qiu. Preclinical pharmacokinetics in cynomolgus monkeys and first in human dose prediction of DB-1303, a HER2-targeting antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2793.

Population pharmacokinetics and pharmacodynamics of cefazolin using total and unbound serum concentrations in patients with high body weight.

The objective of this study was to evaluate the steady state pharmacokinetics and pharmacodynamics of cefazolin in patients with a high body weight. Cefazolin was administered by 0.5-h infusions to 11 patients with total body weight (TBW) ≥120 kg receiving 3 g q8h, and 12 patients with TBW <120 kg receiving 2 g q8h. Total and unbound serum concentration-time data obtained from serial blood samples were analysed simultaneously by population pharmacokinetic modelling using NONMEM. Probability of target attainment (PTA) was calculated for various dosing regimens through Monte Carlo simulations based on the cumulative percentage of the dosing interval that the unbound concentration exceeds the minimum inhibitory concentration (MIC) value for the pathogen at steady state (fTMIC) ≥40%, ≥60% and 100%. A two-compartment model with non-linear protein binding and allometric scaling of the central volume of distribution using TBW best characterized both total and unbound concentration-time data. Unbound clearance was significantly associated with creatinine clearance, and maximum protein binding constant was significantly associated with serum albumin concentration and body mass index (P <0.05). Based on unbound concentration-time profiles, all simulated regimens achieved PTA >90% at MIC values ≤2 mg/L using fTMIC ≥40%, at MIC values ≤1 mg/L using fTMIC ≥60%, and at MIC values ≤0.5 mg/L using fTMIC of 100%. At fTMIC ≥60%, 0.5-h infusion of cefazolin 1 g q8h achieved PTA <90% at MIC values ≥2 mg/L in patients with TBW≥120 kg; however, prolonged-infusion and higher-dose regimens improved PTA to >90%. Overall, cefazolin pharmacokinetics are altered considerably in obese patients. Higher-dose and/or prolonged-infusion cefazolin regimens should be considered in patients with TBW ≥120 kg, particularly those with less-susceptible Gram-negative infections.

Population Pharmacokinetic Study of Benzylpenicillin in Critically Unwell Adults.

Pharmacokinetics are highly variable in critical illness, and suboptimal antibiotic exposure is associated with treatment failure. Benzylpenicillin is a commonly used beta-lactam antibiotic, and pharmacokinetic data of its use in critically ill adults are lacking. We performed a pharmacokinetic study of critically unwell patients receiving benzylpenicillin, using data from the ABDose study. Population pharmacokinetic modelling was undertaken using NONMEM version 7.5, and simulations using the final model were undertaken to optimize the pharmacokinetic profile. We included 77 samples from 12 participants. A two-compartment structural model provided the best fit, with allometric weight scaling for all parameters and a creatinine covariate effect on clearance. Simulations (n = 10,000) demonstrated that 25% of simulated patients receiving 2.4 g 4-hourly failed to achieve a conservative target of 50% of the dosing interval with free drug above the clinical breakpoint MIC (2 mg/L). Simulations demonstrated that target attainment was improved with continuous or extended dosing. To our knowledge, this study represents the first full population PK analysis of benzylpenicillin in critically ill adults.

Demonstration of duality of fractal gravity models by scaling symmetry

A pair of fractal gravity models can be derived from spatial interaction models based on the entropy maximizing principle and the allometric scaling law. The models can be expressed in dual form in mathematics and are important for analyzing and predicting spatial flows in networks of cities. However, the dual relationship of urban gravity parameters has remained an empirical relationship for a long time and lacks theoretical proof. This paper is devoted to proving the duality of fractal gravity models by means of ideas from scaling invariance. The results show that a fractal gravity model can be derived from its dual form. The observational data of interurban spatial flows of the Beijing-Tianjin-Hebei region of China are employed to make a case study, lending further support for the theoretical derivation. It appears that the duality of gravity models rests with the scaling symmetry of fractal structure. This work may be helpful for understanding the theoretical essence and application direction of spatial interaction modeling.

