Bioequivalence of HCP1104, a New Fixed Dose Combination Drug and Co-administration of Eperisone 50 mg and Aceclofenac 100 mg: A Partial Replicated Crossover Study Design to Estimate the Pharmacokinetics of Highly Variable Drugs

Mi Jo Kim; Yo Han Kim; Hee Youn Choi; Hae Sun Jeon; Yook Hwan Noh; Hyeong-Seok Lim; Kyun-Seop Bae

doi:10.12793/jkscpt.2013.21.2.120

Journal List > J Korean Soc Clin Pharmacol Ther > v.21(2) > 1055121

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Kim, Kim, Choi, Jeon, Noh, Lim, and Bae: Bioequivalence of HCP1104, a New Fixed Dose Combination Drug and Co-administration of Eperisone 50 mg and Aceclofenac 100 mg: A Partial Replicated Crossover Study Design to Estimate the Pharmacokinetics of Highly Variable Drugs

Original Article

J Korean Soc Clin Pharmacol Ther 2013;21(2):120-129.

Published online: 11 January 2013

DOI: https://doi.org/10.12793/jkscpt.2013.21.2.120

Bioequivalence of HCP1104, a New Fixed Dose Combination Drug and Co-administration of Eperisone 50 mg and Aceclofenac 100 mg: A Partial Replicated Crossover Study Design to Estimate the Pharmacokinetics of Highly Variable Drugs

Mi Jo Kim^1,², Yo Han Kim^1,², Hee Youn Choi^1,², Hae Sun Jeon^1,², Yook Hwan Noh^3,⁴, Hyeong-Seok Lim^1,², Kyun-Seop Bae^1,²

¹Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, Korea

²University of Ulsan College of Medicine, Seoul, Korea

³Department of Pharmacology, Inje University College of Medicine, Busan, Korea

⁴Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Korea

E-mail: ksbae13@gmail.com

Received 11 December 201317 December 2013 Accepted 19 December 2013

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:

This clinical study was conducted to compare pharmacokinetics of eperisone and aceclofenac of HCP1104, a new fixed dose combination drug with those in co-administration of eperisone 50 mg and aceclofenac 100 mg. The study used a partial replicated study design to characterize intra-subject variability of eperisone when co-administrated with aceclofenac.

Methods:

A partial replicated crossover design was employed in 30 subjects. Each subject received a single dose of co-administration of eperisone 50 mg and aceclofenac 100 mg on two occasions and a single dose of 1 capsule of HCP1104. Blood samples were obtained for 24 hrs after dosing, and plasma was assayed for eperisone and aceclofenac by Liquid chromatography-electrospray ionization-mass spectrometry.

Results:

Using an average bioequivalence criterion, the 90 % confidence limits for Ln-transformed C_max and AUC_last for aceclofenac fell wihin the acceptable range of 80 - 125 %. Point estimates of eperisone AUC_last and C_max were 1.0152 and 1.0490, respectively and the 90 % confidence interval for C_max was 0.8499 - 1.3025. The within-subject coefficient of variation of C_max for the reference was 50.198 %. Acceptance range for eperisone C_max based on new bioequivalence guidance for highly variable drugs was extended to 0.6984 - 1.4319.

Conclusion:

The extent of exposure and rate of absorption of both eperisone and aceclofenac with a single dose of HCP1104 capsule were equivalent to those with co-administration of a marketed eperisone 50 mg tablet and a marketed aceclofenac 100 mg tablet under fasting conditions in healthy adult males.

Keywords: Highly variable drugs, Bioequivalence, Eperisone, Aceclofenac

REFERENCES

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Figure 1.

Plasma eperisone concentration - time curve (A) and plasma aceclofenac concentration - time curve (B) when administrated eperisone 50 mg with aceclofenac 100 mg or HCP1104 alone. Mean and standard deviation are presented as point and bars, respectively.

Table 1.

