Elsevier

Epilepsy Research

Volume 135, September 2017, Pages 64-70
Epilepsy Research

Evidence for a pharmacokinetic interaction between eslicarbazepine and rosuvastatin: Potential effects on xenobiotic transporters

https://doi.org/10.1016/j.eplepsyres.2017.05.005Get rights and content

Highlights

  • Rosuvastatin exposure was decreased (∼40%) with concomitant steady-state ESL.

  • The decreased rosuvastatin exposure may result from reduced oral bioavailability.

  • The reduced rosuvastatin exposure is unlikely due to increased oxidative metabolism.

  • When rosuvastatin is used with ESL, rosuvastatin dose adjustment may be necessary.

  • In healthy subjects, ESL 1200 mg QD was generally well tolerated.

Abstract

Introduction

Patients with partial-onset seizures and comorbid cardiovascular disease may concomitantly receive eslicarbazepine acetate (ESL), an antiepileptic drug, and rosuvastatin, an HMG-CoA reductase inhibitor. This study evaluated the effect of multiple-dose ESL on the pharmacokinetic (PK) parameters of a single dose of rosuvastatin in healthy subjects.

Methods

This was a Phase I, single-center, fixed-sequence, open-label study. Healthy subjects received two treatments, in sequence. Treatment A: a single 40 mg oral dose of rosuvastatin on Day 1, followed by a washout period (Days 1–4); treatment B: titration of ESL (400–800 mg once daily) on Days 5–18, followed by ESL 1200 mg once daily on Days 19–35, with a single dose of rosuvastatin (40 mg) on Day 32. Subjects then entered a 2-week follow-up period. Plasma concentrations of rosuvastatin were quantified for PK analyses. Safety and tolerability were assessed throughout the study.

Results

Thirty-three healthy subjects were enrolled and 30 completed the study. Mean rosuvastatin (standard deviation) t1/2 was similar when rosuvastatin was used concomitantly with ESL and when it was used alone (26.5 [16.3] h, and 22.4 [9.5] h, respectively). The geometric least squares mean ratios (90% confidence intervals) of rosuvastatin exposure levels between rosuvastatin used concomitantly with ESL and rosuvastatin used alone were as follows: Cmax, 64.0% (55.9–73.3%); AUC(0–∞), 63.0% (57.1–69.4%); and AUC(0–last), 60.9% (55.2–67.1%). Concomitant use of ESL and rosuvastatin was generally well tolerated.

Conclusions

Rosuvastatin exposure was 36–39% lower with steady-state administration of ESL, potentially due to reduced oral bioavailability of rosuvastatin. Consequently, when rosuvastatin is used with ESL, a rosuvastatin dose adjustment may be necessary if a clinically significant change in lipids is noted.

Introduction

It has become increasingly recognized that an array of comorbid medical conditions may affect patients with epilepsy. For example, several studies have suggested an over-representation of cardiovascular and cerebrovascular disease in patients with epilepsy compared with the general medical population (Gaitatzis et al., 2004, Janszky et al., 2009). Indeed, epidemiological studies have suggested that cardiovascular disease may be an important contributor to the increased mortality rates in patients with epilepsy compared with the general population (Ding et al., 2006, Janszky et al., 2009, Katsiki et al., 2014, Neligan et al., 2011).

Recent guidelines in the USA have underscored the importance of high potency statins, such as atorvastatin or rosuvastatin, for both primary and secondary prevention of coronary heart disease (Nayor and Vasan, 2016). In addition, use of statins in patients with epilepsy is of growing interest since the publication of preclinical data that suggest statins may improve abnormal brain electrical activity and may have anticonvulsive capabilities (Banach et al., 2014, Seker et al., 2015). Several large prescription database studies in the USA found that ∼10–40% of patients receiving an antiepileptic drug (AED) were also receiving an HMG-CoA reductase inhibitor (a statin; or had vascular diagnoses); the proportion of statin users varied with age (Gidal et al., 2009, Mintzer et al., 2014).

While the reasons underlying the increased prevalence of cardiovascular and cerebrovascular disease in epilepsy patients are likely multifactorial, the potential role of AEDs has been raised not only as a confounding factor, but also as a potential causal factor (Katsiki et al., 2014, Mintzer and Mattson, 2009). Several studies have suggested that enzyme-inducing AEDs (EIAEDs) such as carbamazepine and phenytoin might raise total cholesterol and various lipid fractions in patients with epilepsy (Mintzer et al., 2009, Nikolaos et al., 2004, Sonmez et al., 2006, Verrotti et al., 1997).

