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Jeon, Lee, Hong, Paek, Han, and Yim: Pharmacokinetics and Safety of Levodropropizine Controlled Release Tablet after Repeated Dosing in Healthy Male Volunteers
Original Article

J Korean Soc Clin Pharmacol Ther 2013;21(2):113-119.

Published online: 11 January 2013

DOI: https://doi.org/10.12793/jkscpt.2013.21.2.113

Pharmacokinetics and Safety of Levodropropizine Controlled Release Tablet after Repeated Dosing in Healthy Male Volunteers

Sangil Jeon, Jongtae Lee, Taegon Hong, Jeongki Paek, Seunghoon Han, Dong-Seok Yim

Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary’s Hospital, the Catholic University of Korea, Seoul, Korea, Department of Pharmacology, College of Medicine, the Catholic University of Korea, Seoul, Korea

E-mail: waystolove@catholic.ac.kr

Received 20 May 20133 December 2013       Accepted 6 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:

Levodropropizine is non-opioid agent whose peripheral antitussive action may result from its modulation of sensory neuropeptide levels. Currently, levodropropizine 60 mg is taken three-times daily. A controlled release formulation of levodropropizine (levodropropizine CR) 90 mg was developed, which can be taken twice daily. The aim of this study was to evaluate the safety and pharmacokinetic characteristics after multiple oral administrations of levodropropizine CR 90 mg tablets in healthy male volunteers.

Methods:

A randomized, open-label, cross-over study was conducted in 24 healthy male volunteers. Each subject received levodropropizine syrup 60 mg three times daily or levodropropizine CR 90 mg twice daily for 3 days. Blood samples for pharmacokinetic analysis were collected pre-dose and up to 24 hours on day 4. Pharmacokinetic analysis was conducted by non-compartmental method. Safety assessments including monitoring adverse events, laboratory tests, vital signs, physical examinations and ECGs were performed throughout the study.

Results:

A total of 20 male volunteers completed the study. The maximum steady-state plasma concentration (Css,max) of levodropropizine syrup and levodropropizine CR were 313.28 ng/mL and 285.31 ng/mL and time to reach Css,max (Tmax,ss) were 0.48 hr and 0.88 hr, respectively. The area under the concentration-time curve to the last measured concentration of two groups were 2345.36 hr × ng/mL and 2553.81 hr × ng/mL, respectively. There was no serious adverse event.

Conclusion:

Levodropropizine CR 90 mg tablet was safe and well-tolerated when administered twice daily for 3 days. No statistically significant differences were seen in Css,max and AUCss,24hr between the two formulations. This study provided pharmacokinetic evidences that the twice-daily dosing regimen of levodropropizine 90 mg may substitute the conventional 3-times-daily regimen of levodropropizine 60 mg.

Keywords: Levodropropizine, Pharmacokinetics, Non-compartmental analysis

REFERENCES

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Figure 1.
Mean plasma concentrations of levodropropizine. Left and right panel are normal and semi-logarithmic plot of concentration-time curves, respectively. Black and white arrows mean dosing events of reference and test drug, respectively (Reference drug: Levodropropizine syrup 60 mg, Test drug: Levodropropizine CR 90 mg).
jkscpt-21-113f1.tif
Table 1.
Demographic data of subjects (Mean ± SD)
Characteristics Group 1* (N=12) Group 2* (N=12) Total (N=24) P-value†
Age (years) 23.9 ± 4.0 23.6 ± 3.5 23.8 ± 3.7 0.7955
Height (cm) 75.3 ± 7.5 175.0 ± 4.8 175.1 ± 6.2 0.2599
Weight (kg) 67.0 ± 6.7 69.4 ± 7.3 68.2 ± 6.9 0.3507
BMI (kg/m2) 21.8 ± 2.0 22.6 ± 1.9 22.2 ± 2.0 0.3502

* Subjects in Group 1 were given reference and test drugs, sequentially and subjects in Group 2 were given test and reference drugs, sequentially. †Wilcoxon rank sum test.

Table 2.
Pharmacokinetic parameters
PK parameter* Reference drug† (N=20)
 Test drug‡ (N=20)
Mean SD CV (%) Mean SD CV (%)
Css,max (ng/mL) 313.28 ± 106.26 33.92 285.31 ± 79.34 27.81
Css,min (ng/mL) 10.79 ± 8.19 75.93 14.67 ± 10.04 68.44
Css,av (ng/mL) 121.09 ± 35.81 29.57 86.60 ± 27.16 31.36
AUCss,24hr (hr×ng/mL) 2345.36 ± 875.57 37.33 2553.81 ± 944.98 37.00
AUCss,inf (hr×ng/mL) 2389.72 ± 913.46 38.22 2633.22 ± 1014.26 38.52
Tmax,ss (hr) 0.5 (0.25 -0.75) - 0.5 (0.5-4) -
t1/2 (hr) 2.73 ± 0.46 16.99 2.68 ± 0.55 20.31
Fluctuation (%) 282.08 ± 57.05 20.22 309.70 ± 72.87 23.53
Accumulation index 1.28 ± 0.09 7.23 1.05 ± 0.03 3.19

*Css,max: maximum observed concentration at steady-state. Css,min: minimum observed concentration at steady-state. Css,av: average concentration at steady-state. AUCss,24hr: area under the concentration-time curve from 0 h to 24 h at steady-state. AUCss.inf: area under the concentration-time curve from 0 h to infinite at steady-state. Tmax,ss: time of maximum observed concentration. Tmax, ss is presented as median and range and calculated from time after dose. Fluctuation: peak trough fluctuation within one dosing interval at steady state. † Levodropropizine syrup 60 mg ‡ Levodropropizine CR 90 mg.

Table 3.
Analysis of Variance (ANOVA) of pharmacokinetic parameters for levodropropizine
Ln(Css,max)
Source DF* SS† MS‡ F-stat P-value
Sequence 1 0.0041 0.0041 0.0275 0.8702
Sequence*ID 18 2.6695 0.1483 5.7661 0.0003
Formulation 1 0.0872 0.0872 3.3921 0.0820
Period 1 0.0386 0.0386 1.4993 0.2366
Error
 18
 0.4630
 0.0257
Ln(AUCss,24hr)
Source DF SS MS F-stat P-value
Sequence 1 0.0147 0.0147 0.0561 0.8154
Sequence*ID 18 4.7193 0.2622 40.3988 <0.0001
Formulation 1 0.0455 0.0455 7.0156 0.0163
Period 1 0.0868 0.0868 13.3714 0.0018
Error 18 0.1168 0.0065

* Degree of Freedom. †Sum of Squares. ‡Mean Square.

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