Like gabapentin, pregabalin binds to the α-2-δ subunit of voltage-gated calcium (P/Q) channels, and allosterically modulates calcium (Ca) influx, reducing it by up to 40%—with the greatest reduction occurring in states in which high neuronal activity is present.⁶³ There are four subtypes of the α-2-δ subunit; pregabalin binds to subtypes 1 and 2 only. This modulation has been shown to reduce the presynaptic release of neurotransmitters, including noradrenaline,^20,21 substance P,²⁶ and the excitatory amino acid glutamate.^19,42 These effects require binding of pregabalin at the α-2-δ subunit. Although the α-2-δ type 1 knockout is a lethal mutant, studies have been performed using the R217 A knock-in mice with α-2-δ type 1 receptors that have preserved function but markedly reduced binding of pregabalin,^12,63 especially in the neocortex, hippocampus, basolateral amygdala, and spinal cord. In these mice, pregabalin has no benefit on pain, and has reduced anxiolytic and antiepileptic effects.^28,63 These studies supplement the binding studies by showing that binding of pregabalin to the α-2-δ receptor is necessary for maximal therapeutic effects. In addition, in cultured hippocampal neurons, some evidence suggests that the effects of pregabalin on synaptic vesicular release are greatest before and early in the course of a train of electrical stimuli.⁴² In neuromuscular preparations, pregabalin reduced nerve-evoked muscle contractions by 16%.³⁸ When pregabalin cannot bind to the α-2-δ receptors, as in mutant R217 A mice, it has no effect. There has been no demonstrated effect of pregabalin on L-type Ca channels in muscle. α-2-δ Type 1 and 2 receptors are present outside the central nervous system (CNS) (e. g., in spleen, liver, lung) but at much lower concentrations.⁶¹

Despite the structural similarity of pregabalin to the inhibitory amino acid GABA, the addition of the side chain changes the configuration of the GABA subunit, with the net result that no binding to pre- or postsynaptic GABA (A or B) receptors occurs.^51,62 Pregabalin does not have any GABA mimetic properties, and there is no effect on GABA or chloride flux. In addition, brain GABA levels are not significantly altered by pregabalin,²⁴ and there is no effect on GABA uptake or degradation. Studies to date have not revealed significant effects of pregabalin on other known antiepileptic mechanisms (e.g., voltage-dependent sodium conductances), nor is there evidence that pregabalin affects the postsynaptic responses of any neurotransmitters. Therefore, at present, pregabalin appears to have a specific binding site that modulates and reduces the presynaptic release of neurotransmitter through a mechanism of action that does not depend on any GABAergic actions.

The efficacy of pregabalin has been investigated in various animal models of epilepsy.^63,64 Pregabalin potently inhibits tonic extensor seizures in the electroshock model (ED50 = 1.8 mg/kg, administered orally), and it also prevents tonic extensor seizures in the DBA/2 audiogenic mouse model (ED50 = 2.7 mg/kg, administered orally). The time course of action of pregabalin reflects the time course of radiolabeled drug in the CNS. In a kindled rat model of partial seizures, pregabalin prevented the more fully evolved stage 4 and 5 behavioral
seizures (lowest effective dose 10 mg/kg, intraperitoneally) and also reduced the duration of the electrographic discharges. All these are models of partial epilepsy or models that predict AED efficacy in partial epilepsy (maximum electroshock; MES).

At much higher doses (ED50 = 31 mg/kg, orally), pregabalin prevented seizures in the pentylenetetrazole (PTZ) model of epilepsy in mice. However, pregabalin did not prevent spontaneous absence-like seizures in the genetic absence epilepsy rats from Strasbourg (GAERS) and, in fact, seizures actually increased.⁶⁴ At one time, it was thought that AED efficacy in the PTZ model predicted anti-absence efficacy, but more recently^35,36 this has not been thought to be as reliable as the various genetic models for testing anti-absence efficacy of AEDs. Pregabalin does not appear to have significant anti-absence efficacy.

