Bioequivalence of Intravenous and Oral Formulations of the Antiepileptic Drug Lacosamide

Abstract

Background/Aims: To evaluate the bioequivalence of intravenous and oral lacosamide (tablet), an antiepileptic drug. Methods: Two randomized, single-dose (200 mg) trials were conducted: a 2-way trial (study A, 15-min infusion, oral tablet) and a 3-way crossover trial (study B, 30- and 60-min infusions, oral tablet). Twenty four healthy men participated in study A and 27 in study B. Eighteen blood samples were taken before to 72 h after lacosamide administration during each treatment period, followed by a 1-week washout. Safety and the ratio of intravenous/oral lacosamide for AUC_0–tz (area under the concentration-time curve from zero up to the last measurable plasma concentration) and C_max (maximum plasma concentration) were evaluated. Results: For AUC_0–tz and C_max, 90% confidence intervals for the ratio of intravenous/oral lacosamide fell within the predetermined bioequivalence range (80–125%) for 30- and 60-min infusions. In study A, all adverse events (AEs) were mild, with no discontinuations. In study B, 3 volunteers discontinued due to AEs; one serious AE (epiglottitis) was reported. No clinically relevant effects on vital signs, electrocardiograms or laboratory parameters and no AEs relating to infusion site were reported. Conclusion: Intravenous infusions (15, 30 and 60 min) of 200 mg lacosamide are as well tolerated as the oral tablet. Bioequivalence was demonstrated for 30- and 60-min infusions; therefore, direct conversion from oral to intravenous lacosamide, or vice versa, is possible.

Assessment of the effects of lacosamide on sleep parameters in healthy subjects

“…Overall, lacosamide 300 mg/day was well tolerated and the safety profile was consistent with that seen in other studies in healthy subjects. [31][32][33] These results are consistent with other evidence that lacosamide has a good tolerability profile. [22][23][24]34,35 The impact that AEDs can have on sleep in patients with epilepsy is well documented, although results vary widely based on the agent, whether acute or long-term effects were evaluated, disease severity, and use of concomitant medications.…”

Acute or chronic use of lacosamide does not alter its distribution between serum and cerebrospinal fluid

“…Although the chronic LCM dosing was administered as the oral formulation and the acute presurgical dose was intravenous, the different formulations have been previously shown to produce equivalent free drug in serum. 12 The chronically treated groups also exhibited a positive correlation between the dosage delivered at the time of craniotomy and the CSF level obtained. Of vital importance is that the CSF/serum ratios in our patient populations are congruent with a recent study of epilepsy patients chronically treated with LCM, in which the CSF concentration was reported to be~85% of the serum concentration.…”

“…With the minimum 2‐week dosing period for the chronic treatment group, steady‐state drug levels would have been achieved and contributed to the higher CSF and serum levels found in our chronically treated patients. Although the chronic LCM dosing was administered as the oral formulation and the acute presurgical dose was intravenous, the different formulations have been previously shown to produce equivalent free drug in serum . The chronically treated groups also exhibited a positive correlation between the dosage delivered at the time of craniotomy and the CSF level obtained.…”

Lacosamide in status epilepticus: Systematic review of current evidence

“…Due to its intravenous formulation that is bioequivalent with oral preparations and overall good tolerability of LCM, this anticonvulsant was used as a second‐line or third‐line therapy in SE. Höfler and Trinka described in detail the first evidence on the use of LCM in SE between 2009 and 2012 .…”

“…11,12 Clinical efficacy was shown in five doubleblind randomized controlled trials, 8,[13][14][15][16] and further safety and tolerability data were generated in extension [17][18][19] and postmarketing studies. 20,21 Due to its intravenous formulation that is bioequivalent with oral preparations and overall good tolerability of LCM, [22][23][24] this anticonvulsant was used as a second-line or third-line therapy in SE. H€ ofler and Trinka described in detail the first evidence on the use of LCM in SE between 2009 and 2012.…”