Serum Concentrations and Effects of Gabapentin and Vigabatrin

Abstract

To explore possible concentration-effect relationships, gabapentin (GBP) and vigabatrin (VGB) serum concentrations were obtained from patients participating in an add-on dose-titration trial comparing GBP and VGB in partial epilepsy. Patients randomized to GBP started on 1800 mg/d and could have their dosage increased stepwise to 2400 and 3600 mg/d if seizures persisted. Those randomised to VGB started on 1000 mg/d, and the dose could be increased to 2000 and 4000 mg/d. Blood samples were obtained at steady state, at a nonstandardized time, from 27 patients randomized to GBP and from 36 randomized to VGB. Serum samples were analyzed using high-performance liquid chromatography. The treatment effect was expressed as percentage reduction in number of seizures from baseline. In addition, patients were classified as responders (>50% reduction in number of seizures from baseline) or nonresponders. There was no significant correlation between serum concentrations of GBP and seizure reduction at the lowest dosage, 1800 mg/d (r = -0.02, P = 0.94, Spearman-rank), nor between VGB serum levels and seizure reduction at 1000 mg/d of VGB (r = -0.14, P = 0.44). The serum GBP concentrations among responders to GBP 1800 mg/d were 26 +/- 12 micro mol/L (mean +/- SD), which was not different from serum concentrations in nonresponders, 28+/-13 micro mol/L. Nor was there a difference between serum concentrations of responders and nonresponders to VGB 1000 mg/d (32 +/- 23 and 44 +/- 36 micro mol/L, respectively). Hence, with the present study design we were unable to identify specific target ranges of GBP and VGB serum concentrations.

Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications

“…e Drug shows zero-order elimination kinetics. f References for reference ranges: felbamate [42,43], gabapentin [44], lacosamide [45], lamotrigine [46], levetiracetam [47], oxcarbazepine (10-hydroxycarbazepine metabolite) [48], pregabalin [2], stiripentol [49], tiagabine [50], topiramate [51], vigabatrin [23], zonisamide [52]. …”

“…A wide range of serum/plasma concentrations are associated with clinical effect [66] although effective control of seizures typically requires concentrations above 2 mg/L [67]. An approximate reference range of 2–20 mg/L has been proposed [44]. Multiple analytical methodologies have been reported for the measurement of gabapentin in plasma/serum including HPLC [68,69], HPLC-tandem mass spectrometry (LC/MS/MS) [70], gas chromatography/mass spectrometry (GC/MS) [71] and GC/MS/MS [72].…”

Cardiopulmonary bypass does not affect plasma concentration of preoperatively administered gabapentin

“…The mean plasma concentration of gabapentin attained after a preoperative dose of 600 mg (31.9 ± 12.7 lmolÁL -1 ) compares with that found in previous studies. 12 These levels remained constant throughout and after the period of CPB. Cardiac surgery may affect drug pharmacokinetics in a number of ways, including substantial fluid shifts and specific effects attributable to the CPB circuit and oxygenator.…”

Therapeutic Drug Monitoring of Antiepileptic Medications

“…Table 1 summarizes the pharmacokinetic properties of the AEMs, while Table 2 presents a summary of the justifications of TDM for the AEMs. References for reference ranges used in Table 1 are as follows: carbamazepine, clonazepam, phenobarbital, phenytoin, primodone, valproic acid (Hardman et al, 1996), felbamate (Faught et al, 1993;Sachdeo et al, 1992), gabapentin (Lindberger et al, 2003), lacosamide (Kellinghaus, 2009), lamotrigine (Bartoli et al, 1997) (Friis et al, 1993), pregabalin (Patsalos et al, 2008), stiripentol (Farwell et al, 1993), tiagabine (Uthman et al, 1998), topiramate , vigabatrin (Patsalos, 1999), and zonisamide (Glauser & Pippenger, 2000;Mimaki, 1998).…”

“…The bulk of excretion is via the kidneys, with the halflife increasing in patients with renal failure. Hemodialysis effectively clears gabapentin (Hung et al, 2008;Wong et al, 1995 (Lindberger et al, 2003). TDM is not usually necessary for gabapentin therapy other than to adjust dosing in patients with impaired kidney function or to assess adherance to therapy (Patsalos et al, 2008) …”