Antiepileptic Drugs, 5th Edition

Drugs in Development



Elinor Ben-Menachen MD, PhD*

Alan R. Kugler PhD*

* Associate Professor, Department of Clinical Neuroscience, Neurology Section, Sahlgrenska University Hospital, Goteborg, Sweden

** Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, Michigan


Pregabalin (CI-1008; S-(+)-3-isobutyl-GABA; Pfizer, Inc., New York, NY) is a novel central nervous system (CNS)-active compound with anticonvulsant activity. It is a white solid and is stable for >18 months at 25°C. It is currently being developed as an anticonvulsant as well as an analgesic and an anxiolytic. Although it is similar in action to the antiepileptic drug (AED) gabapentin, it is more potent in animal models of pain and seizures. In general, the effective doses are lower and the duration of effect longer than with gabapentin. The isomer of S-pregabalin is the R-isobutyl γ-aminobutyric acid (GABA), but it is more than 10-fold weaker in animal models of epilepsy and pain than the isomer being developed (1).

Pregabalin, like gabapentin, is a structural analog of GABA; however, neither pregabalin nor gabapentin is active at GABAA or GABAB receptors. In fact, the mechanism of action of both gabapentin and pregabalin remains elusive. Pregabalin competes with [3H]-gabapentin at its specific binding site (α2δ protein) in brain tissues, and the R- isomer has a 10 times lower affinity. Radioligand binding studies show that pregabalin has little affinity to GABA (2), and it exhibits a high affinity and selectivity to the α2δ subunit of voltage-dependent calcium channels.

There are conflicting results if gabapentin and pregabalin in fact alter calcium currents. In a recent study (3), pregabalin, like gabapentin, reduced paired-pulse inhibition in the dentate gyrus in rats. Pregabalin caused a dose-dependent loss of paired-pulse inhibition and blocked the lengthening of the duration of the seizure discharge. Nimodipine, however, could not mimic this response, so the conclusion was that the reduction in paired-pulse inhibition was not due to the L-type calcium channel mechanism.

In other studies, there is an indication that pregabalin can modulate norepinephrine and glutamate release by inhibiting K+-evoked release of the neurotransmitters (4,5).

In animal models of epilepsy, pregabalin has a greater potency than gabapentin in all models tested, although it has a similar profile (6). In the maximal electric shock (MES) model, pregabalin prevented tonic extensor seizures in mice at similar dosages for both oral (p.o.) and intravenous (i.v.) delivery, suggesting high bioavailability [median effective dosage (ED50), 20 mg/kg p.o.]; the same was true in rats (ED50, 1.5 mg/kg p.o.). Maximal effect on MES was seen 2 to 4 hours after dosing. This test suggests that pregabalin would be effective for generalized tonic-clonic seizures.

Pentylenetetrazol administration causes clonic seizures and is a model of primary generalized seizures. Pregabalin prevented threshold clonic seizures (ED50, 97 mg/kg p.o. in mice and >125 mg/kg p.o. in rats). For the bicuculline, picrotoxin, and strychnine seizure models, pregabalin only partially blocked the response. Less than 100% of the mice were protected with dosages up to 500 mg/kg. These three seizure models reflect an effect on the GABAergic system in the brain. Therefore, it is proposed that pregabalin might have some effect on GABA neurotransmitter systems, although so far there is no evidence to suggest that it affects GABA receptors or metabolism.

In the hippocampal kindling rat model, pregabalin at dosages of 9.5 mg/kg reduced behavioral seizures, and higher dosages still prevented both behavioral seizures and afterdischarges. This suggests that pregabalin might be effective for the treatment of focal seizures (7).

There was no effect of pregabalin on genetically susceptible rats with spontaneous absence seizures [genetic absence epilepsy in rats from Strasbourg (GAERS)] with dosages of up to 100 mg/kg. Dosages over 200 mg/kg


intraperitoneally increased the amount of absence seizures (1). This dosage is over 20-fold higher than the highest recommended dosage in humans (600 mg/day). Pregabalin also prevented audiogenic seizures in DBA/2 mice at 3 and 10 mg/kg p.o. (1).


