scholarly journals A Single Animal Species-Based Prediction of Human Clearance and First-in-Human Dose of Monoclonal Antibodies: Beyond Monkey

Antibodies ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 35
Author(s):  
Iftekhar Mahmood
Keyword(s):  
Monoclonal Antibodies ◽  
Flow Rate ◽  
Animal Species ◽  
Dose Range ◽  
Liver Blood Flow ◽  
Blood Flow Rate ◽  
Single Species ◽  
Human Dose ◽  
Single Animal ◽  
Fold Prediction

These days, there is a lot of emphasis on the prediction of human clearance (CL) from a single species for monoclonal antibodies (mabs). Many studies indicate that monkey is the most suitable species for the prediction of human clearance for mabs. However, it is not well established if rodents (mouse or rat) can also be used to predict human CL for mabs. The objectives of this study were to predict and compare human CL as well as first-in-human dose of mabs from mouse or rat, ormonkey. Four methods were used for the prediction of human CL of mabs. These methods were: use of four allometric exponents (0.75, 0.80, 0.85, and 0.90), a minimal physiologically based pharmacokinetics method (mPBPK), lymph flow rate, and liver blood flow rate. Based on the predicted CL, first-in-human dose of mabs was projected using either exponent 1.0 (linear scaling) or exponent 0.85, and human-equivalent dose (HED) from each of these species. The results of the study indicated that rat or mouse could provide a reasonably accurate prediction of human CL as well as first-in-human dose of mabs. When exponent 0.85 was used for CL prediction, there were 78%, 95%, and 92% observations within a 2-fold prediction error for mouse, rat, and monkey, respectively. Predicted human dose fell within the observed human dose range (administered to humans) for 10 out of 13 mabs for mouse, 11 out of 12 mabs for rat, and 12 out of 15 mabs for monkey. Overall, the clearance and first-in-human dose of mabs were predicted reasonably well by all three species (a single species). On average, monkey may be the best species for the prediction of human clearance and human dose but mouse or rat especially; rat can be a very useful species for conducting the aforementioned studies.

Liver Blood Flow Rate and Glucose Metabolism in Hemorrhagic Hypotension and Shock

1982 ◽  
Vol 22 (9) ◽  
pp. 753-758 ◽  
Author(s):  
NACI M. BOR ◽  
MUHLISE ALVUR ◽  
MERAL T. ERCAN ◽  
COŞLKUN F. BEKDIK
Keyword(s):  
Blood Flow ◽  
Glucose Metabolism ◽  
Flow Rate ◽  
Liver Blood Flow ◽  
Blood Flow Rate ◽  
Hemorrhagic Hypotension

scholarly journals Interspecies Scaling of Antibody–Drug Conjugates (ADC) for the Prediction of Human Clearance

Antibodies ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 1
Author(s):  
Iftekhar Mahmood
Keyword(s):  
Prediction Error ◽  
Animal Species ◽  
Allometric Scaling ◽  
Pharmacokinetic Parameters ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Human Dose ◽  
Animal Data ◽  
Fold Prediction ◽  
Antibody Drug

Allometric scaling is a useful tool for the extrapolation of pharmacokinetic parameters from animals to humans. The objective of this study was to predict human clearance of antibody–drug conjugates (ADC) allometrically from one to three animal species and compare the predicted human clearance with the observed human clearance. For three animal species allometric scaling, the “Rule of Exponents” (ROE) was used. The results of the study indicated that three-species allometric scaling in association with the ROE provides acceptable prediction (within 0.5–2-fold prediction error) of human clearance. The two-species allometric scaling resulted in substantial prediction error. One-species scaling using a fixed exponent of 1.0 provided acceptable prediction error (within 0.5–2-fold) by monkey, rat, and mouse, in which monkey and rat were comparable. Overall, the predicted human clearance values of ADCs from animal(s) was good. The allometric method proposed in this article can be used to predict human clearance from the animal data and subsequently to select the first-in-human dose of ADCs.

Effects of upper limb exercise programs on the arteriovenous fistula in patients on hemodialysis: A systematic review and meta-analysis

2021 ◽  
pp. 112972982110011
Author(s):  
Francini Porcher Andrade ◽  
Heloíse Benvenutti ◽  
Kacylen Costa da Silva ◽  
Paula Maria Eidt Rovedder
Keyword(s):  
Systematic Review ◽  
Arteriovenous Fistula ◽  
Flow Rate ◽  
Upper Limb ◽  
Handgrip Strength ◽  
Meta Analysis ◽  
Blood Flow Rate ◽  
Exercise Programs ◽  
Exercise Interventions ◽  
Limb Exercise

Background: The arteriovenous fistula (AVF) is a commonly used vascular access for chronic kidney disease (CKD) patients; exercise interventions may boost its maturation and help in its maintenance. A systematic review and meta-analysis of clinical trials on the effects of upper limb exercise programs on the AVF was conducted. Methods: The primary outcomes were draining vein diameter (DVD) and draining vein blood flow rate (DVBFR), and secondary outcomes were handgrip strength (HGS) and brachial artery flow rate (BAFR). Quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Results: Four studies met the inclusion criteria. When compared to usual care groups, the experimental groups did not improve DVD (mean difference [MD] 0.23, confidence interval [CI] −0.20–0.65). There were significant differences in DVBFR (mL/min) according to the fixed-effect model (MD 141.13, CI 36.84–245.42). HGS (kg) was significantly different between groups (MD 2.95, CI 0.55–5.35), but BAFR (mL/min) was not (MD 91.65, CI −94.72–278.01). Conclusions: Although exercise programs did not improve DVD and BAFR, they increased muscle strength and DVBFR. Therefore, experimental exercise programs should be emphasized for AVF maturation and maintenance. Research Registry number: reviewregistry924.