In one study⁴ using the lithium pilocarpine model of status epilepticus in rats, early treatment with pregabalin delayed the appearance of later epilepsy and reduced neuronal damage in the piriform cortex and entorhinal cortex but not the hippocampus. At present, however, insufficient evidence is available to conclude that pregabalin is neuroprotective or antiepileptogenic; additional studies are needed.

When fasting, oral bioavailability of pregabalin is excellent with >90% absorbed within 1 to 1.5 hours.¹⁴ Absorption is linear for both single doses up to 300 mg and multiple doses up to 900 mg/day (Fig. 2). This is an important difference and advantage of pregabalin compared with gabapentin, which is absorbed slowly, reaching peak doses in 3 to 4 hours. Although both compounds are transported across the gut and blood–brain barrier by an L-amino acid transport system, pregabalin has linear kinetics across and even above the clinical dosing range. This is quite different from the case with gabapentin, where even a 900 mg daily dose, given as 300 mg three times a day, has only 60% bioavailability, and a 3,600 mg daily dose has only 33% bioavailability when given as 1,200 mg three times a day.¹⁴ In comparing these two compounds, dose ranges of gabapentin from 900 mg to 3,600 mg per day and of 150 mg to 600 mg per day of pregabalin are commonly used, recognizing that these doses exceed the maximum approved dose for gabapentin in the United States (1,800 mg/day). Although the rate of pregabalin absorption is decreased slightly with food, the total amount absorbed is not affected.

Like gabapentin, pregabalin has negligible protein binding. The volume of distribution is approximately 0.5 L/kg.³

Pregabalin is not metabolized significantly; more than 90% is excreted unchanged in the urine. Pregabalin is not metabolized in the liver to any extent, nor does it induce or inhibit any of the P450 isoenzymes.^3,9 The major metabolite, an N-methylated derivative, accounts for <1% of the dose.

Elimination of pregabalin is primarily renal; the drug has a mean elimination half-life of 6.3 hours. Pregabalin clearance is proportional to creatinine clearance (CLcr), and patients with renal insufficiency (CLcr <60 mL/min) will need appropriate dose reductions. A 50% reduction in dose is recommended
for patients with a CLCr between 30 and 60 mL/min.⁵⁴ Because of pregabalin’s low protein binding, it will be removed by hemodialysis, and postdialysis adjustments may need to be made. Elderly patients with reduced CLcr will have proportionately reduced pregabalin clearance.

Therapeutic levels for pregabalin have not been established, and there are no recommendations for monitoring of plasma levels. Because of the 6-hour half-life, steady-state levels are achieved rapidly after initiation or dose adjustment, in about 30 hours (five half-lives). Arroyo et al.⁶ found that steady-state doses of 150 mg/day produced mean plasma pregabalin levels of 1.27 μg/mL (range 0.29–2.84 μg/mL), and doses of 600 mg/day produced mean plasma pregabalin levels of 4.88 μg/mL (range 0.87–14.2 μg/mL).³⁴ The dose range study of French et al. had similar findings.³² Beydoun et al.¹¹ reported that 600 mg, given three times a day, produced mean plasma pregabalin levels of 5.82 μg/mL (range 0.38–18.2 μg/mL); twice-daily dosing produced mean plasma pregabalin levels of 6.84 μg/mL (range 0.32–14.80 μg/mL). Although twice-daily dosing resulted in higher peak levels and lower daytime trough levels than the three-times-daily regimen, morning trough levels were similar in both groups. Efficacy in reducing seizures correlated with these mean levels. Because of pregabalin’s rapid elimination, it would be expected that broad fluctuations in serum levels would occur even at steady state, and this is reflected in the broad ranges of plasma levels obtained for a given dose. This characteristic reduces the utility of random pregabalin sampling except to document compliance. It is possible that morning trough levels of pregabalin might be useful, but the range of such levels has not been established. It is not known how the pharmacokinetic profile of pregabalin in the serum relates to the pharmacodynamic profile in the CNS. The fact that efficacy with twice-daily dosing is not significantly different from three-times-daily dosing suggests the possibility of a pharmacodynamic effect distinct from plasma pharmacokinetics, but this has not been studied.