Pregabalin exhibits predictable linear pharmacokinetics. It has been tested in two phase 1 studies to determine its pharmacokinetics after single and rising multiple oral doses (8). The studies entailed single rising doses of 1 to 300 mg and multiple rising doses of 25 to 300 mg given every 8 hours and 300 mg given every 12 hours for 14 days. A total of 86 healthy volunteers between 19 and 50 years of age participated (47 men and 39 women). Concentrations of pregabalin were determined using specific, sensitive, and validated high-performance liquid chromatography-UV methodology (8).

Given orally to healthy volunteers, pregabalin was rapidly absorbed [mean time to maximal concentration (Tmax) approximately 1 hour], with a bioavailability ≥90%, independent of dose. The plasma pregabalin half-life was approximately 6 hours, which was independent of dose and with repeated administration. Maximal plasma pregabalin concentrations (Cmax) and total exposures (area under the concentration-time curve) were dose-proportional after either single or multiple dosing. The concentration-time profiles of pregabalin were similar after twice-daily or three-times-daily administration.

Metabolism and Elimination

Pregabalin is not metabolized to any extent in humans, nor does it bind to plasma proteins. This also is similar to gabapentin. Approximately 98% of the drug can be recovered unchanged in the urine. The percentage excreted was similar with single or multiple dosing and was independent of dose.

Drug Interactions

No drug interactions have been reported clinically and none are anticipated since pregabalin is neither metabolized nor bound to plasma proteins. Population pharmacokinetic analyses (9) demonstrated that pregabalin could be administered with carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, and valproate without concern for clinically significant changes in their pharmacokinetics.

Effects on Renal and Liver Disease

Pregabalin is not expected to affect the liver because it is not metabolized at therapeutic dosages. In the rat, pregabalin induced the cytochrome P450 (CYP) isoenzymes CYP2B1/2 and CYP2E1 only at extreme dosages >1,250 mg/kg/day (approximately 145-fold higher than the highest recommended dose in humans). Because pregabalin is excreted by the kidney, dose adjustments may need to be considered in patients with renal insufficiency.


A population pharmacokinetics analysis (9) showed that the only factor with a clinically significant impact on pregabalin pharmacokinetics was renal function; age was not an independent covariate. The safety and efficacy of pregabalin in the elderly are being assessed.


There is no information available on the effect of pregabalin on pregnancy because the drug is still undergoing clinical trials. However, pregabalin is not teratogenic in mice or rabbits. Teratogenicity was observed in rats at very high dosages of 1,250 to 2,500 mg/kg. These dosages were much higher than those used in humans (usually <10 mg/kg) (data on file; Pfizer, Ann Arbor, MI).


Randomized, Controlled Trials

Pregabalin has been evaluated in more than 1,500 patients with epilepsy (10). Even more patients have been involved in clinical trials for other indications, mainly analgesic and psychiatric.

One monotherapy study (1008-007) (11) has been completed in patients with refractory partial epilepsy admitted for surgical evaluation. Using a typical presurgical inpatient monotherapy protocol, patients were randomized either to 600 mg/day pregabalin (n = 42) or 300 mg/day gabapentin (n = 51) for 8 days. There was a positive trend in favor of pregabalin in time to exit and a significantly higher study completion rate for the pregabalin group.

Three major outpatient randomized, controlled trials for adjunctive therapy in patients with partial seizures with or without secondary generalization have been reported in abstract form. Patients in these three studies had received anticonvulsant therapy for many years before randomization, with a mean duration of epilepsy of 25 years. At entry, 30% of patients were receiving one AED, 50% were receiving two AEDs, and 20% were receiving three AEDs. Despite this treatment, patients remained refractory at baseline with a median of 10 partial seizures per month and a mean of 24 seizures per month. Over 83% of patients entered open-label extensions (12).

