Immediate and controlled-release pregabalin for the treatment of epilepsy

ABSTRACT

Introduction: Epilepsy is a common neurological disease requiring complex therapies, which are unable to achieve seizure control in 30% of patients. Poor adherence has been recognized as a possible determinant of drug-resistance. Prolonged-release formulations of antiepileptic drugs might help increase adherence and minimize side effects.

Areas covered: Pregabalin (PGB) has peculiar pharmacodynamics and almost ideal pharmacokinetics, except for a short half-life and therefore requiring multiple daily dosing. PGB immediate-release (IR) is effective in focal-onset epilepsy (FOE), neuropathic pain, generalized anxiety disorder, and fibromyalgia, despite some tolerability issues, especially at higher doses. The controlled-release formulation (CR) shares PGB IR advantages and requires slight dose adjustments to guarantee bioavailability. In 2014, PGB CR (165 and 330 mg/day) failed to prove superior to placebo in a randomized placebo-controlled trial on 323 subjects with drug-resistant FOE, although it was just as tolerable. Therefore, PGB CR is not currently licensed for epilepsy.

Expert opinion: Considering the disappointing results of the only controlled trial, PGB CR is unlikely to become an established epilepsy treatment anytime soon. Nevertheless, given its peculiar properties and potential advantages, PGB (in either formulation) should be further evaluated in specific populations of patients, especially fragile subjects with several comorbidities and complex polytherapies.

KEYWORDS:

• Adherence
• calcium-channels
• comorbidities
• controlled-release
• epilepsy
• liver impairment
• pregabalin

Article highlights

• Pregabalin (PGB) binds to α2δ subunit of voltage-gated calcium channels and is licensed for the treatment of focal-onset epilepsy (FOE), painful neuropathies, generalized anxiety disorder, and fibromyalgia.

• PGB immediate release (IR) has linear pharmacokinetics (PK), negligible metabolism, protein binding, and drug–drug interaction potential; however, its short half-life requires frequent daily dosing (BID or TID).

• PGB IR, administered at 150–600 mg/day, is effective in adult patients with FOE, in a dose-dependent manner.

• Common side effects include dizziness/incoordination, somnolence, abnormal thinking, weight gain, and peripheral edema, which lead to PGB discontinuation in a variable proportion of cases.

• Prolonged-release formulations of current anti-epileptic drugs might be helpful in minimizing side effects and preventing poor adherence, one of the main determinants of therapeutic failure in epilepsy.

• A single RCT performed in subjects with drug-resistant FOE compared PGB controlled-release (CR) at 165–330 mg/day with placebo and found no significant differences in effectiveness between the two groups in spite of comparable tolerability, preventing PGB CR from obtaining approval for FOE treatment.

• Considering its favorable PK and wide clinical applications, PGB (in both formulations) should be further evaluated in specific groups of patients, especially those with several comorbidities, liver function impairment, and complex polytherapies.

Declaration of interest

E Russo has received speaker fees or funding or has participated in advisory boards for Eisai, Pfizer and GW Pharmaceuticals. AT Giallonardo has received speaker fees from Eisai, UCB Pharma, FB Health and Sandoz. C di Bonaventura has received speaker fees from Eisai, UCB Pharma, FB Health and Sandoz. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.