Population pharmacokinetics of oxcarbazepine and its metabolite 10-hydroxycarbazepine in healthy subjects

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Abstract

Oxcarbazepine is indicated for the treatment of partial or generalised tonic-clonic seizures. Most of the absorbed oxcarbazepine is converted into its active metabolite, 10-hydroxycarbazepine (MHD), which can exist as R-(−)- and S-(+)-MHD enantiomers. Here we describe the influence of the P-glycoprotein (P-gp) inhibitor verapamil, on the disposition of oxcarbazepine and MHD enantiomers, both of which are P-gp substrates. Healthy subjects (n = 12) were randomised to oxcarbazepine or oxcarbazepine combined with verapamil at doses of 300 mg b.i.d. and 80 mg t.i.d., respectively. Blood samples (n = 185) were collected over a period of 12 h post oxcarbazepine dose. An integrated PK model was developed using nonlinear mixed effects modelling using a meta-analytical approach. The pharmacokinetics of oxcarbazepine was described by a two-compartment model with absorption transit compartments and first-order elimination. The concentration-time profiles of both MHD enantiomers were characterised by a one-compartment distribution model. Clearance estimates (95% CI) were 84.9 L/h (69.5–100.3) for oxcarbazepine and 2.0 L/h (1.9–2.1) for both MHD enantiomers. The volume of distribution was much larger for oxcarbazepine (131 L (97–165)) as compared to R-(−)- and S-(+)-MHD (23.6 L (14.4–32.8) vs. 31.7 L (22.5–40.9), respectively). Co-administration of verapamil resulted in a modest increase of the apparent bioavailability of oxcarbazepine by 12% (10–28), but did not affect parent or metabolite clearances. Despite the evidence of comparable systemic levels of OXC and MHD following administration of verapamil, differences in brain exposure to both moieties cannot be excluded after P-glycoprotein inhibition.

Introduction

Oxcarbazepine is indicated as monotherapy or adjunctive therapy in the treatment of partial and generalised tonic-clonic seizures in adults and children (Verrotti et al., 2010, Wellington and Goa, 2001). Oxcarbazepine undergoes rapid pre-systemic reduction metabolism resulting in the formation of its active monohydroxy metabolite 10-hydroxycarbazepine (MHD). MHD has a chiral centre yielding two enantiomers (S-(+)- and R-(−)-MHD), which show similar effects in vitro and in animal models of anticonvulsant activity (May et al., 2003, Schmutz et al., 1994, Volosoc et al., 1999, Volosoc et al., 2000). The absolute bioavailability of oxcarbazepine assessed from MHD plasma data is 99% (Flesch et al., 2011) and its apparent volume of distribution (V/F) is 7.8 to 12.5 L/kg in epileptic patients (Dickinson et al., 1989). Protein binding is approximately 59% for oxcarbazepine (Patsalos et al., 1990), whereas even lower values were found for R-(−)-MHD and S-(+)-MHD (20 and 23%, respectively) (Fortuna et al., 2010). Most of the administered dose of oxcarbazepine (79%) is eventually excreted through the kidneys as glucuronide conjugate MHD and as unchanged MHD (Flesch et al., 2011). Less than 1% is excreted as unchanged oxcarbazepine and 9% as inactive glucuronide conjugates of oxcarbazepine (Tecoma, 1999, Wellington and Goa, 2001). In addition, about 4% of MHD is oxidised with formation of the inactive metabolite 10,11-dihydro-10,11-trans-dihydroxycarbazepine (DHD) (Flesch et al., 2011, Paglia et al., 2007, Schütz et al., 1986, Volosoc et al., 2000).

The extensive metabolic conversion to MHD is supported by data in healthy subjects who were administered a single 250-mg MHD infusion over 30 min. In these subjects, volume of distribution estimates were found to be 9.0 and 8.4 L for R-(−)-MHD and S-(+)-MHD, respectively (Flesch et al., 2011).In addition, enantioselective elimination was observed, as indicated by mean clearance (CL) values of 4.3 L/h for R-(−)-MHD and 3.1 L/h for S-(+)-MHD. These differences result in plasma accumulation of the S-(+)-MHD enantiomer relatively to the other enantiomer, with area under the plasma concentration vs. time curve (AUC) of 119.5 vs. 166.8 μmol·h/L. Similar findings were observed after oral administration of oxcarbazepine to healthy subjects, with AUC values of 63.9 μmol·h/L for R-(−)-MHD and 241.0 for S-(+)-MHD μmol·h/L (Flesch et al., 2011).

