Pregabalin Add-on Treatment: A Randomized, Double-blind, Placebo-controlled, Dose–Response Study in Adults with Partial Seizures
Article first published online: 24 DEC 2003
Volume 45, Issue 1, pages 20–27, January 2004
How to Cite
Arroyo, S., Anhut, H., Kugler, A. R., Lee, C. M., Knapp, L. E., Garofalo, E. A., Messmer, S. and Pregabalin 1008-011 International Study Group (2004), Pregabalin Add-on Treatment: A Randomized, Double-blind, Placebo-controlled, Dose–Response Study in Adults with Partial Seizures. Epilepsia, 45: 20–27. doi: 10.1111/j.0013-9580.2004.31203.x
- Issue published online: 24 DEC 2003
- Article first published online: 24 DEC 2003
- Partial seizures;
Summary: Purpose: To evaluate pregabalin (PGB), 150 mg/day, and PGB, 600 mg/day, as an add-on treatment for patients with refractory partial seizures concurrently treated with one to three anticonvulsants (AEDs).
Methods: An international (13 countries), multicenter (45 centers), 12-week, double-blind, randomized study in which patients with partial seizures received placebo (n = 96); PGB, 150 mg/day (n = 99); or PGB, 600 mg/day (n = 92); given 3 times a day (t.i.d.). The primary efficacy criterion was reduction in seizure frequency during treatment as compared with baseline, as measured by RRatio, the symmetrical percentage change in seizure rates determined from daily seizure diaries. The RRatio between the 8-week baseline (pretreatment phase) and the 12-week treatment period were compared between each of the PGB groups and the placebo group by using an analysis of variance analysis of the intent-to-treat population.
Results: PGB, 150 mg/day and 600 mg/day, were both significantly more effective than placebo in reducing the RRatio [–11.5 (p = 0.0007) and –31.4 (p ≤ 0.0001), respectively, vs. 0.9]. These RRatio values correspond to seizure-frequency reductions from baseline of –1.8, 20.6, and 47.8% for placebo, 150 mg/day, and 600 mg/day, respectively. PGB efficacy was significantly dose related (p ≤ 0.0001). Secondary efficacy variables corroborated the findings of the primary analysis. Significantly more patients were responders (≥50% reduction in seizure frequency) in the PGB, 600 mg/day (43.5%), group than in the placebo group (6.2%) (p ≤ 0.001). PGB was well tolerated. Dose-related, treatment-emergent adverse events (≥10%), mostly mild or moderate in intensity, were somnolence, dizziness, ataxia, diplopia, and weight gain. The withdrawal rate due to adverse events was 10% of patients at 150 mg/day and 18.5% of patients at 600 mg/day, compared with 6.2% of patients receiving placebo.
Conclusions: PGB, 150 mg/day and 600 mg/day, is highly effective and well-tolerated add-on therapy in patients with partial seizures.
The novel agent, pregabalin (PGB), is in late-stage clinical development as an antiepileptic drug (AED) with an initial focus on the treatment of partial seizures (1,2). It is also in advanced clinical development for the treatment of neuropathic pain associated with conditions such as diabetic peripheral neuropathy and postherpetic neuralgia, and for the treatment of generalized anxiety disorder with demonstrated efficacy in these indications in clinical trials (2–6).
Pregabalin is an α2-δ (α2-δ) ligand that has analgesic, anxiolytic, and anticonvulsant activity. α2-δ Is an auxiliary protein associated with voltage-gated calcium channels. PGB binds potently to the α2-δ subunit (7). Potent binding at this site reduces calcium influx at nerve terminals and therefore reduces the release of several neurotransmitters, including glutamate, noradrenaline, and substance P (8–13). Although structurally related to the α2-δ ligand gabapentin (GBP), pregabalin has greater potency in preclinical models of epilepsy, pain, and anxiety. Both compounds are γ-aminobutyric acid (GABA) analogues, but they have no GABAergic activity: they are inactive at GABAA and GABAB receptors, they are not converted metabolically into GABA or a GABA antagonist, and they do not alter GABA uptake or degradation (14,15).
