Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2008
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2008
Report Date:
2008

Materials and methods

Objective of study:
absorption
distribution
excretion
metabolism
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to
Guideline:
EPA OPP 85-1 (Metabolism and Pharmacokinetics)
Deviations:
no
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Solid, powder
Radiolabelling:
yes

Test animals

Species:
other: Combination literture study combined evaluation of mice and rat studies

Administration / exposure

Route of administration:
oral: gavage

Results and discussion

Applicant's summary and conclusion

Conclusions:
A detailed pharmacokinetics study is available
Executive summary:

Pharmacokinetics

• Absorption Lacosamide is a modified aminoacid with a fast and complete absorption. The bioavailability after oral administration approaches 100%. Three formulations are applied for: film-coated tablets 50, 100, 150 and 200mg, solution for infusion 10 mg/ml, and oral solution 15 mg/ml. Bioequivalence has been shown between clinical trial tablets and 30 or 60 minutes of oral infusion. If the infusion is administered over 15 minutes, a 20% higher mean Cmax is obtained and bioequivalence can not be shown. Bioequivalence has also been shown between the clinical trial tablet and an oral solution of a different concentration than the solution applied for marketing (10 mg/ml). The tablet intended for marketing is slightly different than the clinical trial formulation but has not been studied in vivo. A biowaiver from studying bioequivalence between the marketing tablet formulation and the clinical trial Page 25 of 52 formulation was granted as the formulation can be classified as BCS class I and have similar and fast dissolution at different pH in vitro, the drug has high permeability, apparently little intestinal transporter involvement, and the excipients in the formulation are unlikely to affect transport proteins. A biowaiver was also accepted for a bioequivalence study between the oral solutions of different concentrations. As the drug is in solution, and the solution does not contain any excipient known to affect drug absorption, this was granted.

• Distribution Lacosamide has a low protein binding and a volume of distribution of 40-60 L.

