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Abstract
We previously performed a comparative assessment of tissue-level vascular physiological parameters in mice and rats, two of the most commonly utilized species in translational drug development. The present work extends this effort to non-human primates by measuring tissue- and organ-level vascular volumes (Vv), interstitial volumes (Vi), and blood flow rates (Q) in cynomolgus monkeys. These measurements were accomplished by red blood cell labeling, extracellular marker infusion, and rubidium chloride bolus distribution, respectively, the same methods used in previous rodent measurements. In addition, whole-body blood volumes (BV) were determined across species. The results demonstrate that Vv, Vi, and Q, measured using our methods scale approximately by body weight across mouse, rat, and monkey in the tissues considered here, where allometric analysis allowed extrapolation to human parameters. Significant differences were observed between the values determined in this study and those reported in the literature, including Vv in muscle, brain, and skin and Q in muscle, adipose, heart, thymus, and spleen. The impact of these differences for selected tissues was evaluated via sensitivity analysis using a physiologically based pharmacokinetic model. The blood-brain barrier in monkeys was shown to be more impervious to an infused radioactive tracer, indium-111-pentetate, than in mice or rats. The body weight-normalized total BV measured in monkey agreed well with previously measured value in rats but was lower than that in mice. These findings have important implications for the common practice of scaling physiological parameters from rodents to primates in translational pharmacology.
Highlights
The scaling of various physiological parameters across species has been performed for several decades, largely for the purpose of translational pharmacology [1,2,3,4,5,6]
4 To whom correspondence should be addressed. (e–mail: ferl.gregory@gene.com; boswell.andy@gene.com) of physiological parameters is required for derivation of drug concentrations within compartments such as interstitial fluid [7,8,9] and is an important component of many physiologically based pharmacokinetic (PBPK) models [10,11,12,13,14,15,16,17,18]
Higher weightnormalized blood volumes (BV) were measured in immunocompromised strains (108 in nude and 109 in SCID) relative to immunocompetent strains despite a similar body weight range
Summary
The scaling of various physiological parameters across species has been performed for several decades, largely for the purpose of translational pharmacology [1,2,3,4,5,6]. Of physiological parameters is required for derivation of drug concentrations within compartments such as interstitial fluid (often the drug site of action, for biologics) [7,8,9] and is an important component of many physiologically based pharmacokinetic (PBPK) models [10,11,12,13,14,15,16,17,18]. Human tissue/ organ-level physiological parameters are often derived by allometric scaling of corresponding animal data ( [5, 19, 20]). For biologic drugs with minimal cell partitioning (e.g., antibodies), blood correction of whole tissue concentrations and subsequent conversion into interstitial fluid concentrations requires knowledge of the fractional composition of vascular and interstitial spaces, respectively, within each tissue [7, 8]. We expanded our investigations to include immunocompetent mice [26, 27] and rats [28], but comparable experimental data in primates remains unavailable for some parameters (e.g., Vi) and is
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