PGB has been shown to be active in several animal models of seizures and epilepsy (maximal electroshock, pentylenetetrazol, kindling, DBA/2 audiogenic mice) (16–18). However, pregabalin does not reduce spontaneous absence seizures in the genetic absence epilepsy in rats from Strasbourg model (data on file, Pfizer Inc.) (19).
PGB can be distinguished from many other AEDs by its simple and predictable pharmacokinetic profile in humans. It is rapidly absorbed, and maximal plasma pregabalin concentrations (Tmax) occur approximately one hour after dosing, the plasma elimination half-life (t1/2) is ∼6 h, independent of dose, and steady state is achieved within 48 h (2). Maximal plasma PGB concentrations (Cmax) and total exposures (AUC) are dose proportional, and average bioavailability is ≥90% and independent of dose. PGB is not hepatically metabolized, is 98% renally excreted unchanged, and is not plasma protein bound. Therefore it does not have known pharmacokinetic interactions with other AEDs or oral contraceptives (20,21). Overall, these features predict that PGB should be a relatively uncomplicated agent to use in the clinic.
Based on the results from preclinical studies and promising results from a proof-of-concept study of patients with partial seizures, a full clinical-development program for PGB in the treatment of epilepsy was initiated. Here we report the finding from a large, placebo-controlled, international study in this program that evaluated the efficacy, tolerability, and safety of two fixed doses of PGB as an add-on treatment in patients with partial seizures.
PATIENTS AND METHODS
This study was conducted at 45 centers (in Australia, Austria, Belgium, Finland, France, Germany, Italy, The Netherlands, Scotland, U.K., South Africa, Spain, Switzerland) between April 1998 and November 1999. The study received local ethics committee approval and was conducted in accordance with the Declaration of Helsinki (South African 1996 amendment), Good Clinical Practice, and local regulations. Patients or their parent/guardian gave written informed consent. Two patients were aged 17 years; both the patients and their legal representatives gave consent.
Selection of patients
Men or women aged 18 years or older, weighing 50–135 kg, with the International League Against Epilepsy–defined (22) partial seizures (simple, complex, or secondarily generalized tonic–clonic) were allowed to enter. They were required to have unsuccessfully tried at least one AED at the maximum tolerated dose, to have had at least three partial seizures in the month before screening, and were receiving one to three AEDs (vagus-nerve-stimulator device allowed) at tolerated, clinically relevant doses at screening. Patients were required to have at least six partial seizures during the 8-week period before randomization and not to have been free of seizures for any 4-week period during this time.
Patients with absence seizures, Lennox–Gastaut syndrome, status epilepticus in the past year, clinically relevant medical illness or electrocardiogram (ECG) abnormalities or a significant psychiatric disorder (or recurrent episodes of major depression) were excluded. Because PGB and GBP share similar pharmacology, patients receiving GBP were excluded unless this was discontinued ≥1 week before the 8-week baseline period. Patients were required to have an estimated creatinine clearance >60 ml/min. Women were not pregnant or breastfeeding, and those of childbearing age were required to be reliably using contraception.
This was a 12-week, double-blind, placebo-controlled, parallel-group study. The 12-week treatment period immediately followed the 8-week baseline assessment period. Patients were randomized to placebo; PGB, 150 mg/day; or PGB, 600 mg/day. Patients randomized to PGB, 150 mg/day, were titrated to full dose by day 4, and those randomized to 600 mg/day were titrated to full dose by day 8. Randomization was by computer-generated code stratified by center by using a block size of six. Blinding was maintained by presenting study medication in identical capsules containing placebo, PGB 25 mg, or PGB 100 mg. All patients took two capsules 3 times daily. Patients were required to visit the study center at the randomization visit and then subsequently at weeks 2, 4, 8, and 12 of the 12-week double-blind treatment period, or on early discontinuation. Patients were required to maintain their concurrent AED treatment at the same dosage during the study.
Coadministration with drugs that act on the CNS, other than concomitant AEDs and antidepressant monotherapy for mild depression (without recent hospitalization), was not allowed. For safety reasons or known interactions with other AEDs, felbamate, vigabatrin, macrolide antibiotics, astemizole, terfenadine, and class I and III antiarrhythmics were prohibited.
