What this study adds
Abstract
AimThis is the first review to summarize the population pharmacokinetic studies of oxcarbazepine and explored the significant covariates that may have an impact on the dosage regimen and clinical use of oxcarbazepine.
Methods PubMed and Embase databases were searched before 31 October 2020, and references of all selected studies were further screened to identify the pertinent population pharmacokinetic studies of oxcarbazepine. Relevant information about the identified population pharmacokinetic studies was summarised, and the quality of the reports was evaluated. Moreover, studies among infant, children, and adult patients were compared.
Results Twelve studies were included: seven studies enrolled paediatric patients only; two enrolled both paediatric and adult patients; and two enrolled adult patients only. The apparent clearance per weight for children (median: 0.0505 L/h/kg, range: 0.016-0.084) and infants (0.078 L/h/kg) were higher than that for adults (median: 0.036 L/h/kg, range: 0.029-0.06). Furthermore, children had a larger variation on clearance compared to adults. Weight, co-administration with enzyme-inducing antiepileptic drugs, and renal function were found to significantly affect clearance of 10-hydroxycarbazepine.
Conclusion The oxcarbazepine dose regimen was dependent on weight, co-administration with enzyme-inducing medications, and renal function. Further study is essential to explore the pharmacodynamics in epilepsy patients and pharmacokinetics of oxcarbazepine in infants.
Introduction
Oxcarbazepine (OXC) is a commonly used anti-epilepsy drug with a chemical structure similar carbamazepine (CBZ) [1]. It was approved by the Food and Drug Administration as a monotherapy and adjunctive therapy for partial seizures in adult and paediatric patients. It prevents seizures mainly through the blockage of voltage-dependent sodium channels, similar to CBZ [2]. Owing to its comparable effectiveness but better safety and tolerability, OXC is usually used as an alternative to CBZ in patients who are unable to tolerate CBZ [3, 4].
Oxcarbazepine is completely absorbed (>95%) and quickly transformed to its active metabolite 10-hydroxycarbazepine (MHD) by cytosolic enzymes after oral administration [5, 6]. Owing to its rapid metabolism, OXC has a much lower area under the concentration-time curve (AUC) than MHD in vivo (16.05 vs. 215.52 μg·h/ml) [7]. Thus, the effectiveness of OXC is mainly determined by measuring MHD concentration [8]. Following OXC administration, the concentration of MHD reaches a peak in approximately 2–4 h [9]. MHD has a low protein binding rate (~39%) [10], and its volume of distribution (Vd) is between 0.3 and 0.8 L/kg [6]. MHD is excreted unchanged in the urine or eliminated in conjugation with uridine diphosphate-glucuronosyltransferase (UGT), with only a small fraction (4%) being oxidised to its dihydroxy derivative (DHD) [5, 11].
In special patient populations, such as patients with renal insufficiency, patients who are co-administered OXC with enzyme-inducing antiepileptic drugs (EIAEDs) as well as the elderly and infants, the pharmacokinetics (PK) of MHD varies greatly [12]. Rouan et al. [12] reported that the mean AUC0-168 h of MHD in patients with severe renal impairment was around 2–2.5 times higher than that in healthy subjects after receiving a single oral dose of OXC. A high exposure to OXC is associated with an increased incidence of side effects [13]; therefore, to ensure effectiveness and safety, therapeutic drug monitoring (TDM) is essential for patient-specific dose adjustment [14]. Ideally, individualised doses need to be developed at the beginning of treatment; however, the current TDM approach is usually implemented during the course of the treatment. The population pharmacokinetic (PPK) approach has been used to identify significant covariates that influence PK and is often used in clinical practice through Bayesian forecasting to develop individualised therapy at the beginning and even during the course of treatment [15, 16].
Despite the reports of PPK study are numerous, no research has been conducted to review the PPK of MHD. Analysing and understanding the significant covariates and their relationship in different patient populations is critical for the development of appropriate regimens for individualised therapy. In this review, we aim to summarise the significant covariates affecting PK, identify unexplored covariates, and provide evidence for the model informed of OXC.