Study design

Sequence	Number of subject	Period 1	Period 2	Period 3
1	10	R*	R*	T^f
2	10	R*	T^f	R*
3	10	T^f	R*	R*

* Reference: co-administration of eperisone 50 mg and aceclofenac 100 mg. ^†Test : HCP1104.

Table 2.

Pharmacokinetic parameters of eperisone and aceclofenac following HCP1104 and co-administration of eperisone 50 mg and aceclofenac 100 mg in healthy male subjects

Parameter	Test^† (n=30)	Reference* (n=30)
Eperisone
C_max (pg/mL)^‡	1,157.23 (116.35 - 83,167.00)	1,103.13 (94.10 - 25,927.30)
AUC_last (pg·h/mL)^‡	2,586.40 (403.73 - 100,391.93)	2,547.73 (206.31 - 48839.25)
t_max (h)^§	1.00 (0.33 - 3.00)	1.00 (0.58 - 2.00)
t_1/2β (h)^§	8.21 (3.59 - 17.05)	8.43 (3.26 - 29.36)
Aceclofenac
C_max (ng/mL)^‡	10,779.30 (4,140.10 - 15,935.00)	11,258.15 (5,195.60 - 21,196.20)
AUC_last (ng·h/mL)^‡	24,593.33 (11,829.27 - 38,642.35)	24,917.14 (15,482.24 - 40,912.07)
t_max (h)^§	1.50 (1.00 - 5.98)	1.50 (0.62 - 4.00)
t_1/2β (h)^§	4.12 (2.42 - 6.55)	4.37 (2.67 - 8.02)

*Reference: co-administration of eperisone 50 mg and aceclofenac 100 mg. ^†Test : HCP1104. ^‡Data expressed as geometric mean (range). ^§ Data expressed as median (range).

Table 3.

Summary statistics of eperisone and aceclofenac following single oral dose administration of HCP1104 and co-administration of eperisone 50 mg and aceclofenac 100 mg in healthy male subjects

Parameter	Test^†	Reference*	Ratio (T/R)	90 % Confidence Intervals	Acceptance Range	CV_wr^§ (%)
Eperisone
AUC_last (pg·h/mL)	2,586.40^‡	2,547.73^‡	1.0152	0.8635-1.1936	-	-
C_max (pg/mL)	1,157.23^‡	1,103.13^‡	1.0490	0.8449-1.3025	0.6984-1.4319	50.198
Aceclofenac
AUC_last (ng·h/mL)	24,593.33^‡	24,917.14^‡	0.9866	0.9501-1.0245	-	-
C_max (ng/mL)	10,779.30^‡	11,258.15^‡	0.9575	0.8584-1.0680	-	-

*Reference: co-administration of eperisone 50 mg and aceclofenac 100 mg. ^†Test: HCP1104. ^‡Data expressed as geometric mean. ^§ CV_WR, within-subject coefficient of variation of the reference (%).

Table 4.

Treatment-emergent adverse event

	R1* (N=30)	R2* (N=30)	T^† (N=30)	Total (N=30)
N(%)	0(0%)	4(13.33%)	1(3.33%)	5(16.67%)
Investigations
Blood creatine phosphokinase increased	0(0%)	0(0%)	1(3.33%)	1(3.33%)
Eosinophil count increased	0(0%)	1(3.33%)	0(0%)	1(3.33%)
Injury, poisoning and procedural complications
Excoriation	0(0%)	1(3.33%)	0(0%)	1(3.33%)
Gastrointestinal disorders
Diarrhoea	0(0%)	1(3.33%)	0(0%)	1(3.33%)
General disorders and administration site conditions
Pyrexia	0(0%)	1(3.33%)	0(0%)	1(3.33%)

*R: Reference, co-administration of eperisone 50 mg and aceclofenac 100 mg, 1: first administration of reference, 2: replicated administration of reference. ^†T: Test, HCP1104. Data expressed as number of subject (% number of subject) with adverse event.

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