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Kim, Kim, Shin, Cho, Yu, Jang, and Chung: Pharmacokinetics, Pharmacodynamics and Safety of JES9501 after Single and Multiple Oral Administration in Healthy Subjects
Original Article

J Korean Soc Clin Pharmacol Ther 2013;21(2):141-149.

Published online: 11 January 2013

DOI: https://doi.org/10.12793/ikscpt.2013.21.2.141

Pharmacokinetics, Pharmacodynamics and Safety of JES9501 after Single and Multiple Oral Administration in Healthy Subjects

AnHye Kim1, Bo-Hyung Kim2, Dongseong Shin1, Joo-Youn Cho1, Kyung-Sang Yu1, In-Jin Jang1, Jae-Yong Chung3

1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea

2Department of Clinical Pharmacology and Therapeutics, Kyung Hee University Hospital, Seoul, Republic of Korea

3Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea

E-mail: jychung@snubh.org

Received 13 November 201327 December 2013       Accepted 28 December 2013

Copyright © 2013 Korean Society for Clinical Pharmacology and Therapeutics

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background:

JES9501 is dehydroevodiamine, the extract of Evodia rutaecarpa, expected to be a new therapeutic for Alzheimer disease. This study aims to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of JES9501 after single or multiple dosing.

Methods:

A double-blind, randomized, placebo-controlled, dose ascending, parallel study was conducted in healthy subjects. A single dose of JES9501 50 • 100 • 200 • 400 or 800 mg and multiple doses of JES9501 100 - 200 or 400 mg once-daily for 7days was administered. Serial blood and urine samples for PK evaluation were collected. Acetylcholinesterase (AChE) activity was measured for PD evaluation in multiple dose group.

Results:

In the single dose study, means of dose-normalized peak concentration (Cmax) of 100 • 200 • 400 and 800 mg dose group are comparable except 50 mg dose group. Means of dose-normalized area under the plasma concentration-time curve (AUC) from dosing to the last quantifiable concentration of corresponding dose group were similar. At steady state in the multiple dose study, means of dose-normalized Cmax and AUC for dosing interval of 100 • 200 and 400 mg dose group decreased as the dose increased, however those were not relevant. There was no significant difference of AChE activity between three dosage groups and placebo group. Adverse events related to study drug were all mild and there were no remarkable findings.

Conclusion:

JES9501 was safe and well-tolerated after single or multiple doses in healthy male subjects. Further studies are warranted to evaluate the PK of optimized dosage form and to prove the drug effect in clinical trials for Alzheimer disease patients.

Keywords: Alzheimer disease, Pharmacokinetics, Pharmacodynamics, Healthy volunteer

REFERENCES

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Figure 1.
Mean JES9501 plasma concentration-time profiles after single oral administration (Left: linear scale, Right: log-linear scale, bar: standard deviation).
jkscpt-21-141f1.tif
Figure 2.
Mean JES9501 plasma concentration-time profiles after multiple oral administration of JES9501 once daily for 7days (Left: linear scale, Right: log-linear scale, bar: standard deviation).
jkscpt-21-141f2.tif
Figure 3.
Acetylcholinesterase activity-time profile at predose, Day 4, Day 7 and Day 9 after multiple oral administrations of JES9501 once daily for 7days (bar: standard deviation); Acetylcholinesterase was measured in Placebo group (N=5), and 200 mg group (N=2) on day 4.
jkscpt-21-141f3.tif
Table 1.
Pharmacokinetic parameters of JES9501 after single oral administration of JES9501*
Dose Cmax †(µg/L) Cmax/D (µg/L/mg) AUClast† (µg×h/L) AUClast/D (µg×h/L/mg) Tmax‡ (h) CL/F (L/h) t1/2 (h) CLR (L/h)
50 mg (N=6) 206.8 ± 83.5 (40.4) 4.1 ± 1.7 689.3 ± 254.1 (36.9) 13.8 ± 5.1 3.0 [2.0 ~ 4.0] 78.8 ± 30.2 1.8 ± 0.6 4.0 ± 0.9
100 mg (N=6) 164.7 ± 112.6 (68.4) 1.7 ± 1.1 1176.2 ± 758.0 (64.4) 11.8 ± 7.6 4.0 [2.0 ~ 4.0] 85.0 ± 38.7 14.1 ± 8.7 5.5 ± 0.9
200 mg (N=6) 245.7 ± 114.7 (46.7) 1.2 ± 0.6 2316.8 ± 1025.3 (44.3) 11.6 ± 5.1 3.5 [2.0 ~ 4.0] 93.7 ± 41.3 10.4 ± 4.8 9.9 ± 3.7
400 mg (N=6) 339.5 ± 167.7 (49.4) 0.9 ± 0.4 4131.2 ± 2289.0 (55.4) 10.3 ± 5.7 4.0 [3.0 ~ 8.0] 151.5 ± 108.2 7.8 ± 3.7 9.9 ± 5.9
800 mg (N=6) 985.9 ± 535.0 (54.3) 1.2 ± 0.7 9451.5 ± 5874.6 (62.2) 11.8 ± 7.3 3.0 [3.0 ~ 8.0] 119.2 ± 73.9 9.2 ± 7.1 6.6 ± 2.0§

*The values are presented by mean ± standard deviation. †(%, coefficient of variation), ‡median / [min - max]. § N=4.

Table 2.
Pharmacokinetic parameters of JES9501 on Day 7 after multiple oral administration of JES9501 once daily for 7 days*
Dose Cmax, ss† (µg/L) Cmax, ss/D (µg/L/mg) AUCτ, ss† (µg×h/L) AUCτ,ss/D (µg×h/L/mg) Tmax, ss ‡ (h) CLss/F (L/h) t1/2 (h) Accumulation index CLR (L/h)
100 mg (N=6) 403.9 ± 167.2 (41.4) 4.0 ± 1.7 2437.7 ± 878.9 (36.1) 24.4 ± 8.8 3.0 [3.0-4.0] 41.8 ± 20.1 9.4 ± 3.4 1.13 ± 0.23 3.6 ± 0.7
200 mg (N=6) 635.4 ± 566.3 (89.1) 3.2 ± 2.8 3227.8 ± 2559.9 (79.3) 16.1 ± 12.8 3.0 [3.0-4.0] 95.0 ± 71.0 11.1 ± 4.1 1.17 ± 0.37 9.4 ± 7.4
400 mg (N=6) 955.6 ± 735.9 (77.0) 2.4 ± 1.8 6164.3 ± 3694.4 (59.9) 15.4 ± 9.2 3.5 [1.5-8.0] 50.1 ± 21.9 7.0 ± 4.0 1.45 ± 0.62 9.5 ± 11.9§

*The values are presented by mean ± standard deviation. †(%, Coefficient Variation). ‡ median / [min - max]. §N=5.

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