Population Pharmacokinetics and Exposure-Response Analysis for the Phase 3 COSMIC-311 Trial of Cabozantinib for Radioiodine-Refractory Differentiated Thyroid Cancer.

In the USA, cabozantinib was approved for the treatment of patients aged ≥12 years with radioiodine-refractory differentiated thyroid cancer (DTC) who progressed on prior vascular endothelial growth factor(VEGFR)-targeted therapy based on the Phase 3 COSMIC-311 trial, which evaluated cabozantinib 60 mg/day versus placebo. Approved dosing is 60 mg/day for adults and for pediatric patients aged ≥12 years with body surface area (BSA) ≥1.2 m2, and 40 mg/day for pediatric patients aged ≥12 years with BSA <1.2 m2. This report describes a population pharmacokinetic (PopPK) and exposure-response analysis of COSMIC-311. A PopPK model was developed using concentration-time data from COSMIC-311 and 6 other cabozantinib studies. The final (full) PopPK model was used to simulate the effect of sex, body weight, race, and patient population. For exposure-response analysis, derived datasets from COSMIC-311 were constructed for time-to-event analyses of progression-free survival (PFS) and safety endpoints. The PopPK analysis included 4746 cabozantinib PK samples from 1745 patients and healthy volunteers. Body weight had minimal impact on cabozantinib exposure but increasing body weight was associated with increased apparent volume of distribution. Based on model-based simulation, adolescents <40 kg had higher maximum plasma concentration at steady state of cabozantinib 60 mg/day compared to adults. Allometric scaling simulation in adolescents <40 kg demonstrated higher exposure with 60 mg/day relative to adults receiving the same dose, while exposure with 40 mg/day in adolescents <40 kg was similar to 60 mg/day in adults. The exposure-response analysis included 115 patients. There was no clear relationship between PFS or dose modification and cabozantinib exposure. A statistically significant relationship was demonstrated for cabozantinib exposure and hypertension (Grade ≥3) and fatigue/asthenia (Grade ≥3). These results support the dosing strategy implemented in COSMIC-311 and the BSA-based label recommendationsfor adolescents. The cabozantinib dose should be reduced to manage adverse events as indicated.

Sexual size and shape dimorphism, and allometric scaling in the pupal and adult traits of Eristalis tenax.

The patterns and amount of variation in size, shape, and/or life history traits between females and males are fundamentally important to gain the comprehensive understanding of the evolution of phenotypic diversity. In addition, the covariation of phenotypic traits can significantly contribute to morphological diversification and sexual dimorphism (SD). Using linear and geometric morphometrics, 237 Eristalis tenax specimens sampled from five populations were, therefore, comparatively assessed for the variation in sexual size dimorphism (SSD), sexual shape dimorphism (SShD), and life history traits, as well as for trait covariation (ontogenetic and static allometry). Pupal body, adult wing, and body mass traits were analyzed. Female-biased SSD was observed for pupal length, width, and centroid size, adult wing centroid size, mass, wing loading, and wing area. Conversely, pupal length/width ratio, developmental time, and mass were not found to be sexually dimorphic. Next, wing SShD, but not pupal body SShD was revealed, while allometry was found to be an important "determinant of SD" at the adult stage, with only a minor impact at the pupal stage. By comparing the patterns of covariance (based on allometric slope and intercept) between respective body mass and morphometric traits of pupae and adults, greater variation in allometric slopes was found in adult traits, while static allometries of the two stages significantly differed, as well. Finally, the results indicate that changes in the allometric intercept could be an important source of intraspecific variation and SD in drone fly adults.