Analyses used an intent-to-treat population, defined as those randomized to treatment and taking at least one dose


of study medication. Two end points were evaluated in each study, response ratio and responder rate. Response ratio (RRatio), the primary efficacy parameter, is a measure of the percentage change from baseline in seizure frequency during treatment, such that:

[(T - B)/(T + B)] × 100

where B = baseline seizure frequency and T = seizure frequency during treatment. RRatio, using parametric statistical methods, reflects a direct transformation of the difference in percentage of seizures that occur during treatment compared with baseline. Results are distributed normally in the range of -100 to +100. A zero value would indicate no change in seizure frequency and a -100 value would indicate complete elimination of seizures. A 50% reduction would result in an RRatio of -33. For display purposes (Figure 96.1), mean RRatio values were converted to seizure reductions. Responder rate, a secondary efficacy parameter, is defined as the percentage of patients with ≥50% reduction in seizure frequency during treatment compared with baseline.

The first study (1008-009) (13) was a 43-center, doubleblind, placebo-controlled, parallel-group, randomized trial of pregabalin as add-on therapy in patients with refractory partial epilepsy not controlled on one to three drugs. A total of 312 patients with at least 6 seizures during an 8-week baseline were given pregabalin 300 mg twice daily (bid), pregabalin 200 mg three times daily (tid), or placebo for 12 weeks. Baseline AEDs were not changed during the study time. Of the 312 patients, 76% completed the study. RRatio was significantly better for pregabalin bid and tid groups than placebo (p ≤ .0001). The mean RRatio for the various treatment groups was -28 (600 mg/day administered bid), -36 (600 mg/day administered tid), and 0.6 (placebo). Responder rates were 43%, 49%, and 9%, respectively for the bid, tid, and placebo groups. Seizure freedom (last 28 days of the study) rates were 3% for placebo, 3% for pregabalin 600 mg/day bid, and 14% for pregabalin 600 mg/day tid. The most common side effects reported were dizziness, somnolence, and ataxia. The dropout rate due to adverse events was 26% in the bid group, 19% in the TID group, and 7% in the placebo group.


FIGURE 96.1. Seizure reduction by study, regimen, and daily dose.

In the second randomized, controlled trial (1008-034) (14), the efficacy and tolerability of pregabalin in 453 patients with refractory partial seizures was determined. This study included 80 centers and was a double-blind, parallel-group study with an 8-week baseline and a 12-week treatment period. Patients were taking one to three other AEDs and were randomized to one of five groups: pregabalin 50, 150, 300, or 600 mg/day bid or placebo with no titration phase. RRatio was significantly better for pregabalin 150, 300, and 600 mg/day groups than placebo (p ≤ .0001). The mean RRatio for the various treatment groups was -4 (placebo), -6 (50 mg/day), -21 (150 mg/day), -28 (300 mg/day), and -37 (600 mg/day). Responder rates were 14%, 15%, 31%, 40%, and 51%, respectively. Seizure freedom (last 28 days of the study) rates were 8%, 5%, 6%, 11%, and 17%, respectively. Withdrawal rates due to adverse events were 5%, 7%, 1%, 14%, and 24%, respectively. The most common adverse events were dizziness and somnolence, and both were dose related. Pharmacokinetics were found to be dose proportional, low variability, and predictable. The conclusion of the abstract was that pregabalin treatment can be initiated at a dosage of 150 mg/day, administered in two divided doses, and can be increased based on individual response both to efficacy and tolerability.

In the third multicenter, double-blind, placebo-controlled study (1008-011) (15), 287 patients with severe refractory partial seizures were given the study drug. After an 8-week baseline phase, patients were given either placebo, pregabalin 150 mg/day tid, or pregabalin 600 mg/day tid for 12 weeks, with only 1 week of titration. RRatio was significantly better for the pregabalin 150 mg/day (p = .0007) and 600 mg/day (p ≤ .0001) groups than for placebo. The mean RRatio for the various treatment groups was -12 (150 mg/day), -31 (600 mg/day), and 0.9 (placebo). Responder rates were 6.2% for the placebo group, 14.1% for the 150 mg/day group, and 43.5% for the 600 mg/day group. Seizure freedom (last 28 days of the study) rates were 1% for the placebo group, 7% for the 150 mg/day group, and 12% for the 600 mg/day group. Adverse events were judged to be transient, mild to moderate in intensity, and CNS related.