Patients were required to maintain a daily seizure diary during the 8-week baseline period and during the 12-week double-blind period, with or without assistance. From these entries in the seizure diaries provided by all patients, the frequency and types of seizures were determined. All spontaneously reported or observed adverse events were recorded by the investigator and classified by using the COSTART IV dictionary (23). The investigator also evaluated the intensity (mild, moderate, severe) of adverse events and ascribed the possible relation to study treatment. Blood and urine samples were taken at the start of the 8-week baseline period and at each clinic visit during the 12-week treatment period for the analysis of clinical laboratory variables at a central laboratory. Clinically significant laboratory abnormalities were a priori defined by the study protocol. Blood samples also were collected, at random times with respect to time elapsed from last dose of study medication, for the determination of plasma PGB concentrations in patients who attained steady state (≥48 h on randomized dose). Plasma samples were assayed for PGB concentrations by using a sensitive, specific, and validated high-performance liquid chromatography method with UV detection.
The sample size was calculated based on results from previous trials conducted by the sponsor. It was estimated that 80 patients per group were needed to be able to detect a difference in the mean primary efficacy criterion (RRatio) of 12 (SD, 25) between PGB and placebo, with a power of 80% (α= 0.05; two-sided), assuming a 10% dropout rate. Calculations based on a 20% difference in responder rates led to the same number of patients needed.
The analysis of efficacy was based on the intent-to-treat (ITT) population (patients who received at least one dose of medication). All statistical tests were two-tailed, with a statistical significance level of 0.05. For centers with fewer than 18 randomized patients, clustering was performed.
The primary efficacy criterion was seizure-frequency change from baseline expressed as RRatio. It is defined as [(T – B)/(T + B)]× 100, where B is the patient's 28-day baseline seizure frequency, and T is the patient's 28-day seizure frequency during treatment. Negative RRatio values indicate a reduction in the seizure rate from baseline. The RRatio is distributed within the range –100 to +100, with a zero value indicating no change. An RRatio value of –100 represents seizure freedom. An RRatio of –33 corresponds to a 50% reduction of seizure frequency, and a +33 corresponds to a doubling in seizure frequency. RRatios were compared by using an analysis of variance (ANOVA) model with Treatment and Cluster as the main effects and the Rank of the RRatio as the dependent variable. The Treatment-by-Cluster interaction term was tested at a significance level of 0.15, considered as evidence of lack of generalizability.
Seizure reduction based on percentage change from baseline also is shown for more ready clinical relevance, which is derived by transformation of the mean RRatio by using [(200 × RRatio)/(100 – RRatio)] (5).
Pairwise comparisons were performed by using a step-down procedure (24) to maintain an overall 5% type I error. PGB dose–response relation was analyzed by testing the linear contrast from the main ANOVA model.
The secondary efficacy variables included the responder rate, percentage of patients free of seizures, and the median percentage change in seizure frequency. The responder rate, defined as the percentage of patients with a ≥50% reduction in seizure frequency during treatment, was compared between each PGB group and the placebo group by using the Cochran–Mantel–Haenszel test adjusting for cluster. The percentages of patients free of seizures during their last 28 days of treatment were compared between each PGB group and placebo by using Fisher's exact test. The median percentage changes in seizure frequency also were calculated but were not subject to formal statistical analysis.
In addition to the analysis of all partial seizures detailed earlier, analysis by seizure type also was explored. No formal statistical testing of tolerability or safety data was undertaken. Pharmacokinetic data were evaluated by using a nonlinear, mixed-effects model, developed by the sponsor, with NONMEM Version V.
In total, 288 patents were randomized, and 287 took at least one dose of study medication and were included in the ITT analysis. The baseline demographic and illness characteristics were well matched across the three treatment groups (Table 1). The small differences in some variables were not considered to affect the results. Approximately half the patients were men, most patients were white, and the overall mean age was 37 years. The median duration of epilepsy was 23 years, and the median seizure rate during the 8-week baseline period was 11 seizures/28 days. The types of seizures experienced before baseline also were similar across the three treatment groups.