Ingestion kinetics of mixotrophic and heterotrophic flagellates

AbstractIn sunlit waters, significant predation is performed by unicellular, phagotrophic mixotrophs, that is, predators that also possess plastids. The success of a mixotrophic lifestyle will depend in part on how well mixotrophs acquire prey relative to specialized heterotrophs. Likewise, consequences of mixotrophy for productivity and element cycling will depend on the rate and efficiency at which mixotrophs consume prey biomass relative to heterotrophs. However, trait differences between mixotrophs and heterotrophs are not well characterized. In addition, cell size of mixotrophs varies widely, and constitutive mixotrophs include small flagellates deriving from diverse taxa, while larger species are primarily dinoflagellates. To determine whether similar constraints apply to phagotrophs across this broad range of size and taxa, we compiled 83 measurements of flagellate functional responses and compared maximum clearance rates (Cmax) and maximum ingestion rates (Imax) between trophic modes. We found that the average mixotroph has a 3.7‐fold lower Cmax and 7.8‐fold lower Imax than the average heterotroph, after controlling for cell size. The smaller penalty for Cmax suggests that relative fitness of mixotrophs will be enhanced under dilute prey concentrations that are common in pelagic ecosystems. We also find that growth efficiency is greater for mixotrophs and for flagellates with lower Cmax, indicating a spectrum of trophic strategies that may be driven by phototrophy vs. phagotrophy allocation as well as fast vs. slow metabolic variation. Allometric scaling shows that Imax is constrained by a common relationship among dinoflagellates and other taxa, but dinoflagellates achieve a greater volume‐specific Cmax. These results should aid in interpreting protistan communities and modeling mixotrophy.

Population Pharmacokinetic Analysis of Rifampicin in Plasma, Cerebrospinal Fluid, and Brain Extracellular Fluid in South African Children with Tuberculous Meningitis.

Limited knowledge is available on the pharmacokinetics of rifampicin in children with tuberculous meningitis (TBM) and its penetration into brain tissue, which is the site of infection. In this analysis, we characterize the distribution of rifampicin in cerebrospinal fluid (CSF), lumbar (LCSF) and ventricular (VCSF), and brain extracellular fluid (ECF). Children with TBM were included in this pharmacokinetic analysis. Sparse plasma, LCSF, and VCSF samples were collected opportunistically, as clinically indicated. Brain ECF was sampled using microdialysis (MD). Rifampicin was quantified with liquid chromatography with tandem mass spectrometry in all samples, and 25-desacetyl rifampicin in the plasma samples. The data were interpreted with nonlinear mixed-effects modeling, with the CSF and brain ECF modeled as "effect compartments." Data were available from 61 children, with median (min-max) age of 2 (0.3 to 10) years and weight of 11.0 (4.8 to 49.0) kg. A one-compartment model for parent and metabolite with first-order absorption and elimination via saturable hepatic clearance described the data well. Allometric scaling, maturation, and auto-induction of clearance were included. The pseudopartition coefficient between plasma and LCSF/VCSF was ~5%, while the value for ECF was only ~0.5%, possibly reflecting low recovery of rifampicin using MD. The equilibration half-life between plasma and LCSF/VCSF was ~4 h and between plasma and ECF ~2 h. Our study confirms previous reports showing that rifampicin concentrations in the LCSF are lower than in plasma and provides novel knowledge about rifampicin in the VCSF and the brain tissue. Despite MD being semiquantitative because the relative recovery cannot be quantified, our study presents a proof-of-concept that rifampicin reaches the brain tissue and that MD is an attractive technique to study site-of-disease pharmacokinetics in TBM.

One-stop patient-specific myocardial blood flow quantification technique based on allometric scaling law

Establishing a patient-specific and non-invasive technique to derive blood flow as well as coronary structural information from one single cardiac CT imaging modality. 336 patients with chest pain or ST segment depression on electrocardiogram were retrospectively enrolled. All patients underwent adenosine-stressed dynamic CT myocardial perfusion imaging (CT-MPI) and coronary computed tomography angiography (CCTA) in sequence. Relationship between myocardial mass (M) and blood flow (Q), defined as log(Q) = b · log(M) + log(Q0), was explored based on the general allometric scaling law. We used 267 patients to obtain the regression results and found strong linear relationship between M (gram) and Q (mL/min) (b = 0.786, log(Q0) = 0.546, r = 0.704; p < 0.001). We Also found this correlation was applicable for patients with either normal or abnormal myocardial perfusion (p < 0.001). Datasets from the other 69 patients were used to validate this M−Q correlation and found the patient-specific blood flow could be accurately estimated from CCTA compared to that measured from CT-MPI (146.480 ± 39.607 vs 137.967 ± 36.227, r = 0.816, and 146.480 ± 39.607 vs 137.967 ± 36.227, r = 0.817, for the left ventricle region and LAD-subtended region, respectively, all unit in mL/min). In conclusion, we established a technique to provide general and patient-specific myocardial mass-blood flow correlation obeyed to allometric scaling law. Blood flow information could be directly derived from structural information acquired from CCTA.

