1 Departments of Nephrology Tenon Hospital 2 Pitie-Salpetriere Hospital Paris France
Sir,
Gabapentin (1-(aminomethyl) cyclohexane acetic acid), a structural analogue of gamma-aminobutyric acid (GABA), has been developed for the treatment of epilepsy. Unlike GABA, gabapentin crosses the blood-brain barrier after systemic administration. Its precise antiepileptic mechanism of action is unknown [1]. Gabapentin is an effective antiepileptic drug in patients with partial and secondarily generalized seizures which remain uncontrolled with existing anticonvulsant drug therapy [2]. In one case, gabapentin was also effective in brachoradial pruritus [3] and in another case in the treatment of post herpetic neuralgia [4]. Following oral administration and intestinal absorption gabapentin is excreted unchanged in urine [5]. Gabapentin clearance is linearly related to creatinine clearance and is decreased in the elderly and in individuals with impaired renal function. We report here the case of a chronic haemodialysis patient who developed signs of neurological toxicity due to gabapentin overdosage. The pharmacokinetics of gabapentin after a 300 mg oral dose were also studied.
Case.
The patient was a 35-year-old female who had epilepsy with generalized tonic seizures for the first time at the age of 12 years. She developed chronic renal failure of unknown origin at the age of 33. One year later, she started intermittent haemodialysis treatment, three times per week. She received valproic acid and was maintained on 1500 mg/day in divided doses, with serum levels of 60 pg/ml (therapeutic levels of 60100 pg/ml), diazepam 5 mg/day, clonazepam 2 mg/day, and lamotrigine 25 mg tid.
When the patient developed thrombopenia, this was attributed to valproic acid and the drug was stopped progressively. It was replaced by gabapentin 400 mg/day. Three weeks later, the patient developed absences, but the electroencephalogram showed no epileptic activity. The plasma gabapentin level was 56.2 mg/l (reference level 210 mg/l). The dose of gabapentin was decreased to 300 mg following each haemodialysis session. A pharmacokinetic study was performed after the oral administration of 300 mg of gabapentin. Blood samples were collected just before the dialysis session and 2, 4, 12, 24, 48 and 72 h later. The last sample was withdrawn just before the following haemodialysis session. Another blood sample was collected at the end of this dialysis session. Plasma gabapentin concentrations were determined by high-performance liquid chromatography (HPLC). The haemodialysis session lasted 4 h using a polyflux 8 l membrane (synthetic polyamide dialyser, surface area 1.8 m2, thickness 45 µm), with a double needle access to her arteriovenous fistula, with a constant dialysate flow rate at 500 ml/min and a blood flow rate of between 250 to 300 ml/min.
Pharmacokinetics.
Pharmacokinetic analysis showed that at time 0 before administration of the 300 mg dose, plasma gabapentin concentration was 20.2 mg/l. Maximum plasma concentration (Cmax) was 29.4 mg/l, area under the concentration-time curve from 0 to infinity (AUC(0-inf)) was 81361 mg h/l, and elimination half-life (T1/2) was 2257 h.
Discussion.
Drug therapy for epilepsy continues to be a challenge for clinicians and patients. Because a significant number of patients exhibit refractory epilepsy, the long-term administration of multiple drug regimens is often required [5]. Gabapentin has a wide therapeutic range. Its major side-effects include fatigue, somnolence, dizziness, ataxia and visual disturbances [3].
Pharmacokinetic studies in humans have shown that gabapentin is not metabolized, is not bound to serum proteins, and is cleared by renal excretion alone [1]. Gabapentin dosage should thus be adjusted to renal function [1]. For patients with end-stage renal disease maintained on haemodialysis, an initial loading dose of 300400 mg of gabapentin has been recommended [6]. Approximately 35% of gabapentin is removed during a haemodialysis session [6]. Accordingly, administration of 200300 mg of gabapentin after each 4-h dialysis session may replace cleared gabapentin, and may therefore be sufficient to maintain steady-state plasma concentration similar to that in patients with normal renal function [6].
Our patient initially received 400 mg/day of gabapentin and developed absences. Gabapentin serum levels at that time were very high. This is in contrast to the suggestion by Verma et al. that gabapentin is extremely well-tolerated even in haemodialysis patients with high serum concentration [7]. Our pharmacokinetic study showed that even the recommended dose of 300 mg gabapentin [6] after each haemodialysis session was excessive and that the patient had very high serum levels. Gabapentin pharmacokinetic values in our patient differed from those previously reported by Wong et al. in haemodialysis patients [6]. However, the pharmacokinetic parameters of gabapentin in our patient should not be compared to those of Wong et al. since our patient was clearly overdosaged. At time 0 before administration, the parameters were already much higher than the Cmax of haemodialysed patients (6 mg/l) reported by Wong et al. [6] or in non-uraemic subjects (2.7 mg/l) after a dose of 300 mg. Furthermore, gabapentin is not metabolized and is entirely excreted in urine with a clearance that is linearly proportional to creatinine clearance. Consequently, in patients with terminal renal insufficiency accumulation of gabapentin occurs. Gabapentin is a highly hydrophilic compound which diffuses into adipose tissues only weakly. Therefore, excessive accumulation of the drug in plasma easily leads to a concomitant accumulation in cerebrospinal fluid and neurotoxicity. For these reasons, the dose of gabapentin was decreased in our patient to as low as 100 mg after each haemodialysis session. During the subsequent 4 months the patient experienced neither absences nor epileptic seizures.
We therefore suggest that in chronic haemodialysis patients gabapentin treatment be initiated with a 300-mg loading dose, as previously advised by Wong et al. [6]. However, post-haemodialysis dosing should be reduced to 100 mg. Furthermore, our case illustrates that in haemodialysis patients plasma gabapentin levels should be monitored if there is a suspicion of drug-induced side-effects, even in patients receiving the minimal recommended dosage.
Acknowledgments
We thank Dr Elisabeth Rey of the Department of Pharmacology, Saint-Vincent de Paul Hospital, Paris, France for her assistance in plasma gabapentin determinations.
References