|Placebo||Pregabalin 150 mg/day||Pregabalin 600 mg/day|
|Number of patients||96||99||92|
|Mean (SD)||38.1 (12.4)||36.5 (11.3)||36.4 (10.5)|
|Gender, N (%)|
|Men||54 (56.3)||44 (44.4)||47 (51.1)|
|Women||42 (43.7)||55 (55.6)||45 (48.9)|
|Race, N (%)|
|White||89 (92.7)||93 (93.9)||84 (91.3)|
|Black||1 (1.0)||2 (2.0)||2 (2.2)|
|Hispanic||2 (2.1)||2 (2.0)||1 (1.1)|
|Mean (SD)||73.00 (14.49)||75.12 (18.39)||71.22 (16.21)|
|Creatinine clearance at baseline|
|Years with epilepsy|
|Mean (SD)||22.78 (13.58)||24.8 (12.65)||25.06 (11.63)|
|Baseline 28-day seizure rate|
|Mean (SD)||23.5 (41.1)||26.2 (40.8)||19.3 (24.4)|
|Seizure history at screening, N (%)|
|Simple partial||47 (49.0)||40 (40.4)||37 (40.2)|
|Complex partial||88 (91.7)||89 (89.9)||88 (95.7)|
|Partial secondarily generalized||72 (75.0)||65 (65.7)||69 (75.0)|
|Generalized||3 (3.1)||9 (9.1)||6 (6.5)|
|Concurrent AED,a N (%)|
|1 AED||23 (24.0)||14 (14.1)||16 (17.4)|
|2 AEDs||42 (43.8)||54 (54.5)||51 (55.4)|
|3 AEDs||30 (31.3)||31 (31.3)||24 (26.1)|
In total, 147 (51.2%) took two concurrent AEDs during the study, and 85 (29.6%) took three. The pattern of concomitant AED use was similar across the three treatment groups. The most commonly used AEDs (>10% of all patients) were carbamazepine (CBZ; 61.3%), lamotrigine (LTG; 33.1%), topiramate (TPM; 18.8%), clobazam (CLB; 17.1%), phenytoin (PHT; 14.3%), phenobarbital (PB; 12.5%), valproic acid (VPA; 11.8%), and valproate sodium (11.1%). The most frequently used AED combinations were CBZ plus LTG, CBZ plus CLB, and CBZ plus TPR.
The 12-week treatment period was completed by 86.6% in the placebo group; 88.9% in the 150-mg/day PGB group; and 75.0% in the 600-mg/day PGB group; most of these patients (81%) elected to enter the subsequent open-label study. The mean duration of therapy during the double-blind and withdrawal phases was 82.5 days in the placebo group, 82.7 days in the 150-mg/day PGB group, and 74.8 days in the 600-mg/day PGB group.
Lack of efficacy resulted in the discontinuation of five (5.2%) patients from the placebo group, none from the 150-mg/day PGB group, and one (1.1%) from the 600-mg/day PGBgroup. Treatment-emergent adverse events resulted in the discontinuation of six (6.2%), 10 (10.1%), and 17 (18.5%) from the groups, respectively. The other eight (2.8%) patients discontinued for other reasons.
The reduction in seizures between baseline and end point was significantly greater in the 150-mg/day PGB and 600-mg/day PGB groups compared with placebo. The 150-mg/day and 600-mg/day PGB dosages were both significantly more effective than placebo in reducing the RRatio [−11.5 (p = 0.0007) and −31.4 (p ≤ 0.0001), respectively, vs. 0.9] (Fig. 1, right y-axis). These RRatio values correspond to seizure-frequency reductions from baseline of 20.6, and 47.8% for 150 mg/day, and 600 mg/day, respectively, and a seizure-frequency increase of 1.8% with placebo (Fig. 1, left y-axis). Difference in the treatment means [95% confidence interval (CI)] compared with the placebo group was −12.4 (−20.5; −4.3) in the 150-mg/day PGB group and –32.3 (−40.6; −24.0) in the 600-mg/day PGB group. The 600-mg/day PGB group was statistically superior to the 150-mg/day PGB group (p ≤ 0.0001). The analysis of treatment effects also demonstrated a significant, linear PGB dose–response (p ≤ 0.0001). No significant treatment-by-cluster interaction was found (p = 0.7028).