Scaling of Activity Space in Marine Organisms across Latitudinal Gradients.

AbstractUnifying models have shown that the amount of space used by animals (e.g., activity space, home range) scales allometrically with body mass for terrestrial taxa; however, such relationships are far less clear for marine species. We compiled movement data from 1,596 individuals across 79 taxa collected using a continental passive acoustic telemetry network of acoustic receivers to assess allometric scaling of activity space. We found that ectothermic marine taxa do exhibit allometric scaling for activity space, with an overall scaling exponent of 0.64. However, body mass alone explained only 35% of the variation, with the remaining variation best explained by trophic position for teleosts and latitude for sharks, rays, and marine reptiles. Taxon-specific allometric relationships highlighted weaker scaling exponents among teleost fish species (0.07) than sharks (0.96), rays (0.55), and marine reptiles (0.57). The allometric scaling relationship and scaling exponents for the marine taxonomic groups examined were lower than those reported from studies that had collated both marine and terrestrial species data derived using various tracking methods. We propose that these disparities arise because previous work integrated summarized data across many studies that used differing methods for collecting and quantifying activity space, introducing considerable uncertainty into slope estimates. Our findings highlight the benefit of using large-scale, coordinated animal biotelemetry networks to address cross-taxa evolutionary and ecological questions.

Predicting riverine fish production using empirical models and the metabolic theory of ecology

AbstractFish production integrates many different measures of community performance, such as abundance, biomass, growth, and reproduction, into one valuable quantitative metric but requires resource intensive data for empirical estimation. While published empirical models and the metabolic theory of ecology (MTE) represent alternative methods to estimate fish production, few studies have focused on productivity models for stream fish assemblages. The goal of our study was to determine whether existing empirical models and elements of the metabolic theory of ecology can reliably estimate stream fish productivity. We used production estimates from the literature (n = 107) to parameterize models based on the metabolic theory of ecology and new estimates of stream fish production from North America (n = 78) to compare and validate all models. Using major axis regression, we determined that while all models had strongly correlated production estimates relative to the observed values (r2 range: [0.496, 0.815]), not all the models produced accurate estimates. The MTE model with the temperature component had a poorer predictive performance (RMSE = 0.502) relative to models based solely on allometric scaling (RMSE range: [0.299, 0.380]). We conclude that standard production models can generate relative estimates of production using general fish sample data, however, the accuracy and precision of the estimates can vary among the models. Our study highlights the need for productivity estimates for stream fish assemblages from different geographic regions, to test empirical models with novel datasets, and for further investigation of temperature effects on fish productivity.

Development of population pharmacokinetics model and Bayesian estimation of rifampicin exposure in Indonesian patients with tuberculosis

BackgroundInterindividual variability in the pharmacokinetics (PK) of anti-tuberculosis (TB) drugs is the leading cause of treatment failure. Herein, we evaluated the influence of demographic, clinical, and genetic factors that cause variability in RIF PK parameters in Indonesian TB patients. MethodsIn total, 210 Indonesian patients with TB (300 plasma samples) were enrolled in this study. Clinical data, solute carrier organic anion transporter family member-1B1 (SLCO1B1) haplotypes *1a, *1b, and *15, and RIF concentrations were analyzed. The population PK model was developed using a non-linear mixed effect method. ResultsA one-compartment model with allometric scaling adequately described the PK of RIF. Age and SLCO1B1 haplotype *15 were significantly associated with variability in apparent clearance (CL/F). For patients in their 40s, each 10-year increase in age was associated with a 10% decrease in CL/F (7.85 L/h). Patients with the SLCO1B1 haplotype *15 had a 24% lower CL/F compared to those with the wild-type. Visual predictive checks and non-parametric bootstrap analysis indicated good model performance. ConclusionAge and SLCO1B1 haplotype *15 were significant covariates of RIF CL/F. Geriatric patients with haplotype *15 had significantly greater exposure to RIF. The model could optimize TB pharmacotherapy through its application in therapeutic drug monitoring (clinical trial no. NCT05280886).

