scholarly journals Predicting human pharmacokinetics from preclinical data: volume of distribution

2020 ◽  
Vol 28 (4) ◽  
pp. 169
Author(s):  
Dong-Seok Yim ◽  
Suein Choi
Keyword(s):  
Volume Of Distribution ◽  
Human Pharmacokinetics ◽  
Preclinical Data ◽  
Data Volume

scholarly journals Preclinical Pharmacokinetics of MI-219, a Novel Human Double Minute 2 (HDM2) Inhibitor and Prediction of Human Pharmacokinetics

2012 ◽  
Vol 15 (2) ◽  
pp. 265 ◽  
Author(s):  
Peng Zou ◽  
Nan Zheng ◽  
Yanke Yu ◽  
Shanghai Yu ◽  
Wei Sun ◽  
...  
Keyword(s):  
Allometric Scaling ◽  
Human Study ◽  
Volume Of Distribution ◽  
Time Profile ◽  
In Vitro Assays ◽  
Pharmacokinetic Studies ◽  
Human Pharmacokinetics ◽  
Preclinical Pharmacokinetics ◽  
Concentration Time

Purpose. The two purposes of this study were evaluating preclinical pharmacokinetics of MI-219 and predicting clearance (CL) and volume of distribution at steady-state (Vdss) of MI-219 in humans. Methods. Pharmacokinetic studies were conducted on mice, rats, dogs, and monkeys. Human CL of MI-219 was predicted using allometric scaling (SA), multi-exponential allometric scaling (ME), rule of exponents (RoE), single species scaling, two-term power equation (TTPE), physiologically based in vitro-in vivo extrapolation (IVIVE), and fu corrected intercept method (FCIM). In vitro assays were conducted to determine in vitro intrinsic CL, protein binding, and blood-plasma partition coefficients. To estimate half-life of MI-219, plasma concentration–time profile in humans was predicted using kallynochron and apolysichron time transformation (Dedrick plots) and normalization with MRT and Vdss (Wajima’s method). In addition, simultaneous interspecies scaling of CL, Vdss and concentration–time profile were performed by using Nonlinear Mixed Effects Modeling (NONMEM). Results. Preclinical studies showed that the elimination of MI-219 was mainly through metabolism. The validation using observed monkey CL and Vdss showed that MA, IVIVE and Oie-Tozer methods were accurately than the other methods. Human CL of MI-219 predicted by ME and IVIVE was between 0.237-0.342 L*h-1*kg-1. Human Vdss predicted by Oie-Tozer method and allometric scaling of unbound volume of distribution of tissues (VT/fuT) method was between 0.93-1.40 L*kg-1. Superimposition of rat, monkey and dog data was observed in Dedrick plots and Wajima’s transformations. Conclusions. The predicted human pharmacokinetics is useful for the design of first-in-human study. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Predicting blood-to-plasma concentration ratios of drugs from chemical structures and volumes of distribution in humans

2021 ◽  
Author(s):  
Hideaki Mamada ◽  
Kazuhiko Iwamoto ◽  
Yukihiro Nomura ◽  
Yoshihiro Uesawa
Keyword(s):  
Plasma Concentration ◽  
Prediction Model ◽  
Correlation Coefficient ◽  
Prediction Models ◽  
Molecular Descriptors ◽  
Volume Of Distribution ◽  
Human Pharmacokinetics ◽  
Chemical Structures ◽  
Drug Concentrations ◽  
Concentration Ratios

Abstract Despite their importance in determining the dosing regimen of drugs in the clinic, only a few studies have investigated methods for predicting blood-to-plasma concentration ratios (Rb). This study established an Rb prediction model incorporating typical human pharmacokinetics (PK) parameters. Experimental Rb values were compiled for 289 compounds, offering reliable predictions by expanding the applicability domain. Notably, it is the largest list of Rb values reported so far. Subsequently, human PK parameters calculated from plasma drug concentrations, including the volume of distribution (Vd), clearance, mean residence time, and plasma protein binding rate, as well as 2702 kinds of molecular descriptors, were used to construct quantitative structure–PK relationship models for Rb. Among the evaluated PK parameters, logVd correlated best with Rb (correlation coefficient of 0.47). Thus, in addition to molecular descriptors selected by XGBoost, logVd was employed to construct the prediction models. Among the analyzed algorithms, artificial neural networks gave the best results. Following optimization using six molecular descriptors and logVd, the model exhibited a correlation coefficient of 0.64 and a root-mean-square error of 0.205, which were superior to those previously reported for other Rb prediction methods. Since Vd values and chemical structures are known for most medications, the Rb prediction model described herein is expected to be valuable in clinical settings. Graphical abstract

scholarly journals Predicting human pharmacokinetics from preclinical data: clearance

