What this study adds
- In
this review, we identified weight, renal function, and co-administered
medications as covariates that most likely to influence oxcarbazepine
pharmacokinetics.
- Comparing to adult patients, paediatric patients show a higher
clearance per kilogramme weigh which lead to higher doses per
kilogramme; they may also require therapeutic drug monitoring owing to
a larger variation in clearance.
- Further studies are essential to evaluate oxcarbazepine
pharmacokinetics in special populations such as infants.
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.