The responder rate (≥50% reduction in seizure frequency) was significantly greater in the 600-mg/day PGB group (43.5%) than in the placebo group (6.2%) (p ≤ 0.001). In the 150-mg/day PGB group, the difference from placebo approached significance (14.1%; p = 0.087; Fig. 2). Responder rate for the 600-mg/day PGB group was statistically superior to the 150-mg/day PGB group (p ≤ 0.001).
A median percentage reduction was seen in all partial seizures of 16.5% in the 150-mg/day PGB group and 42.6% in the 600-mg/day PGB group, and an increase of 1.3% in the placebo group.
During the last 28 days of treatment, 12% of patients in the 600-mg/day PGB group were free of seizures, as were 7% in the 150-mg/day PGB group and just 1% in the placebo group (p = 0.002 and p = 0.065 vs. placebo, respectively). The analysis of median percentage change in seizure frequency according to seizure type was consistent with the analysis of all partial seizures combined. One patient in the placebo group experienced a new seizure type during the study (generalized myoclonic), and two in the 600-mg/day group (generalized myoclonic; simple partial with motor symptoms).
Tolerability and safety
Treatment-emergent adverse events were reported in most patients, and the overall frequency was higher in the PGB treatment groups than in the placebo group (Table 2). Adverse events were generally mild or moderate in intensity. Severe, associated adverse events were reported in 12 (4%) patients overall. The two most frequently reported adverse events, somnolence and dizziness, which were reported with higher frequency in the PGB treatment groups than in the placebo group, appeared to be dose related (Table 2) and, in most cases, were attributed to study treatment by the investigator. However, relatively few patients discontinued because of somnolence (three patients from the 600-mg/day PGB group) and dizziness (one, five, and six patients from the placebo, 150-mg/day, and 600-mg/day PGB groups, respectively). Somnolence was most frequent among patients receiving three concomitant AEDs and least frequent in those receiving one other AED. The other commonly reported adverse events listed in Table 2 also were infrequently associated with discontinuation of treatment. The three most common adverse events associated with PGB that led to discontinuation affected the CNS (dizziness, asthenia, and ataxia). The median time to onset of adverse events including somnolence, dizziness, ataxia, asthenia, and blurred vision, was less than a week in the PGB treatment groups. The median duration of any adverse events was similar among the 600-mg/day PGB group (54 days) and the placebo group (55 days) and was shortest in the 150-mg/day group (28 days).
|Placebo||150 mg/day||600 mg/day|
|Number of patients||97b||99||92|
|Any adverse event||61 (63.5)||75 (75.8)||80 (87.0)|
|Discontinued with adverse event||6 (6.2)||10 (10.1)||17 (18.5)|
|Adverse events occurring in ≥10% of patients|
|Somnolence||7 (7.3)||6 (6.1)||27 (29.3)|
|Dizziness||8 (8.3)||19 (19.2)||24 (26.1)|
|Ataxia||3 (3.1)||2 (2.0)||16 (17.4)|
|Asthenia||11 (11.5)||13 (13.1)||13 (14.1)|
|Diplopia||5 (5.2)||6 (6.1)||13 (14.1)|
|Weight gain||2 (2.1)||7 (7.1)||13 (14.1)|
|Headache||15 (15.6)||6 (6.1)||11 (12.0)|
|Tremor||3 (3.1)||3 (3.0)||10 (10.9)|
|Blurred visionc||3 (3.1)||7 (7.1)||9 (9.8)|
Accidental injury was reported in four patients in the placebo group, eight in the 150-mg/day PGB group, and seven in the 600-mg/day group. Review of each individual case of accidental injury did not indicate a clear relation of accidental injury with study treatment. PGB was associated with dose-related weight gain. However, the severity was considered mild, and only one patient taking 600 mg/day consequently discontinued. Mild myoclonus was reported in four patients in the 600-mg/day PGB group. EEG recording in one patient with the highest frequency of myoclonic jerks failed to show EEG changes. Only isolated reports were noted of anxiety, depression and other events linked to fluctuation in mood. Similarly, only isolated reports were made of the adverse event, thinking abnormal, the term ascribed to encompass concentration difficulties and other forms of mild cognitive impairment. Peripheral edema was reported in two, three, and six patients in the placebo, 150-mg/day, and 600-mg/day PGB groups, respectively. No changes in blood pressure or cardiovascular events were observed in these patients.
