Enantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms

Robert Hermann,1 Julius Mungo,2 Peter Jürgen Cnota,2 Dan Ziegler3 1Clinical Research Appliance (cr appliance), Gelnhausen, Germany; 2MEDA Pharma GmbH & Co KG, Bad Homburg, Germany; 3Institute for Clinical Diabetology, German Diabetes Center, Heinrich Heine University, Düss...

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Autores principales: Hermann R, Mungo J, Cnota PJ, Ziegler D
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Publicado: Dove Medical Press 2014
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spelling oai:doaj.org-article:d525027ec73242fbae96fefebfa7c2f52021-12-02T00:59:31ZEnantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms1179-1438https://doaj.org/article/d525027ec73242fbae96fefebfa7c2f52014-11-01T00:00:00Zhttp://www.dovepress.com/enantiomer-selective-pharmacokinetics-oral-bioavailability-and-sex-eff-peer-reviewed-article-CPAAhttps://doaj.org/toc/1179-1438 Robert Hermann,1 Julius Mungo,2 Peter Jürgen Cnota,2 Dan Ziegler3 1Clinical Research Appliance (cr appliance), Gelnhausen, Germany; 2MEDA Pharma GmbH & Co KG, Bad Homburg, Germany; 3Institute for Clinical Diabetology, German Diabetes Center, Heinrich Heine University, Düsseldorf, Germany Abstract: The present study aimed to examine the enantiomer-selective pharmacokinetics (PK), relative bioavailability (Frel), and sex effects of various oral dosage forms of racemic alpha-lipoic acid (ALA). In an open-label, randomized, four-period, four-sequence crossover study, 24 healthy adult subjects (12 males and 12 females) received single doses of 600 mg of ALA in fasted state at four different occasions as follows: three 200 mg tablets (T 200); two 300 mg tablets (T 300); one 600 mg tablet (T 600); and a racemic ALA solution (OS). All tablet formulations (Thioctacid HR) were considered test treatments, while the OS (Thioctacid, 600 T) served as the reference treatment. Serial blood samples were collected over 8 hours postdose to quantify R-(+)- and S-(–)-ALA enantiomer plasma concentrations for the PK evaluation. The maximum observed plasma concentration (Cmax) and total exposure (area under the curve [AUC]0–t) were compared between treatments by analysis of variance. Weight-normalized Cmax and the AUC data of male and female study subjects were applied to examine the presence of sex effects. All treatments displayed rapid absorption of both enantiomers with median time to maximum concentration (tmax) values ranging from 0.33–0.5 hours. The Frel of all tablet formulations was comparable, with R-(+)-enantiomer Cmax test/reference ratios ranging from 36% (T 600) to 43% (T 200), and R-(+)-enantiomer AUC test/reference ratios ranging from 64% (T 600) to 79% (T 300), indicating a favorable Frel of all tablet formulations, especially in terms of the total extent of absorption (AUC). An examination of weight-normalized female/male Cmax and AUC sex ratios for both ALA enantiomers indicated the absence of a significant sex effect for Cmax, as well as 20%–26% and 25%–32% higher R-(+)- and S-(–)-ALA enantiomer AUC outcomes in females when compared to males. The observed modest sex effect was comparable for both ALA enantiomers and across all formulations, and it did not appear to require a dose adjustment in clinical practice. Keywords: alpha-lipoic acid, thioctic acid, enantiomers, sex effect, formulation effect, bioavailabilityHermann RMungo JCnota PJZiegler DDove Medical PressarticleTherapeutics. PharmacologyRM1-950ENClinical Pharmacology: Advances and Applications, Vol 2014, Iss default, Pp 195-204 (2014)
institution DOAJ
collection DOAJ
language EN
topic Therapeutics. Pharmacology
RM1-950
spellingShingle Therapeutics. Pharmacology
RM1-950
Hermann R
Mungo J
Cnota PJ
Ziegler D
Enantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms
description Robert Hermann,1 Julius Mungo,2 Peter Jürgen Cnota,2 Dan Ziegler3 1Clinical Research Appliance (cr appliance), Gelnhausen, Germany; 2MEDA Pharma GmbH & Co KG, Bad Homburg, Germany; 3Institute for Clinical Diabetology, German Diabetes Center, Heinrich Heine University, Düsseldorf, Germany Abstract: The present study aimed to examine the enantiomer-selective pharmacokinetics (PK), relative bioavailability (Frel), and sex effects of various oral dosage forms of racemic alpha-lipoic acid (ALA). In an open-label, randomized, four-period, four-sequence crossover study, 24 healthy adult subjects (12 males and 12 females) received single doses of 600 mg of ALA in fasted state at four different occasions as follows: three 200 mg tablets (T 200); two 300 mg tablets (T 300); one 600 mg tablet (T 600); and a racemic ALA solution (OS). All tablet formulations (Thioctacid HR) were considered test treatments, while the OS (Thioctacid, 600 T) served as the reference treatment. Serial blood samples were collected over 8 hours postdose to quantify R-(+)- and S-(–)-ALA enantiomer plasma concentrations for the PK evaluation. The maximum observed plasma concentration (Cmax) and total exposure (area under the curve [AUC]0–t) were compared between treatments by analysis of variance. Weight-normalized Cmax and the AUC data of male and female study subjects were applied to examine the presence of sex effects. All treatments displayed rapid absorption of both enantiomers with median time to maximum concentration (tmax) values ranging from 0.33–0.5 hours. The Frel of all tablet formulations was comparable, with R-(+)-enantiomer Cmax test/reference ratios ranging from 36% (T 600) to 43% (T 200), and R-(+)-enantiomer AUC test/reference ratios ranging from 64% (T 600) to 79% (T 300), indicating a favorable Frel of all tablet formulations, especially in terms of the total extent of absorption (AUC). An examination of weight-normalized female/male Cmax and AUC sex ratios for both ALA enantiomers indicated the absence of a significant sex effect for Cmax, as well as 20%–26% and 25%–32% higher R-(+)- and S-(–)-ALA enantiomer AUC outcomes in females when compared to males. The observed modest sex effect was comparable for both ALA enantiomers and across all formulations, and it did not appear to require a dose adjustment in clinical practice. Keywords: alpha-lipoic acid, thioctic acid, enantiomers, sex effect, formulation effect, bioavailability
format article
author Hermann R
Mungo J
Cnota PJ
Ziegler D
author_facet Hermann R
Mungo J
Cnota PJ
Ziegler D
author_sort Hermann R
title Enantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms
title_short Enantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms
title_full Enantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms
title_fullStr Enantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms
title_full_unstemmed Enantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms
title_sort enantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms
publisher Dove Medical Press
publishDate 2014
url https://doaj.org/article/d525027ec73242fbae96fefebfa7c2f5
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AT cnotapj enantiomerselectivepharmacokineticsoralbioavailabilityandsexeffectsofvariousalphalipoicaciddosageforms
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