In addition to any intrinsic effects that older EIAEDs may have on lipid metabolism, the possibility of drug–drug interactions (DDIs) is also a concern. Multiple studies have demonstrated significant pharmacokinetic (PK) interactions between statins and EIAEDs such as phenytoin and carbamazepine (Bullman et al., 2011, Neuvonen, 2010, Ucar et al., 2004, Zhang, 2015). Many commonly-used statins, such as atorvastatin, lovastatin, and simvastatin, are extensively metabolized via intestinal and hepatic oxidative metabolism, which is mediated primarily via cytochrome P450 (CYP) 3A4 (Hirota and Ieiri, 2015). In addition, statins are also substrates for efflux transporters such as P-glycoprotein (ABCB1) and breast cancer resistance protein (BCRP, ABCG2), as well as uptake transporters such as OATP1B1 (SLCO1B1) (Elsby et al., 2012, Moßhammer et al., 2014); these xenobiotic transporters significantly affect the systemic exposure of statins.

Data from Candrilli and colleagues (Candrilli et al., 2010) suggest that PK interactions between EIAEDs and statin compounds may have clinical consequences, such as complicating lipid management in patients with epilepsy (Brodie et al., 2013). One might therefore presume that drug combinations including AEDs with less enzyme inducing potential, together with a statin that does not undergo oxidative drug metabolism, might mitigate possible drug interactions between EIAEDs and statin compounds.

Eslicarbazepine acetate (ESL) is a dibenzazepine carboxamide with potentially important structural and metabolic differences to older AEDs of the same class (e.g. carbamazepine and oxcarbazepine) (Almeida and Soares-da-Silva, 2007, Bialer and Soares-da-Silva, 2012, Perucca et al., 2007). ESL is rapidly, and completely, converted to S-licarbazepine (eslicarbazepine); small fractions of eslicarbazepine are further converted to the R-licarbazepine enantiomer, and to oxcarbazepine (Almeida and Soares-da-Silva, 2007, Bialer and Soares-da-Silva, 2012). Data from the pre-clinical and clinical ESL development programs suggest that eslicarbazepine has potential to induce CYP3A4. With respect to PK interactions between ESL and statins, a 41–61% reduction in plasma exposure of simvastatin (a CYP3A4 substrate) and its active metabolite (β-hydroxyacid simvastatin) was observed when a single dose of simvastatin (80 mg) was administered after receiving ESL 800 mg/day for 14 days (Bialer and Soares-da-Silva, 2012).

Rosuvastatin is one of the most recently approved statins and has potential advantages over other statins in terms of potency, bioavailability and PK profile (Calza, 2009, Toth and Dayspring, 2011, White, 2002). Oral systemic availability of rosuvastatin is ∼20% (Calza, 2009). Rosuvastatin is unlike other statins in being quite hydrophilic and not extensively metabolized by the CYP isozyme system. In addition, rosuvastatin is excreted largely unchanged (Martin et al., 2003). Only 10% of a radiolabeled dose is recoverable as metabolite and most of the major metabolite is produced by the activity of CYP2C9 (Crestor® Prescribing Information, 2003; McTaggart, 2003, Toth and Dayspring, 2011). These properties suggest that CYP mediated drug interactions are unlikely to be clinically relevant for rosuvastatin. Given the above PK considerations related to concomitant use of statins and EIAEDs, rosuvastatin might be considered a logical option for ESL-treated patients who require statin treatment.

Thus, the primary objective of this Phase I study was to investigate whether oral administration of ESL (1200 mg once daily [QD]) affected the PK parameters of a single dose of rosuvastatin (40 mg); a secondary objective was to investigate safety and tolerability outcomes when these drugs were used together.

Section snippets

Study design

This was a Phase I, single-center, fixed-sequence, open-label study in healthy subjects, lasting approximately 10 weeks. After a 3-week screening period, subjects received study medication(s) in two treatment periods over 5 weeks (Table 1). During treatment period A, subjects received only a single, oral dose of 40 mg rosuvastatin on Day 1, followed by a washout period (Days 1–4). In treatment period B (Days 5–35) ESL was titrated over Days 5–18 (1 × 400 mg QD for 7 days from Day 5, then 2 × 400 mg QD

Subjects

Of 69 subjects who were screened, 33 enrolled and received at least one dose of study medication, and 30 completed the study (Table 2). Both the ITT and the PK population comprised 33 subjects. Two subjects had no rosuvastatin PK data for Day 32, so were excluded from statistical analysis of the primary and secondary PK endpoints, which required non-missing values for all patients. Baseline characteristics and demographics were the same across both treatment periods (Table 3). Concomitant

Discussion

The results of this study suggest that concomitant use of ESL may lead to an overall reduction in rosuvastatin systemic exposure. Specifically, rosuvastatin exposure (least squares means for Cmax, AUC(0–∞), and AUC(0–last)) decreased by between 36% and 39% with concomitant steady-state ESL use. Consequently, when rosuvastatin is used with ESL, a rosuvastatin dose adjustment should be considered if a clinically significant change in lipids is noted. While overall systemic exposure to

Conclusion

The use of clinically relevant doses of ESL with rosuvastatin resulted in a decrease in rosuvastatin systemic exposure, potentially due to a reduced oral bioavailability of rosuvastatin. Due to the absence of significant CYP interactions, the decrease in rosuvastatin exposure is unlikely to be driven by increased oxidative metabolism, and may be due, at least in part, to an interaction involving human uptake or efflux membrane transporters which mediate the disposition of rosuvastatin. However,

Funding

This study was supported by Sunovion Pharmaceuticals, Inc. Sunovion Pharmaceuticals Inc. was involved in the design and conduct of the clinical studies, in the collection, analysis and interpretation of the data, in the writing of the report, and in the decision to submit the article for publication.