Serious treatment-emergent adverse events were reported in 11 patients but were considered only possibly, probably, or definitely related to treatment in three patients. Of these three, one patient in the placebo group had hemiplegia, one in the 150-mg/day PGB group had a maculopapular rash, and one in the 600-mg/day group had amblyopia and dizziness. These events resolved after discontinuation of treatment. No patient died during the study.
No changes in vital signs of clinical concern were reported. Similarly, review of changes in clinical laboratory parameters did not yield findings of clinical relevance related to study medication. No clinically relevant visual field defects were observed in the 118 patients who were tested at baseline and on entry to the subsequent open-label extension trial that followed this double-blind study.
Plasma pregabalin concentrations
In total, 300 blood samples were collected from 108 patients who had reached pharmacokinetic steady state. The mean (range) plasma PGB concentrations associated with the 150-mg/day and 600-mg/day doses were 1.27 μg/ml (0.29–2.84 μg/ml) and 4.88 μg/ml (0.87–14.2 μg/ml), respectively. Close agreement was found between the observed mean and the model-predicted steady-state plasma PGB concentration–time profiles for both doses.
The results of this international study involving 287 patients demonstrated that PGB doses of 150 mg/day and 600 mg/day were effective and well tolerated as add-on treatment for partial seizures.
The dose-related efficacy of PGB was demonstrated in the analysis of the primary efficacy variable, in which both doses were significantly superior to placebo (p ≤ 0.001). The reduction in seizure frequency observed in the 600-mg/day PGB group in this study, which corresponds to a 42.6% mean reduction, is highly consistent with the efficacy of this dose, administered either 2 or 3 times a day, in studies of similar design that evaluated similar patient populations with partial seizures (5,6,27). Likewise, 150-mg/day PGB showed a significant difference in reduction in seizure frequency (20.6%) compared with placebo. This finding is in agreement with data from another dose–response trial in which the seizure frequency was reduced by 34% in the 150-mg/day PGB group (5).
Analysis of the secondary efficacy variables corroborated the findings of the primary analysis. In the 600-mg/day PGB group, 43.5% of patients were responders (≥50% seizure reduction), a significantly higher proportion than in the placebo group (6.2%; p ≤ 0.001). Although the 14.1% responder rate in the 150-mg/day PGB group did not attain statistical significance, the trend was favorable. Similarly, the 42.6% median reduction in seizure frequency in the 600-mg/day PGB group and the 16.5% reduction associated with the 150-mg/day dose, compared with the 1.3% increase in the placebo group, further support the observation that both doses were associated with clinically relevant degrees of improvement in seizure control. Collectively, the results of the primary and secondary efficacy analyses in this study suggest that 150-mg/day PGB is likely to be the minimally effective dose at which significant seizure reduction can be achieved. Our findings, taken in conjunction with results from another fixed-dose PGB studies in similar patients (5,6), suggest that the therapeutic dose range is 150–600 mg/day as an add-on treatment for partial seizures. In this study, 150-mg/day PGB was considered the lowest effective dose because 50-mg/day PGB was not distinguishable from placebo (5).
The significant and robust efficacy of 150-mg/day and 600-mg/day PGB in this study was demonstrated in patients who had a long history of partial seizures and had poor seizure control. More than 80% of patients were taking two or three concomitant AEDs, and despite this, the median seizure rate before treatment was ∼11 per month. Taking into account the usual cautions of comparing response rates and effects sizes across different studies, we observed that the seizure control with both PGB doses in this study compared favorably with those observed with other recently available add-on AEDs (25,26). Furthermore, 12% of patients taking 600 mg/day PGB (p = 0.002) and 7% taking 150 mg/day (p = 0.065) were completely free of seizures during their last month of treatment, a noteworthy finding given the nature of the patient population. We suggest that the efficacy associated with PGB we observed in this difficult-to-treat population might be applicable to a wider range of patients with partial seizures in the clinical setting.
