Vigabatrin pharmacokinetics

Schramm et al. [48] described a gas chromatographic method for determination of vigabatrin enantiomers in plasma. The method used a double derivatization step on a megabore Chirasil-Val capillary column and thermionic specific detection. The calibration graphs for the R-(-) and (S)-(+)-enantiomers were linear over the concentration range of 1.0-200 and 0.5-100 fig/ml, respectively. The assay was suitable for pharmacokinetic studies and routine therapeutic drug monitoring in humans. 

Table 7.8 shows the pharmacokinetic characteristics of vigabatrin in a single-dose kinetic study for both enantiomers [63]. Haegele and Schechter [64] demonstrated that peak plasma concentrations for both enantiomers were achieved within 0.5 and 2 h after a 1500-mg dose. The concentration of the two enantiomers did not differ after 24 h. The AUC for the (+) enantiomer is less than the R(—), this discrepancy is due to that only the S(+) enantiomer is used by GABA-T as a substrate, whereas the R(—) enantiomer is inactive and is not recognized by GABA-T. 

The pharmacokinetics of the S(+) enantiomer were not influenced by the R(-) enantiomer. Furthermore, no R(—) enantiomer was detected after the administration of pure S(+) vigabatrin, thus demonstrating that no chiral inversion occurs in humans [63]. 

Tong et al. [65] studied the pharmacokinetics of vigabatrin in rat blood and cerebrospinal fluid (CSF), and the major findings of this study are that (i) the pharmacokinetics of vigabatrin in serum are linear and dose-dependent, while in CSF are dose-independent (ii) vigabatrin is not protein bound in serum (iii) the elimination of vigabatrin from serum is rapid and (vi) vigabatrin is rapidly penetrated the blood-brain barrier (BBB). 

Vigabatrin is rapidly and completely absorbed after oral administration and about 80% of the dose is recovered in the urine [4]. In healthy volunteers, its absorption was rapid and beak plasma concentrations occurred within 2 h [65]. The effect of food on the bioavailability of vigabatrin tablets has been studied [4, 66]. The AUC for fasted and fed volunteers was not significantly different. This indicates that food does not alter the extent of absorption. The pharmacokinetics profiles of vigabatrin in tablet form and in solution were strikingly similar [66]. 

Grant, S. M. and Heel, R. C. 1991. Vigabatrin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy and disorders of motor control. Drugs 41 889-926. 

Battino D, Estienne M, Avanzini G. Clinical pharmacokinetics of antiseizure drugs in pediatric patients. Part II. Phenytoin, carbamazepine, sulthiame, lamotrigine, vigabatrin, oxcarbazepine, and felbamate. Clin Pharmacokinet 1995 29 341-369. 

Battino, D., Estienne, M., and Avanzini, G., Chnical pharmacokinetics of antiepUeptic drugs in paediatric patients. Part II. Phenytoin, carhamazepine, sulthiame, lamotrig-ine, vigabatrin, oxcarbazepine and felbamate, Clin. Pharmacokinet., 29 341-369,... 

In the presence of end-stage renal failure, the pharmacokinetics of vigabatrin enantiomers can become profoundly stereoselective in comparison to patients with normal renal function [173]. Under steady-state conditions, the R S Cmax and AUC ratios of vigabatrin were 7.9 and 6.2 in a 15-year-old female patient with end-stage renal disease. 

Sanchez-Alcaraz A, Quintana B, Lopez E, Rodriguez I, Llopis P Effect of vigabatrin on the pharmacokinetics of carbamazepine. J Clin Pharm Ther (2002) 27,427-30. 

In an early clinical study, tiagabine was reported to have no significant effect on the plasma levels of carbamazepine, phenytoin, valproate, and vigabatrin. Similarly, tiagabine (titrated from 8 mg up to a maximum of 48 mg daily over 18 days) did not alter the steady-state pharmacokinetics of phenytoin or carbamazepine in 12 patients with epilepsy. However, in another similar study, it reduced the AUC of valproate by 10%, but this reduction is not expected to be elinieally significant. ... 

No clinically relevant pharmacokinetic interactions appear to occur between vigabatrin and felbamate. 

Reidenberg P, Glue P, Banfield C, Colucci R, Meehan J, Rey E, Radwanski E, Nomeir A, Lim J, Lin C, Guillaume H Affrime MB. Pharmacokinetic interaction studies between felb ate and vigabatrin. BrJ Clin Pharmacol (1995) 40,157-60. 

No pharmacokinetic interaction appears to occur between vigabatrin and valproate, but one retrospective study found a correlation between valproate levels and vigabatrin levels. 

Vigabatrin appears not to alter the pharmacokinetics of ethiny-loestradiol or levonorgestrel given as a combined oral contraceptive. 

The pharmacokinetics, mechanism of action, and toxicology of vigabatrin have been reviewed [416 ]. Another review focused on clinical problems [417 ]. 

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