Jangsoo Yoon; Seol Ju Moon; Kwang-Ok Lee; Seo Hyun Yoon; In-Jin Jang; Kyung-Sang Yu; SeungHwan Lee

doi:10.12793/tcp.2016.24.3.137

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Yoon, Moon, Lee, Yoon, Jang, Yu, and Lee: Comparison of R(+)-α-lipoic acid exposure after R(+)-α-lipoic acid 200 mg and 300 mg and thioctic acid 600 mg in healthy Korean male subjects

Original Article

Translational and Clinical Pharmacology 2016;24(3):137-142.

Published online: 19 January 2016

DOI: https://doi.org/10.12793/tcp.2016.24.3.137

Comparison of R(+)-α-lipoic acid exposure after R(+)-α-lipoic acid 200 mg and 300 mg and thioctic acid 600 mg in healthy Korean male subjects

Jangsoo Yoon¹, Seol Ju Moon¹, Kwang-Ok Lee², Seo Hyun Yoon¹, In-Jin Jang¹, Kyung-Sang Yu¹, SeungHwan Lee^∗,¹

¹Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Korea

²Bukwang Pharm. Co., Ltd., Seoul 06955, Korea

^∗Correspondence: S. Lee; Tel: +82-2-2072-2343, Fax: +82-2-742-9252, E-mail: leejh413@snu.ac.kr

Received 25 Jul 2016 Revised 31 August 2016 Accepted 1 September 2016

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

Alpha-lipoic acid, a physiological form of thioctic acid, is a strong antioxidant that relieves diabetic neuropathic symptoms. R(+)-α-lipoic acid shows superior antioxidative effects to its racemate. We compared the pharmacokinetics (PKs) and tolerability of R(+)- and S(-)-α-lipoic acid after a single oral dose of R(+)-α-lipoic acid, Dexid®, and its racemate, thioctic acid in healthy male subjects. We used an open-label, randomized, single-dose, three-treatment, parallel study design to compare the PK exposure of the active form, R(+)-α-lipoic acid. Thirty subjects completed the study with no clinically relevant safety issues. The peak concentrations (C_max, mean±SD) of R(+)-α-lipoic acid after doses of R(+)-α-lipoic acid 200 mg, 300 mg and thioctic acid 600 mg were 4186.8±1956.7, 6985.6±3775.8 and 6498.4±3575.6 μg/L, respectively, and the areas under the plasma concentration-time curve from 0 to the last measurable concentration (AUC_last) were 1893.6±759.4, 3575.2±1149.2 and 3790.0±1623.0 μg·h^-1·L^-1, respectively. The geometric mean ratio and 90% confidence intervals of R(+)-α-lipoic acid 200 mg to thioctic acid 600 mg for the C_max and AUC_last were 0.71 (0.43–1.15) and 0.51 (0.37–0.70), respectively. The corresponding R(+)-α-lipoic acid 300 mg to thioctic acid 600 mg values were 1.11 (0.68-1.80) and 0.97 (0.71-1.34), respectively. In conclusion, R(+)-α-lipoic acid 300 mg showed PK characteristics similar to those of thioctic acid 600 mg and both formulations were well tolerated.

Keywords: pharmacokinetics, racemate, R(+)-α-lipoic acid, thioctic acid, tolerability

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Figure 1.

Disposition of the study subjects.

Figure 2.

Mean plasma concentration-time profiles of R(+)-α-lipoic acid after a single oral administration of R(+)-α-lipoic acid 200 mg or 300 mg or thioctic acid 600 mg. Inset shows profile by log-linear scale. Bars represent SD. (∗ N=2 for R(+)-α-lipoic acid 200 mg, N=7 for R(+)-α-lipoic acid 300 mg and thioctic acid 600 mg)

Figure 3.

Comparison of peak concentration (C_max, upper) and area under the plasma concentration-time curve from 0 to the last measurable concentration (AUC_last, lower) of R(+)-α-lipoic acid after a single oral administration of R(+)-α-lipoic acid 200 mg or 300 mg or thioctic acid 600 mg. Boxes indicate interquartile range and whisker bars indicate 10th and 90th percentiles. Horizontal bars locate in the middle of the boxes represent median and the long-dashed line shows mean.

Table 1.

Demographic characteristics of the study subjects

	Treatment
	R(+)-α-lipoic acid 200 mg (Dexid^® 320 mg) (N=10)	R(+)-α-lipoic acid 300 mg (Dexid^® 480 mg) (N=10)	Thioctic acid 600 mg (N=10)	Total (N=30)	p-value¹⁾
Age (years)	25.3±4.9	25.2±5.2	23.2±1.8	24.6±4.2	0.78
Height (cm)	174.6±4.5	172.0±6.5	174.5±5.6	173.7±5.5	0.58
Weight (kg)	68.0±6.3	64.5±9.3	68.8±5.1	67.1±7.1	0.17

^∗ Values are presented as mean±SD,

¹⁾ Kruskal-Wallis test.