Both PGB doses were well tolerated. The most frequently reported adverse events associated with PGB that were more frequent than in the placebo group generally affected the CNS, an expected finding given the pharmacology of PGB. However, most adverse events were of mild or moderate intensity, occurred soon after initiation of treatment, and infrequently resulted in treatment discontinuation. The presence of a relatively high proportion of patients with at least one adverse event in the placebo group (64%) suggests that the high concomitant drug use could be partially responsible for the occurrence of adverse events in this study. In the evaluation of treatment-emergent adverse events, it also is worth noting that >80% of patients were taking two or three concurrent AEDs, most likely at maximal tolerated doses.
At the highest dose, PGB was associated with a higher frequency of adverse events than were 150-mg/day PGB and placebo. Somnolence and dizziness were the most common adverse events but resulted in discontinuation in only three patients taking 150-mg/day PGS and six patients taking 600-mg/day PGB respectively. The only adverse events associated with 150-mg/day PGB that distinguished this dose from placebo were dizziness and weight gain. Other adverse events of potential concern that have been associated with AED treatment (such as myoclonus, changes in mood, and psychiatric symptoms and events associated with cognitive impairment) were very infrequent in this study. Although three patients taking 150-mg/day PGB and six taking 600 mg/day had peripheral edema, no evidence was found linking this with clinically important changes in cardiovascular function. No clinically important changes in vital signs or laboratory variables were observed. No ophthalmologic abnormalities were associated with PGB.
Both the efficacy and tolerability of PGB observed in this study are remarkably consistent with the findings of others (5,6). The consistency of therapeutic response, the predictability of side effects, and the ability to tolerate side effects are important considerations in the selection of an AED. In the case of PGB, some of these features may be attributable to its predictable and linear pharmacokinetic profile. The pharmacokinetic profile of PGB in this study was highly consistent with that based on modeling of a much larger dataset. In addition, the lack of pharmacokinetic drug interactions associated with PGB because it is renally excreted and not metabolized by CYP450 isoforms is a beneficial attribute in the treatment of epilepsy when polypharmacy is difficult to avoid. We conclude that this study demonstrates that 150-mg/day and 600-mg/day PGB are significantly effective and well tolerated as adjunctive therapy for patients with partial seizures and propose that PGB will be a valuable addition to the armamentarium of AEDs.
ACKNOWLEDGMENT: We thank the patients who took part in the study and the principal investigators in the Pregabalin 1008-011 International Study Group (listed below).
Australia: Roy Beran, MD, Samuel Berkovic, MD, Andrew Black, MD, Gytis Danta, MD, Graham Schapel, MD, Ernest Somerville, MD
Austria: Gerhard Bauer, MD, Eva Koerner, MD
Belgium: Patrick van Coillie, MD
Finland: Salle Lamusuo, MD, Olli Waltimo, MD
France: Michel Baulac, MD, Olivier Guard, MD, Bernard Gueguen, MD, Bernard Montagne, MD, Philippe Ryvlin, MD
Germany: Andreas Schulze-Bonhage MD, Peter Lüdemann, MD, Soheyl Noachtar, MD, Hermann Stefan, MD, Bernhard Steinhoff, MD, Stefan Stodieck, MD, Barbara Tettenborn, MD
The Netherlands: M. J. Jongsma, MD, T. W. Rentmeester, MD
Italy: Luigi Murri, MD, A. Tartara, MD, Camillo Tiacci, MD, Gaetano Zaccara, MD
South Africa: Pierre L. A. Bill, MD, Jonathon Carr, MD
Spain: Oscar Fernández, MD, Albert Molins, MD, Adolfo López de Munain, MD, Francisco Villalobos, MD
Sweden: Elinor Ben-Menachem, MD
Switzerland: Giovani Foletti, MD, Fabio Baronti, MD
United Kingdom: Tim Betts, MD, Martin J. Brodie, MD, David Chadwick, MD, Pamela M. Crawford, MD, Richard Roberts, MD, Josemir Sander, MD
Dr. Arroyo has received travel grants, consultancy fees, and has been on the Speakers Panel of Parke-Davis/Warner-Lambert and Pfizer Inc. Drs. Anhut, Knapp, Garofalo, and Messmer, and Ms. Lee are employees of Pfizer Inc. Dr. Kugler is a former employee of Parke-Davis/Warner-Lambert and Pfizer Inc.
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