Application of Allometric Methods for Indexation of Left Ventricular End-Diastolic Volume to Normal Echocardiographic Data and Assessing Gender and Racial Differences

Gender and racial differences in cardiac chamber size are vital to establish normal ranges of cardiac chamber size in healthy subjects. Many studies report either non-indexed raw measurements or indexation to isometric body surface area (BSA) when establishing normal reference values. Other studies advocate allometric indexation for standardization of heart size. We compared several allometric methods on gender and racial differences in left ventricular end-diastolic volume (LVEDV) measured by three-dimensional echocardiography (3DE). 3DE LVEDV data from the World Alliance Societies of Echocardiography (WASE) normal values study were indexed to isometric BSA, BSA1.5, BSA1.8, isometric height, height2.3, height2.9, and estimated lean body mass (ELBM). Gender, racial, national, and regional differences in indexed and non-indexed LVEDV were assessed using Cohen's d or Cohen's f statistics, according to the number of groups being compared. Cohen's d < 0.20 and Cohen's f < 0.10 were regarded as very small relative magnitude of differences. Differences in LVEDV among White, Black, and Asian races were smallest when BSA1.5 or BSA1.8 was used for indexation, followed by ELBM. LVEDV/BSA1.5 was nearly identical for males and females (very small, d = 0.05). However, both LVEDV/BSA1.5 and LVEDV/BSA1.8 still provided moderate relative magnitude of differences (f = 0.22 to 0.37) among geographic regions. Specifically, among Asians, Indians had the smallest LVEDV/BSA1.5 (1.8). Brazilians had the smallest LVEDV/BSA1.5 (1.8) among Whites. Gender and racial differences in LVEDV became smaller when LVEDV was indexed to BSA1.5 or BSA1.8. However, differences in LVEDV among nations remain even after applying allometric scaling. This finding suggests that differences in body composition and/or hemodynamics are potentially more important determinants of heart size than race or gender.

Interplay of Breast Cancer Resistance Protein (Bcrp/Abcg2), Sex, and Fed State in Oral Pharmacokinetic Variability of Furosemide in Rats

Poor and variable oral bioavailability of furosemide (FUR) presents critical challenges in pharmacotherapy. We investigated the interplay of breast cancer resistance protein (Bcrp)-mediated transport, sex, and fed state on FUR pharmacokinetics (PK) in rats. A crossover PK study of FUR (5 mg/kg, oral) was performed in Sprague-Dawley rats (3 males and 3 females), alone or with a Bcrp inhibitor, novobiocin (NOV) (20 mg/kg, oral), in both fed and fasted states. Co-administration of NOV significantly increased FUR extent (AUC) and rate (Cmax) of exposure by more than two-fold, which indicates efficient Bcrp inhibition in the intestine. The female rats showed two-fold higher AUC and Cmax, and two-fold lower renal clearance of FUR compared to the male rats. The latter was correlated with higher renal abundance of Bcrp and organic anion transporters (Oats) in the male rats compared to age-matched female rats. These findings suggest that the PK of Bcrp and/or Oat substrates could be sex-dependent in rats. Moreover, allometric scaling of rat PK and toxicological data of Bcrp substrates should consider species and sex differences in Bcrp and Oat abundance in the kidney. Considering that Bcrp is abundant in the intestine of rats and humans, a prospective clinical study is warranted to evaluate the effect of Bcrp inhibition on FUR PK. The potential confounding effect of the Bcrp transporter should be considered when FUR is used as a clinical probe of renal organic anion transporter-mediated drug-drug interactions. Unlike human data, no food-effect was observed on FUR PK in rats.

