Pharmacokinetic interaction study between eslicarbazepine acetate and topiramate in healthy subjects

Abstract

Objective:

Combination therapy is frequently required in the management of epilepsy. The primary objective of this study was to investigate the pharmacokinetic interaction between eslicarbazepine acetate (ESL) 1200 mg once daily and topiramate (TPM) 200 mg once daily in healthy subjects.

Methods:

Multiple-dose, open-label, one-sequence study in two parallel groups of 16 healthy male volunteers. After an 8-day treatment with ESL (Group A) or TPM (Group B), ESL and TPM were co-administered for 19 days. A bioequivalence approach based on a within-subject comparison was used to investigate a potential drug–drug interaction. End/start of treatment geometric mean ratios (GMR, %) and 90% confidence intervals (90% CI) were calculated for maximum plasma concentration (C_max) and area under the plasma concentration–time curve over the dosing interval at steady-state (AUC_ss) of eslicarbazepine (ESL major active metabolite), R-licarbazepine (ESL minor active metabolite) and TPM at Day 8 and Day 27.

Results:

In Group A, eslicarbazepine GMR (90% CI) was 86.79% (81.06%; 92.94%) for C_max and 92.70% (89.21%; 96.32%) for AUC_ss. In Group B, TPM GMR (90% CI) was 81.50% (77.48%; 85.89%) for C_max and 81.81% (79.69%; 84.00%) for AUC_ss. The 90% CI of eslicarbazepine C_max and AUC_ss fell within the pre-specified bioequivalence range (80.00%; 125.00%), allowing it to be concluded that the extent of systemic exposure to eslicarbazepine was unaffected by the concomitant administration of TPM. The 90% CI for topiramate AUC_ss was borderline in relation to the pre-specified bioequivalence range and topiramate C_max fell outside the pre-specified bioequivalence range. Therefore, the extent of systemic exposure to TPM following co-administration with ESL was not formally bioequivalent to the extent of systemic exposure to TPM when TPM was administered alone. However, there was no difference between TPM elimination half-life following TPM co-administered with ESL and TPM administered alone (24.0 and 24.3 h, respectively). The bioavailability of R-licarbazepine was essentially bioequivalent. Two subjects discontinued due to adverse events. No clinical interaction appeared to be present in terms of adverse events when both drugs were given concomitantly.

Conclusion:

Concomitant administration of eslicarbazepine acetate 1200 mg once daily and topiramate 200 mg once daily showed no significant change in exposure to eslicarbazepine but an 18% decrease in exposure to topiramate, most likely caused by a reduced bioavailability of topiramate. No dose adjustment is required.

Key words::

• Drug interaction
• Eslicarbazepine
• Eslicarbazepine acetate
• Healthy subjects
• Pharmacokinetics
• Topiramate

Transparency

Declaration of funding

This trial was sponsored by BIAL (Portela & Co, S.A., S. Mamede do Coronado, Portugal). The authors from BIAL substantially contributed to the design and conception of the study and wrote the first and final versions of the manuscript, but played no role in data collection or pharmacokinetic analysis. All authors had full access to the data and substantially contributed to the interpretation of the data and the writing of the manuscript.

Declaration of financial/other relationships

T.N., L.A., J.R. and P.S. are or were employees of BIAL (the sponsor of the study) at the time of the study. The other authors are or were employees of contract research organizations contracted by the sponsor to conduct the clinical part and reporting of the study (Algorithme Pharma) or to review the pharmacokinetic data (4Health).

Peer reviewers may receive honoraria for their review work for CMRO. The peer reviewers have disclosed no relevant financial relationships.

Acknowledgements

The authors thank the healthy subjects who participated in the study and the clinical and laboratory staff of Algorithme Pharma.