Effect of repeated administration of eslicarbazepine acetate on the pharmacokinetics of simvastatin in healthy subjects

Highlights

• ESL significantly decreased the exposure to simvastatin and simvastatin-β-hydroxyacid.

• This effect is most likely mediated by an induction of CYP3A4 metabolism.

• Dose adjustment of simvastatin may be required when used concomitantly with ESL.

Summary

Objective

To investigate the effect of eslicarbazepine acetate (ESL) on the pharmacokinetics of simvastatin (SMV), a known CYP3A4 substrate, in healthy subjects.

Methods

Single centre, two-way cross-over, randomized, open-label study in 24 healthy volunteers. The volunteers received an oral single-dose of SMV 80 mg on two occasions (once administered alone and once after treatment with an oral once-daily dose of 800 mg of ESL for 14 days), separated by a wash-out period of 3 weeks or more. The analysis of variance (ANOVA) was used to test for differences between Test (SMV under co-administration with ESL) and Reference (SMV administered alone) treatments for AUC_0−∞, AUC_0−t and C_max of SMV and SMV-acid.

Results

Mean systemic exposure (AUC) measurements for both SMV and SMV-β-hydroxyacid (SMV-acid) were up to 54% lower during ESL use. The Test/Reference geometric mean ratios (GMR) (90% CI) for the AUC_0−t of SMV and SMV-acid were 46% (38%; 55%) and 49% (44%; 55%), respectively. Mean peak concentrations (C_max) of both SMV and SMV-acid were reduced by 60% and 41%, respectively, when SMV was administered with ESL.

Conclusions

A significant effect of repeated ESL administration on the pharmacokinetics of SMV and its metabolite SMV-acid was observed. Therefore, dose adjustment of SMV may be required when used concomitantly with ESL, if a clinically significant change in lipids is noted.

Introduction

Epilepsy affects more than 50 million adults and children worldwide. The mean prevalence of active epilepsy is approximately 6–10 per 1000 of the general population with an annual incidence of 40–70 per 100,000 (WHO, 2009). Anti-epileptic drugs (AEDs) are the major therapeutic intervention for subjects with epilepsy. Recent studies have shown that up to 70% of newly diagnosed subjects with epilepsy can be successfully treated; however, up to 30% may not respond to current therapy (WHO, 2009). This lack of seizure control leads to a combination therapy and careful consideration should be given to the consequences of any drug interaction between the various AEDs. Even when using AED monotherapy, patients may not be free of the consequences of potential drug interactions, as in many patients, concomitant diseases or other conditions may require co-administration of non-AED drugs (Patsalos et al., 2002, Johannessen Landmark and Patsalos, 2012).

Clinically relevant drug interactions are now identified based on a rational approach subsequent to the discovery and characterization of the enzyme systems responsible for the metabolism of AEDs, as these enzymes are the potential target for interference with concomitant drugs (Patsalos et al., 2002). Consequently, a comprehensive characterization of pharmacokinetic properties of AEDs is of fundamental importance.

Enzymatic biotransformation and metabolism is the principal determinant of the pharmacokinetic properties of most AEDs (Sander, 2004). The metabolic pathways of AEDs are normally achieved via oxidative metabolism and/or glucuronidation. Oxidative metabolism occurs via the cytochrome P450 (CYP) isoenzyme system. Although this system has more than 50 enzymes, six of them metabolize 90% of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6 (Lynch and Price, 2007).

Eslicarbazepine acetate (ESL) is a once-daily (QD) anticonvulsant approved in 2009 by the European Medicines Agency (EMA) as adjunctive therapy in adults with partial-onset seizures (POS), with or without secondary generalization (Almeida et al., 2009, Rauchenzauner and Luef, 2011, Patsalos and Berry, 2012). ESL is structurally distinct from carbamazepine (CBZ) and oxcarbazepine (OXC) although the three compounds are dibenz[b,f]azepine derivatives (Benes et al., 1999). This molecular distinction results in differences in metabolism (Hainzl et al., 2001). CBZ and ESL do not share any common metabolite and, contrarily to CBZ, ESL is not susceptible to metabolic auto-induction (Almeida et al., 2009, Bialer and Soares-da-Silva, 2012).

Following oral administration, ESL undergoes extensive first pass hydrolysis to its major active metabolite eslicarbazepine (also known as (S)-licarbazepine) (Falcao et al., 2007, Almeida et al., 2008a, Almeida et al., 2008b, Maia et al., 2008, Perucca et al., 2011), which represents approximately 95% of circulating active moieties and is believed to be responsible for its antiseizure effects (Pekcec et al., 2011, Pires et al., 2011, Sierra-Paredes et al., 2011, Soerensen et al., 2011, Torrao et al., 2011) most likely though blockade of voltage-gated sodium channels and type T calcium channels (Brady et al., 2011, Hebeisen et al., 2011). Plasma levels of ESL usually remain below the limit of quantification. Minor active metabolites are (R)-licarbazepine and oxcarbazepine. Steady-state of eslicarbazepine plasma concentrations are reached within 4–5 days of QD dosing (Almeida and Soares-da-Silva, 2004, Almeida et al., 2005). Inactive metabolites in plasma are the glucuronic acid conjugates of ESL, eslicarbazepine, (R)-licarbazepine and oxcarbazepine, all found in minor amounts (Almeida et al., 2008b, Maia et al., 2008). More than 90% of an oral ESL dose is recovered in urine as ESL metabolites (Almeida et al., 2008b, Maia et al., 2008).

In human liver microsomes, eslicarbazepine appeared to have minimal or no inhibitory effect on the activity of CYP isoforms – CYP1A2, CYP2A6, CYP2B6, CYP2D6 and CYP2E1, CYP3A4, and CYP4A9/11 – as well as on the enzymes UGT1A1 and UGT1A6 and the epoxide hydrolase. A moderate inhibitory effect was found on the CYP2C9 and CYP2C19 activity. Studies with eslicarbazepine in fresh human hepatocytes showed no induction of CYP1A2, CYP3A4, and phase II hepatic enzymes involved in glucuronidation and sulfation (Bialer and Soares-da-Silva, 2012). In humans, administration of ESL concomitantly with a combined steroid oral contraceptive containing ethinylestradiol and levonorgestrel was shown to decrease the plasma concentrations of both hormonal components, presumably by stimulating their CYP3A-mediated metabolism (Almeida and Soares-da-Silva, 2007, Bialer and Soares-da-Silva, 2012).

Given the potential for pharmacokinetic interaction between ESL and CYP3A4 the primary objective of this study was to evaluate the effect of repeated ESL administration on the pharmacokinetics of simvastatin (SMV), a known CYP3A4 substrate.