Scaling laws of vascular trees: of form and function

2006 ◽  
Vol 290 (2) ◽  
pp. H894-H903 ◽  
Author(s):  
Ghassan S. Kassab
Keyword(s):  
Flow Rate ◽  
Scaling Laws ◽  
Minimum Energy ◽  
Blood Flow Rate ◽  
Tree Structure ◽  
Conservation Of Energy ◽  
Form And Function ◽  
And Function ◽  
The Cost ◽  
Vascular Trees

The branching pattern and vascular geometry of biological tree structure are complex. Here we show that the design of all vascular trees for which there exist morphometric data in the literature (e.g., coronary, pulmonary; vessels of various skeletal muscles, mesentery, omentum, and conjunctiva) obeys a set of scaling laws that are based on the hypothesis that the cost of construction of the tree structure and operation of fluid conduction is minimized. The laws consist of scaling relationships between 1) length and vascular volume of the tree, 2) lumen diameter and blood flow rate in each branch, and 3) diameter and length of vessel branches. The exponent of the diameter-flow rate relation is not necessarily equal to 3.0 as required by Murray's law but depends on the ratio of metabolic to viscous power dissipation of the tree of interest. The major significance of the present analysis is to show that the design of various vascular trees of different organs and species can be deduced on the basis of the minimum energy hypothesis and conservation of energy under steady-state conditions. The present study reveals the similarity of nature's scaling laws that dictate the design of various vascular trees and the underlying physical and physiological principles.

The Effect of Furosemide on the Intrarenal Blood Flow Distribution in the Dog

1972 ◽  
Vol 50 (8) ◽  
pp. 774-783 ◽  
Author(s):  
Serge Carrière ◽  
Michel Desrosiers ◽  
Jacques Friborg ◽  
Michèle Gagnan Brunette
Keyword(s):  
Blood Flow ◽  
Flow Rate ◽  
Urine Volume ◽  
Flow Distribution ◽  
Blood Flow Rate ◽  
Initial Distribution ◽  
Blood Flow Distribution ◽  
Intrarenal Blood Flow ◽  
Femoral Blood ◽  
Furosemide Administration

Furosemide (40 μg/min) was perfused directly into the renal artery of dogs in whom the femoral blood pressure was reduced (80 mm Hg) by aortic clamping above the renal arteries. This maneuver, which does not influence the intrarenal blood flow distribution, produced significant decreases of the urine volume, natriuresis, Ccreat, and CPAH, and prevented the marked diuresis normally produced by furosemide. Therefore the chances that systemic physiological changes occurred, secondary to large fluid movements, were minimized. In those conditions, however, furosemide produced a significant increase of the urine output and sodium excretion in the experimental kidney whereas Ccreat and CPAH were not affected. The outer cortical blood flow rate (ml/100 g-min) was modified neither by aortic constriction (562 ± 68 versus 569 ± 83) nor by the subsequent administration of furosemide (424 ± 70). The blood flow rate of the outer medulla in these three conditions remained unchanged (147 ± 52 versus 171 ± 44 versus 159 ± 54). The initial distribution of the radioactivity in each compartment remained comparable in the three conditions. In parallel with the results from the krypton-85 disappearance curves, the autoradiograms, silicone rubber casts, and EPAH did not suggest any change in the renal blood flow distribution secondary to furosemide administration.

The Effect of Hematocrit on the Clearance of Small Molecules during Hemodialysis

1983 ◽  
Vol 6 (3) ◽  
pp. 127-130 ◽  
Author(s):  
C. Woffindin ◽  
N.A. Hoenich ◽  
D.N.S. Kerr
Keyword(s):  
Blood Flow ◽  
Regression Analysis ◽  
Small Molecules ◽  
Flat Plate ◽  
Flow Rate ◽  
Distribution Curve ◽  
Blood Flow Rate ◽  
Hollow Fibre ◽  
Urea Clearance ◽  
Flow Rates

Data collected during the evaluation of a series of hemodialysers were analysed to see the effect of hematocrit on the clearance of urea and creatinine. All evaluations were performed on patients with a range of hematocrits with a mean close to 20%. The urea clearance of those in the upper half of the distribution curve (mean hematocrit 29.4%) was not significantly different from that of patients in the lower half of the distribution curve (mean hematocrit 16.9%) whether the clearance was studied at high or low blood flow rates and with hollow fibre or flat plate disposable hemodialysers. Likewise, there was no correlation between hematocrit and urea clearance by regression analysis. In contrast, the clearance of creatinine was affected by hematocrit being greater at lower hematocrit values. This difference was independent of blood flow rate and dialyser type and was confirmed by regression analysis.

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