Previous studies have shown that oxcarbazepine and MHD are substrates of the P-glycoprotein (P-gp) efflux transporter (Clinckers et al., 2005, Clinckers et al., 2008, Zhang et al., 2011). P-gp can have major influence on the processes of absorption, distribution and elimination of drugs (Marzolini et al., 2004). P-gp may also affect the absorption rate and bioavailability of drugs administered orally (Estudante et al., 2013, Fortuna et al., 2012, Shugarts and Benet, 2009). On the other hand, the expression of P-gp in the blood brain-barrier limits the penetration of (substrate) moieties into the central nervous system (CNS), thereby potentially reducing their pharmacological effects (Yamamoto et al., 2016). Changes in the expression of P-gp in the brain are associated with differences in antiepileptic drug levels in the brain parenchyma. It has also been shown that seizures in mice increase the MDR1 expression in the hippocampus and reduce the brain/plasma concentration ratios of phenytoin (Marchi et al., 2005, Rizzi et al., 2002). Considering the possible involvement of the P-gp over-expression on the mechanisms underlying pharmacoresistance to epilepsy treatment, the inhibition of P-gp function by selective blockers may become a viable strategy to facilitate the distribution of drugs into the CNS. However, from a clinical safety perspective, implementation of such a strategy requires further understanding of the impact of P-gp inhibition on systemic exposure. Verapamil is a known P-gp inhibitor in various tissues including the brain (Clinckers et al., 2008), gut (Lemma et al., 2006) and liver (Lemma et al., 2006). Moreover, verapamil was found to potentiate the anticonvulsant activity of oxcarbazepine in an experimental seizure model in rats. This effect was associated with increased MHD levels in the rat brain (Clinckers et al., 2005, Clinckers et al., 2008). The current study aimed to characterise the pharmacokinetics of oxcarbazepine and the MHD enantiomers in the presence and absence of verapamil in humans using a model-based population pharmacokinetic approach. This investigation will allow the assessment of the impact of P-gp inhibition on systemic drug exposure and provide the basis for further investigation of the use of oxcarbazepine in combination with P-gp inhibitors in patients.

Section snippets

Clinical trial protocol

Details of the clinical trial used in this analysis have been described previously (de Jesus Antunes et al., 2016). Briefly, 12 (8 female and 4 male) healthy subjects were enrolled into an open label, randomised, two-way crossover pharmacokinetic study. The study protocol was approved by the local research ethics committee. Individual subjects were enrolled into the study after signing an informed consent form. Only non-obese, non-smokers healthy adult subjects with clinical laboratory results

Results

A total of 185 plasma samples were included in this analysis, with a mean number of 16 samples per subject. An initial non-compartmental analysis of the data (Table 2) indicated rapid absorption of oxcarbazepine (tmax 0.9–1.2 h) and conversion into MHD enantiomers (tmax 2.8–3.5 h) (de Jesus Antunes et al., 2016). The disposition of oxcarbazepine and rapid conversion into MHD enantiomers is depicted in Fig. 1. By contrast, MHD elimination was slow (t1/2 11.7–13.5 h). The administration of verapamil

Discussion

Effective treatment and management of epileptic seizures remains a challenging objective in clinical practice (Piana et al., 2014). Whilst variation in response to treatment is often assigned to the heterogeneity in the underlying disease progression and other clinical and genetic factors, interindividual differences in drug exposure also result in treatment failure. Population modelling approaches offer an opportunity to assess drug disposition properties taking into account pharmacokinetic

Conclusion

An integrated population model has been identified that describes the pharmacokinetics of oxcarbazepine, including the formation and disposition of its active metabolite enantiomers. Concurrent estimation of clearances suggested that MHD formation may be rate limiting. As such, this process represents a critical step for the onset of the antiepileptic effects of MHD. Verapamil co-administration was associated with a modest increase of 12% in the relative bioavailability, but not on any other

Competing interests

The authors declare no conflict of interest.

Acknowledgments

The authors are grateful to Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Grant numbers: 2011/06887-1 and 2012/18175-9), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FAEPA) for their financial support.

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