Cover Image

Ecological MonographsVolume 93, Issue 1 e1533 COVER IMAGEFree Access Cover Image First published: 01 February 2023 https://doi.org/10.1002/ecm.1533AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract COVER PHOTO: Bushbuck (Tragelaphus sylvaticus) in Mozambique's Gorongosa National Park. Daskin et al. (Article e1549; doi:10.1002/ecm.1549) tracked movement and foraging behaviors of three closely related but different-sized spiral-horned antelopes: bushbuck, nyala (T. angasii), and kudu (T. strepsiceros). The authors found that behavioral metrics scaled allometrically with body mass, which in turn reduced spatial and dietary overlap among species. Allometric scaling of behavior may promote niche differentiation and species coexistence throughout the animal kingdom. Photo credits: Brett Kuxhausen / Gorongosa Media Project. Volume93, Issue1February 2023e1533 RelatedInformation

Gene expression databases for physiologically based pharmacokinetic modeling of humans and animal species.

In drug research, developing a sound understanding of the key mechanistic drivers of pharmacokinetics (PK) for new molecular entities is essential for human PK and dose predictions. Here, characterizing the absorption, distribution, metabolism, and excretion (ADME) processes is crucial for a mechanistic understanding of the drug-target and drug-body interactions. Sufficient knowledge on ADME processes enables reliable interspecies and human PK estimations beyond allometric scaling. The physiologically based PK (PBPK) modeling framework allows the explicit consideration of organ-specific ADME processes. The sum of all passive and active ADME processes results in the observed plasma PK. Gene expression information can be used as surrogate for protein abundance and activity within PBPK models. The absolute and relative expression of ADME genes can differ between species and strains. This is affecting both, the PK and pharmacodynamics and is therefore posing a challenge for the extrapolation from preclinical findings to humans. We developed an automated workflow that generates whole-body gene expression databases for humans and other species relevant in drug development, animal health, nutritional sciences, and toxicology. Solely, bulk RNA-seq data curated and provided by the Swiss Institute of Bioinformatics from healthy, normal, and untreated primary tissue samples were considered as an unbiased reference of normal gene expression. The databases are interoperable with the Open Systems Pharmacology Suite (PK-Sim and MoBi) and enable seamless access to a central source of curated cross-species gene expression data. This will increase data transparency, increase reliability and reproducibility of PBPK model simulations, and accelerate mechanistic PBPK model development in the future.

Pediatric Population Pharmacokinetic Modeling and Exposure-Response Analysis of Ambrisentan in Pulmonary Arterial Hypertension and Comparison With Adult Data.

This study aimed to develop a population pharmacokinetic (PK) model of ambrisentan in pediatric patients (8 to <18 years) with pulmonary arterial hypertension (PAH) and compare pediatric ambrisentan systemic exposure with previously reported adult data. Association of ambrisentan exposure with efficacy (6-minute walking distance) and safety (adverse events) were exploratory analyses. A population PK model was developed using pediatric PK data. Steady-state systemic exposure metrics were estimated for the pediatric population and compared with previously reported data in adult patients with PAH and healthy subjects. No covariates had a significant effect on PK parameters; therefore, the final covariate model was the same as the base model. The pediatric population PK model was a 2-compartment model including the effect of body weight (allometric scaling),first-order absorption and elimination, and absorption lag time. Steady-state ambrisentan exposure was similar between the pediatric and adult population when accounting for body weight differences. Geometric mean area under the concentration-time curve at steady state in pediatric patients receiving ambrisentan low dose was 3% lower than in the adult population (and similar in both populations receiving high dose). Geometric mean maximum plasma concentration at steady state in pediatric patients receiving low and high doses was 11% and 18% higher, respectively, than in the adult population. There was no apparent association in the pediatric or adult population between ambrisentan exposure and change in 6-minute walking distance or incidence of ambrisentan-related adverse events in pediatric patients. The similar ambrisentan exposure and exposure-response profiles observed in pediatric and adult populations with PAH suggests appropriateness of body-weight-based dosing in the pediatric population with PAH.