J Korean Soc Clin Pharmacol Ther.  2013 Dec;21(2):141-149. 10.12793/jkscpt.2013.21.2.141.

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

• Kim A
• Kim BH
• Shin D
• Cho JY
• Yu KS
• Jang IJ
• Chung JY

• KMID: 2203227
• DOI: http://doi.org/10.12793/jkscpt.2013.21.2.141

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.

Keyword

Alzheimer disease; Pharmacokinetics; Pharmacodynamics; Healthy volunteer

MeSH Terms

Acetylcholinesterase
Administration, Oral*
Alzheimer Disease
Area Under Curve
Dosage Forms
Evodia
Humans
Male
Pharmacokinetics*
Plasma
Acetylcholinesterase
Dosage Forms

Figure

• 

  Figure 1. Mean JES9501 plasma concentration-time profiles after single oral administration (Left: linear scale, Right: log-linear scale, bar: standard deviation).

• 

  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).

• 

  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.

Reference

1. Seoul National University Hospital. Nationwide Study on the Prevalence of Dementia in Korean Elders. 2008; (Korean).

2. Han SH. Novel Pharmacotherapies for Alzheimer’s Disease. J Korean Med Assoc. 2009; 52(11):1059–1068. (Korean).

3. Williams P, Sorribas A, Howes M J. Natural products as a source of Alzheimer’s drug leads. Nat Prod Rep. 2011; 28(1):48–77.

4. Lee JY, Cha MR, Chois CW, Kim YS, Lee BH, Ryu SY. Cholinesterase Inhibitors Isolated from the Fruits Extract of Evodia officinalis. Kor J Pharmacogn. 2012; 43(2):122–126. (Korean).

5. Lee SW, Hwang BY, Kim SE, Kim HM, Kim YH, Lee KS, Lee JJ, Ro JS. Isolation of modulators for multdrug resistance from the fruits of Evodia officinalis. Kor J Pharmacogn. 1995; 26(4):344–348. (Korean).

6. Yun HJ, Heo SK, Lee YT, Park WH, Park SD. Anti-inflammatory effect of Evodia officinalis Dode in mouse macrophage and human vascular endotherial cells. Kor J Herbology. 2008; 23(1):29–38. (Korean).

7. ORHAN İ, ŞENER B. Acetylcholinesterase Inhibitors from Natural Resources. FABAD J Pharm Sci. 2003; 28:51–58.

8. Jeil Pharmaceutical Co., Ltd.Investigator’s Brochure. 2003; (Korean).

9. FDA. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. Guidance for Industry. 2005.

10. Mosca A, Ghezzi A, Luzzana M, Paleari R, Imbimbo BP. Pharmacodynamic monitoring of eptastigmine in capillary blood. Eur J Clin Pharmacol. 1996; 50(5):425–427.

11. Worek F, Mast U, Kiderlen D, Diepold C, Eyer P. Improved determination of acetylcholinesterase activity in human whole blood. Clin Chim Acta. 1999; 288(1-2):73–90.

12. Lotti M. Cholinesterase inhibition: complexities in interpretation. Clin Chem. 1995; 41(12):1814–1818.

13. Augustinsson K-B. The normal variation of human blood cholinesterase activity. Acta Physiol Scand. 1955; 35(1):40–52.

14. Sidell FR, Kaminskis A. Influence of age, sex, and oral contraceptives on human blood cholinesterase activity. Clin Chem. 1975; 21(10):1393–1395.

15. Biagioni MC, Galvin JE. Using biomarkers to improve detection of Alzheimer’s disease. Neurodegener Dis Manag. 2011; 1(2):127–139.

16. Coley N, Andrieu S, Delrieu J, Voisin T, Vellas B. Biomarkers in Alzheimer’s disease: not yet surrogate endpoints. Ann N Y Acad Sci. 2009; 1180:119–124.

17. Galasko D, Golde TE. Biomarkers for Alzheimer’s disease in plasma, serum and blood-conceptual and practical problems. Alzheimers Res Ther. 2013; 5(2):10.