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.

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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.

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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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