Table 2.

Summary of Pharmacokinetic Parameters of R(+)-α-lipoic acid and S(-)-α-lipoic acid after a single oral administration of R(+)-α-lipoic acid 200 mg, 300 mg or thioctic acid 600 mg

Parameters∗		R(+)-α-lipoic acid 200 mg (Dexid^® 320 mg) (N=10)		R(+)-α-lipoic acid 300 mg (Dexid^® 480 mg) (N=10)		Thioctic acid 600 mg (N=10)
Parameters∗		R(+)-α-lipoic acid	S(-)-α-lipoic acid	R(+)-α-lipoic acid	S(-)-α-lipoic acid	R(+)-α-lipoic acid	S(-)-α-lipoic acid
t_max (h)	Median Range	0.33 (0.25-0.75)	-	0.33 (0.25-1.00)	-	0.33 (0.25-0.75)	0.33 (0.25-0.75)
C_max (µg/L)	Mean±SD	4186.8±1956.7	-	6985.6±3775.8	-	6498.4±3575.6	3552.6±1942.4
C_max (µg/L)	Range	(1761.0-8099.0)	-	(1655.0-14170.0)	-	(930.1-12680.0)	(532.8-2908.2)
^AUC_last (µg·h/L)	Mean±SD	1893.6±759.4	-	3575.2±1149.2	-	3790.0±1623.0	1969.4±1031.5
^AUC_last (µg·h/L)	Range	(1031.2-3448.0)	-	(1622.7-5085.3)	-	(1610.4-6807.3)	(812.3-3770.5)
AUC_0-∞ (µg·h/L)	Mean±SD	1900.7±758.9	-	3585.5±1146.0	-	3805.0±1623.7	2073.6±951.8
AUC_0-∞ (µg·h/L)	Range	(1038.6-3454.0)	-	(1627.8-5091.9)	-	(1621.3-6833.4)	(851.5-3777.9)
t_1/2 (h)	Mean±SD	0.7±0.2		0.7±0.3		0.6±0.2	0.9±1.4
t_1/2 (h)	Range	(0.5-1.1)	-	(0.4-1.2)	-	(0.3-0.9)	(0.3-4.8)
CL/F (L/h)	Mean±SD	120.4±44.6	-	95.5±42.6	-	95.3±46.9	175.5±83.3
CL/F (L/h)	Range	(57.9-192.6)	-	(58.9-184.3)	-	(43.9-185.0)	(79.4-352.3)

^∗ C_max: the peak plasma concentration, t_max: time to maximum plasma concentration, AUC_last: the area under the plasma concentration versus time curve from 0 to the last measurable concentration, AUC_0-∞: the area under the plasma concentration versus time curve from 0 extrapolated to infinity, t_1/2: terminal half-life, CL/F: apparent clearance.

Table 3.

Comparison of pharmacokinetic parameters after a single oral administration of R(+)-α-lipoic acid 200 mg, 300 mg or thioctic acid 600 mg

Parameters	Geometric mean			Geometric Mean Ratio (90% Confidence Interval)
Parameters	R(+)-α-lipoic acid 200 mg (Dexid^® 320 mg) (N=10)	R(+)-α-lipoic acid 300 mg (Dexid^® 480 mg) (N=10)	Thioctic acid 600 mg (N=10)	R(+)-α-lipoic acid 200 mg / Thioctic acid 600 mg	R(+)-α-lipoic acid 300 mg / Thioctic acid 600 mg
^C_max (µg/L)	3781.7	5926.9	5353.0	0.71	1.11
^C_max (µg/L)	3781.7	5926.9	5353.0	(0.43-1.15)	(0.68-1.80)
AUC_last (µg·h/L)	1766.6	3369.1	3460.6	0.51	0.97
AUC_last (µg·h/L)	1766.6	3369.1	3460.6	(0.37-0.70)	(0.71-1.34)
AUC_0-∞ (µg·h/L)	1774.2	3381.7	3477.0	0.51	0.97
AUC_0-∞ (µg·h/L)	1774.2	3381.7	3477.0	(0.37-0.70)	(0.71-1.33)

^∗ C_max: the peak concentration, AUC_last: the area under the plasma concentration versus time curve from 0 to the last measurable concentration, AUC_0-∞,: the area under the plasma concentration versus time curve from 0 extrapolated to infinity.

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