Figure 96.1 shows the RRatio values converted to seizure reductions for all three adjunctive studies. There was a statistically significant increase in efficacy with increasing dose in studies 1008-034 and 1008-011 (linear dose-response; p ≤ .0001 for both studies) (12,16). In all three controlled studies, statistically significant efficacy was present by week 1 (17).



Adverse Events

Data from all three studies also were pooled to assess safety (12). The most frequently occurring adverse events were dizziness and somnolence. Some of the adverse events appeared to be dose related. However, in general, events were mild to moderate in intensity. Withdrawal rates due to adverse events ranged from 1.2% to 25% and also appeared to be dose related. Studies are ongoing to determine whether a longer titration to the higher doses would result in fewer dropouts and an improved safety profile. Serious adverse events were infrequent, and no deaths occurred during these studies. There were some mild, transient increases in hepatic enzymes in the multiple-dose study in healthy volunteers at 900 mg/day (8). The highest recommended dose in clinical trials is 600 mg/day. Overall, pregabalin was well tolerated as reflected by the fact that 83% of pregabalin-treated patients enrolled in open-label extensions to the double-blind studies.

Two epilepsy investigators have published their singlesite observations of myoclonus. Huppertz et al. (18) reported myoclonus in 21% (4 of 19 pregabalin-treated patients) and Asconape et al. (19) reported myoclonus in 33% (2 of 6 pregabalin-treated patients). However, myoclonus has been reported in only 1.2% (60 of 5,026 patients) of all patients treated with pregabalin in 29 controlled and uncontrolled epilepsy and analgesia studies, and led to withdrawal in 0.12% (6 of 5,026) of patients (Data on file; Pfizer, Ann Arbor, MI). Of the 60 cases, 56 had epilepsy and were receiving 1 to 3 other AEDs. The overall incidence of myoclonus in epilepsy trials was 3.5% (56 of 1,160 patients). Electroencephalograms were obtained in six of the cases and none showed visible correlates, thus indicating that the myoclonus did not appear to be cortical in origin.


Place of the Drug in Therapy

So far, pregabalin has been tested in patients with refractory partial seizures and has been found to be efficacious and well tolerated. Preliminary preclinical studies indicate that this drug might not be as effective in idiopathic epilepsy forms, but this has not been tested in humans yet. Monotherapy trials for new-onset partial seizures, as well as pediatric studies, comparative studies, and studies in patients with other seizure types, are in the planning stages.

Dose and Titration Rates

From the randomized clinical trials, there is evidence that the starting dosage of pregabalin should be 150 mg/day given in two divided doses. Efficacy and tolerability should then be evaluated before further titration is contemplated. Titration should depend on individual tolerability and response to the drug. In the clinical studies, titration was either over 1 week, or therapy was initiated without titration at dosages up to 600 mg/day.

Therapeutic Ranges

In clinical trials, the drug has been tested at dosages between 50 and 600 mg/day. Studies 1008-034 (14) and 1008-011 (15) demonstrate a significant dose-response relationship up to the maximum dosages tested of 600 mg/day. Because the pharmacokinetics of pregabalin are linear and predictable, the benefit of therapeutic drug monitoring to guide dosing is thought to be minimal.


Several clinical studies demonstrate the effectiveness and safety of pregabalin for the treatment of focal epilepsy (all partial seizures with or without secondary generalization). The efficacy data appear very encouraging considering the refractory nature of patients enrolled in studies to date. More details on the safety and tolerability of pregabalin are required to understand more fully the position of pregabalin in the therapy of patients with epilepsy.


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