2021 ◽  
Vol 29 (2) ◽  
pp. 78
Author(s):  
Dong-Seok Yim ◽  
Soo Hyeon Bae ◽  
Suein Choi
Keyword(s):  
Human Pharmacokinetics ◽  
Preclinical Data

PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 2: Comparative assessment of prediction methods of human volume of distribution

2011 ◽  
Vol 100 (10) ◽  
pp. 4074-4089 ◽  
Author(s):  
Rhys Do Jones ◽  
Hannah M. Jones ◽  
Malcolm Rowland ◽  
Christopher R. Gibson ◽  
James W.T. Yates ◽  
...  
Keyword(s):  
Predictive Models ◽  
Volume Of Distribution ◽  
Comparative Assessment ◽  
Prediction Methods ◽  
Human Pharmacokinetics

scholarly journals Predicting human pharmacokinetics from preclinical data: absorption

2020 ◽  
Vol 28 (3) ◽  
pp. 126
Author(s):  
Dong-Seok Yim ◽  
Suein Choi ◽  
Soo Hyeon Bae
Keyword(s):  
Human Pharmacokinetics ◽  
Preclinical Data

Human Pharmacokinetics and Pharmacodynamics of MF 701 Dermatan Sulfate Administered by Continuous Intravenous Infusion

1990 ◽  
Vol 64 (02) ◽  
pp. 256-259 ◽  
Author(s):  
Giancarlo Agnelli ◽  
Benilde Cosmi ◽  
Cinzia Renga ◽  
Fiorella Federici ◽  
Giuseppe G Necil ◽  
...  
Keyword(s):  
Pharmacokinetic Model ◽  
Dermatan Sulfate ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Human Pharmacokinetics ◽  
Bolus Administration ◽  
Thrombin Inhibition ◽  
Chromogenic Assay ◽  
Single Compartment ◽  
Human Thrombin

SummaryThe pharmacokinetics and haemostatic effects of MF 701 dermatan sulfate (DS) administered by i. v. infusion were studied in 11 healthy volunteers. Each subject received 0.6 mg kg-1 h-1 MF 701 for 10 h. DS plasma concentrations were measured by a chromogenic assay based on the catalysis of thrombin inhibition by HCII. DS plasma levels followed a single compartment pharmacokinetic model, with a half-life of 1.28 ± 0.46 h, a plasma clearance of 2.75 ± 0.46 1/h and a volume of distribution of 4.92 ± 1.36 1 (means ± SD). Steady-state was reached 3 to 6 h after infusion started. The maximal DS plasma concentration was 16.4 ± 5.7 μg/ml. Maximal APTT prolongation over pre-infusion values was 42 ± 7%; TCT performed with bovine and human thrombin was prolonged by 16 ± 7% and 83 ± 35% respectively. No anti-IIa or anti-Xa activities were detected by chromogenic tests. The treatment was well tolerated. The pharmacokinetics of MF 701 infusion are consistent with those previously described after i. v. bolus administration. The infusion of MF 701 allows fast achievement and steady maintenance of elevated DS plasma concentrations.

Pharmacokinetics of Full Length and Two-Domain Tissue Factor Pathway Inhibitor in Combination with Heparin in Rabbits

1993 ◽  
Vol 70 (03) ◽  
pp. 454-457 ◽  
Author(s):  
Claus Bregengaard ◽  
Ole Nordfang ◽  
Per Østergaard ◽  
Jens G L Petersen ◽  
Giorgio Meyn ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Anticoagulant Activity ◽  
Fold Increase ◽  
Volume Of Distribution ◽  
Full Length ◽  
Heparin Binding ◽  
Extrinsic Pathway ◽  
C Terminus ◽  
Tissue Factor Pathway

SummaryTissue factor pathway inhibitor (TFPI) is a feed back inhibitor of the initial activation of the extrinsic pathway of coagulation. In humans, injection of heparin results in a 2-6 fold increase in plasma TFPI and recent studies suggest that TFPI may be important for the anticoagulant activity of heparin. Full length (FL) TFPI, but not recombinant two-domain (2D) TFPI, has a poly cationic C-terminus showing very strong heparin binding. Therefore, we have investigated if heparin affects the pharmacokinetics of TFPI with and without this C-terminus.FL-TFPI (608 U/kg) and 2D-TFPI (337 U/kg) were injected intravenously in rabbits with and without simultaneous intravenous injections of low molecular weight heparin (450 anti-XaU/kg).Heparin decreased the volume of distribution and the clearance of FL-TFPI by a factor 10-15, whereas the pharmacokinetics of 2D-TFPI were unaffected by heparin. When heparin was administered 2 h following TFPI the recovery of FL-TFPI was similar to that found in the group receiving the two compounds simultaneously, suggesting that the releasable pool of FL-TFPI is removed very slowly in the absence of circulating heparin.

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