Disclosures

BEG received consulting fees from Upsher-Smith, Eisai and Sunovion Pharmaceuticals Inc. SM received speaker’s honoraria from GSK and consultancy fees from UCB Pharma, Upsher-Smith and Eisai. MS received consultancy fees from Sunovion Pharmaceuticals Inc. RS has no conflict to declare. JK is currently employed by Indivior Inc. and was employed by Sunovion Pharmaceuticals Inc. at the time of the study. DB, TG and SS are currently employed by Sunovion Pharmaceuticals Inc.

Acknowledgments

Medical writing support was funded by Sunovion Pharmaceuticals, Inc. and was provided by Mallory Gough, Ph.D., of FireKite, an Ashfield company, part of UDG Healthcare plc. Matthias Schwab is supported by the Roberts Bosch Stiftung, Stuttgart, Germany.

References (43)

  • E. Perucca et al.

    Pharmacokinetics of eslicarbazepine acetate at steady-state in adults with partial-onset seizures

    Epilepsy Res.

    (2011)
  • F.B. Seker et al.

    HMG-CoA reductase inhibitor rosuvastatin improves abnormal brain electrical activity via mechanisms involving eNOS

    Neuroscience

    (2015)
  • T. Zhang

    Physiologically based pharmacokinetic modeling of disposition and drug–drug interactions for atorvastatin and its metabolites

    Eur. J. Pharm. Sci.

    (2015)
  • M. Bialer et al.

    Pharmacokinetics and drug interactions of eslicarbazepine acetate

    Epilepsia

    (2012)
  • M.J. Brodie et al.

    Enzyme induction with antiepileptic drugs: cause for concern?

    Epilepsia

    (2013)
  • J. Bullman et al.

    Effects of lamotrigine and phenytoin on the pharmacokinetics of atorvastatin in healthy volunteers

    Epilepsia

    (2011)
  • L. Calza

    Long-term use of rosuvastatin: a critical risk benefit appraisal and comparison with other antihyperlipidemics

    Drug Healthc. Patient Saf.

    (2009)
  • C. Crestor® Prescribing Information

    Crestor

    (2003)
  • R. Elsby et al.

    Understanding the critical disposition pathways of statins to assess drug–drug interaction risk during drug development: it's not just about OATP1B1

    Clin. Pharmacol. Ther.

    (2012)
  • R. Elsby et al.

    Solitary inhibition of the breast cancer resistance protein efflux transporter results in a clinically significant drug–drug interaction with rosuvastatin by causing up to a 2-fold increase in statin exposure

    Drug Metab. Dispos.

    (2016)
  • A. Gaitatzis et al.

    The epidemiology of the comorbidity of epilepsy in the general population

    Epilepsia

    (2004)
  • Cited by (9)

    • Markers of bone and lipid metabolism with eslicarbazepine acetate monotherapy

      2019, Epilepsy Research
      Citation Excerpt :

      With respect to lipids, some patients were also taking 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (–EIAED subgroup, 12%; +EIAED subgroup, 10%). However, the lipid-lowering effect of these agents also appears to be impacted by EIAEDs (Gidal et al., 2009; Mintzer et al., 2018a) and not by ESL (which appears to have only a pharmacokinetic, not a pharmacodynamic, interaction with HMG-CoA reductase inhibitors) (Gidal et al., 2017; Mintzer et al., 2018b), so that one would expect the same direction of lipid changes when EIAEDs are replaced by ESL. The similarity of our lipid data to other published work also suggests that this may not have been a major factor in our findings.

    • Effects of adjunctive eslicarbazepine acetate on serum lipids in patients with partial-onset seizures: Impact of concomitant statins and enzyme-inducing antiepileptic drugs

      2018, Epilepsy Research
      Citation Excerpt :

      As and its active entity are CYP3A4 substrates, this interaction is most likely due to CYP3A4 induction by ESL (Bialer and Soares-da-Silva, 2012; Falcão et al., 2013). The latter interaction is more curious, as rosuvastatin undergoes minimal enzymatic metabolism, and the nature of the ESL-rosuvastatin interaction is not well understood at present (Gidal et al., 2017). Moreover, the clinical impact of reduced statin exposure, while assumed, has never been directly demonstrated in any study of any AED.

    • Antiseizure Medication Interactions: A Clinical Guide, Fourth Edition

      2022, Antiseizure Medication Interactions: A Clinical Guide, Fourth Edition
    View all citing articles on Scopus
    1

    Clinical Pharmacology, Infinity Pharmaceuticals, Inc., 780 Memorial Drive, Cambridge, MA 02139, USA.

    View full text