• Elimination The elimination half-life is 11-16 hours and clearance ca 3 l/h. The inter-individual variability is low (ca 20%). Lacosamide shows 1-compartment kinetics and the kinetics is dose and time proportional in the therapeutic range. Lacosamide is eliminated partly (30%) through renal excretion and partly by metabolism. The non-renal elimination has not been fully characterised. In the mass-balance study, 19- 40% of the dose was found in urine as the inactive metabolite SPM12809. (The metabolite coeluted with another metabolite, so the figure is imprecise.) However, the formation of the metabolite is said to be catalysed by CYP2C19 but absence or inhibition of CYP2C19 only gave a 7-17% reduction of oral clearance. Thus, either the contribution of the pathway is rather small or another enzyme is contributing to the SPM12809 formation. The applicant has tried to identify the remaining metabolic pathways and enzymes responsible as catalysts, but although quite extensive investigations, no further information has been collected. The identification of dose-related compounds in plasma is borderline acceptable. Only a pooled plasma sample from all time points of a full sampling curve was studied. The rough estimation results in lacosamide contributing to 60-100% of plasma radioactivity. SPM12809 was the only metabolite found in plasma. The pharmacokinetics of SPM12809 has been investigated in several studies. The exposure of SPM12809 is usually 15% of the lacosamide exposure. • Chirality Lacosamide has one chiral centre and is administered in the R-form. There is no significant interconversion in vivo. • Special populations Impaired renal function gives an expected increase in lacosamide exposure (47% in severe renal impairment). The drug is eliminated by haemodialysis and an additional half morning dose should be taken after end of dialysis. A maximum dose of 250 mg (instead of 400mg) is recommended for patients with severe renal impairment and in patients with end-stage renal disease. Very high concentrations of SPM12809 were noticed in patients with severe impairment and end-stage renal disease. The exposure margin to preclinically obtained exposures is, as for the parent drug, small or non-existent. In patients with end-stage renal disease, the plasma concentrations were increased and continued to rise during the complete sampling period. Thus, AUC could not be determined. However, no pharmacological activity of the metabolite has been observed. A recommendation of caution when treating patients with end-stage renal disease is proposed in the SPC. The AUC of lacosamide was increased by 60% in moderately impaired hepatic function. However, the studied patients also had an impaired renal function and it was estimated that the increase in AUC resulting from a decrease in non-hepatic clearance was 19%. The exposure was also similar in Asians, Blacks and Whites. Elderly women had approximately 50% higher mean AUC than young men both after the first dose and at steady state, and elderly men had approximately 33% higher exposure than young men. After normalising the parameters for bodyweight, the differences were reduced (to 23% for elderly women and 26% in elderly men as compared to young men). Only a minor part of the difference is likely to be due to decreased renal function. The pharmacokinetics in children has not been studied. However, studies in this age group are planned. Weight appears to modestly influence the pharmacokinetics of lacosamide. The population PK analysis supported that women will have an increased lacosamide Page 26 of 52 exposure and indicated that decreased weight will lead to increased exposure. Combining information from the various sources, indicates that elderly females with low body weight may have increased lacosamide exposure. Clinical trials indicate that gender does not have a clinically significant influence on the plasma concentrations of lacosamide. • Pharmacokinetic interaction studies In vitro studies indicate that CYP3A4 may both be induced and inhibited by lacosamide. The signal is not very strong but nevertheless, it may not be excluded that lacosamide can affect this enzyme activity in a moderate way. The applicant will study this in a multiple dose study with oral midazolam. A Caco-2 cell transport study indicates that there is some efflux transport. The concentration dependency of the transport has not been evaluated. The concentrations used in the study are quite high and the possibility of lacosamide to be transported by aminoacid transporters or peptide transporters such as PEPT1 may not be excluded. However, as there are no indications of relevant transporter involvement in vivo (high permeability, no active renal or biliary excretion), no further investigations were considered as needed. Lacosamide does not affect digoxin transport in vivo and the transport was not affected by the Pgp inhibitor verapamil in vitro. In vivo interaction studies showed that multiple-dose omeprazole (40 mg q.d.) increased lacosamide exposure by 19%, lacosamide slightly (9%) increased ethinylestradiol and levonogestrel exposure, did not affect the pharmacokinetics of digoxin. There was no interaction between lacosamide and metformin, valproic acid and carbamazepine. However, the interaction study with carbamazepine did not include a sufficiently long carbamazepine treatment period at the target dose for full induction to be reached. The population analysis indicated that concomitant treatment with phenytoin, phenobarbital and carbamazepine moderately decrease lacosamide exposure. • PK/PD relationship Lacosamide increases the PR interval. The effect is dose-dependent and a relationship between concentration and increase in PR interval has been found. There is one PK-PD analysis on efficacy which estimates that the plateau in response will be reached at higher lacosamide doses than indicated by the clinical efficacy data. However, the analysis is a rough estimation. Pharmacodynamics The mechanism of action for lacosamide is incompletely known but is thought to involve an enhancement of the slow inactivation of sodium channels, and possibly an interaction with collapsin response mediator protein-2 (CRMP-2), a protein involved in neuronal differentiation and control of axon outgrowth. Lacosamide has demonstrated antiepileptic activity in some rodent seizure models for generalized and complex partial-onset seizures and status epilepticus, i.e., maximal electroshock seizures (MES), hippocampal kindling, audiogenic seizures (AGS), self sustaining status epilepticus (SSSE), and in 1 chemoconvulsant-induced seizure model (for details see non-clinical section). Lacosamide has also shown effect in animal models of neuropathic pain. Administration of lacosamide in healthy subjects showed dose-dependent mild sedation. There was no evidence for extrapyramidal effects and no significant influence on the saccadic eye movement as an indicator of possible central nervous system (CNS) effects. Phase 1 trials with ECG investigation showed that lacosamide causes a dose-related increase of the PR interval. In Study SP640, the maximum mean changes on Day 6 (steady-state) were observed at 1 hour post dose and were 6.3ms, 13.6ms, and 18.2ms in the placebo, lacosamide 400mg/day, and lacosamide 800mg/day dose groups,