Dose-proportionality of oral thioctic acid — coincidence of assessments via pooled plasma and individual data

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Abstract

Thioctic acid (TA), a racemate of R-(+)- and S-(−)-enantiomers of α-lipoic acid, acts as a powerful lipophilic, free-radical scavenger and is used in the treatment of diabetic neuropathy. This trial investigated the dose-linearity of enantiomer pharmacokinetics following the oral administration of single doses of 50 to 600 mg TA (formulation provided by ASTA (Medica)) in healthy volunteers. TA enantiomer concentrations in individual and pooled plasma samples were determined using enantioselective, high-performance liquid chromatography. TA was rapidly absorbed (tmax, 0.5 to 1 h). Maximum plasma concentrations (Cmax) of the R-(+)-enantiomer were about 40–50% higher than those of the S-(−)-enantiomer (50 mg: 135.45 ng/ml R-(+)-TA, 67.83 ng/ml S-(−)-TA; 600 mg: 1812.32 ng/ml R-(+)-TA, 978.20 ng/ml S-(−)-TA; geometric means). The decline observed in the plasma concentration was steep (t1/2, 0.5 h). The dose-linearity and proportionality of pharmacokinetic parameters could be demonstrated on an intra-individual basis and for the group geometric means. An analysis of pooled plasma samples proved to be a suitable means for deriving reliable first-sight results prior to individual assessments.

Introduction

Thioctic acid (TA) is a well known drug for the treatment of both autonomic and peripheral diabetic neuropathy (Ziegler et al., 1995, Ziegler et al., 1997). TA is a racemic mixture containing the R-(+)- and S-(−)-enantiomers of 1,2-dithiolane-3-pentanoic acid. It is an essential coenzyme in mitochondrial multienzyme complexes which catalyzes the oxidative decarboxylation of such α-keto acids as pyruvate and α-ketoglutarate (Reed, 1974). The therapeutic efficacy of TA in diabetic neuropathy can be related to its potential as a lipophilic antioxidant and as a free-radical scavenger (Suzuki et al., 1991, Packer et al., 1995). Free radical-mediated oxidative stress in diabetic patients seems to induce neurovascular defects which may result in endoneural hypoxia and nerve dysfunction (Ziegler et al., 1995). The neuroprotective properties of TA include the reduction of oxidative stress, an improvement in insulin-stimulated glucose disposal, the enhancement of nerve blood flow, protection against protein glycation, elevation of glutathione levels, and metal chelation (Hermann et al., 1996).

A highly specific and sufficiently sensitive, enantioselective HPLC assay for the determination of the enantiomers of TA only became available a few years ago (Niebch et al., 1997) and the pharmacokinetics of both TA enantiomers have been studied subsequently (Hermann et al., 1996, Hermann and Niebch, 1997, Hermann et al., 1998, Gleiter et al., 1996).

This trial investigated the dose-proportionality of TA following the oral administration of single doses of 50, 100, 200, 300 and 600 mg (therapeutic dose range) to healthy volunteers. An assessment of plasma concentrations of the two enantiomers in the individual samples was preceded by an analysis of pooled plasma and resulted in average plasma profiles for each dose administered. Comparison of the data obtained with both methods allowed an estimation of the reliability of pooled plasma determinations as a means of first-sight evaluation.

Section snippets

Subjects and study design

The study was performed according to the revised Declarations of Helsinki and the protocol was approved by an independent ethics committee. After having given their fully informed written consent, 15 healthy male subjects (age: 29.1±3.44, weight: 77.9±9.87; means±S.D.) were admitted to the study. Single oral doses of 50, 100, 200, 300 and 600 mg of racemic TA (formulation provided by ASTA Medica) were administered under fasting conditions (12 h of fasting overnight) according to an open,

Pharmacokinetic data derived from the pooled plasma samples

The plasma concentration–time curves derived from the pooled samples are shown in Fig. 1. This data was suitable for curve fitting and AUC extrapolation. The pharmacokinetic data of the R-(+)- and S-(−)-enantiomers is summarized in Table 1. Maximum plasma concentrations of both enantiomers were attained rapidly (within 0.5 h of all doses except the highest dose, where the tmax was seen to be 1 h). The R-(+)-enantiomer demonstrated about 40 to 50% higher Cmax and AUC values than the S

Discussion

This study investigated the dose-linearity of racemic TA following the oral administration of single doses of 50 to 600 mg to healthy, fasting volunteers. As enantiomers of racemic drugs often differ in their pharmacologic activities as well as in their distribution and disposition profiles (Karim, 1996), the relevant pharmacokinetic data was determined separately for the R-(+)- and S-(−)-enantiomers.

Since enantioselective assays require especially resourceful and time-consuming analytical

Conclusion

After a single oral administration of TA tablets (dose range 50 to 600 mg), dose-proportional pharmacokinetics (AUC) could be demonstrated for both enantiomers on an intra-individual basis as well as for the group geometric means. The analysis of pooled plasma samples could be qualified as being a suitable means for deriving reliable first-sight results prior to more time-consuming individual assessments.

Acknowledgements

The authors gratefully acknowledge the most valuable contributions of C. de Mey in study planning, of D. Geyer and S. Roll in study conduct and of G. Brandt, A. Eisen, S. Grieb and P. Kampa in the analytical work.

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