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\begin{document}

\title{Population Pharmacokinetics of Oxcarbazepine: A Systematic Review}



\author[1]{Yue-ting Chen}%
\author[2]{chenyu wang}%
\author[1]{Yi-wei Yin}%
\author[3]{Ziran Li}%
\author[2]{Wei-wei Lin}%
\author[1]{Min Zhu}%
\author[1]{Zheng Jiao}%
\affil[1]{Shanghai Jiao Tong University Affiliated Chest Hospital}%
\affil[2]{Affiliation not available}%
\affil[3]{Huashan Hospital Fudan University}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Aim This 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.%
\end{abstract}%



\sloppy


\textbf{Population Pharmacokinetics of Oxcarbazepine: A Systematic
Review}

Yue-ting Chen \textsuperscript{1, 2\#}; Chen-yu Wang
\textsuperscript{1\#}; Yi-wei Yin \textsuperscript{1\#}; Zi-ran Li
\textsuperscript{3}; Wei-wei Lin \textsuperscript{4}; Min Zhu
\textsuperscript{1,2}; Zheng Jiao\textsuperscript{1*}

\textsuperscript{1}Department of Pharmacy, Shanghai Chest Hospital,
Shanghai Jiao Tong University, Shanghai, China;\textsuperscript{2}School
of Basic Medicine and Clinical Pharmacy, China Pharmaceutical
University, Nanjing, China; \textsuperscript{3}Department of Pharmacy,
Huashan Hospital, Fudan University, Shanghai,
China;\textsuperscript{4}Department of Pharmacy, The First Affiliated
Hospital, Fujian Medical University, Fuzhou, China.

\# Yue-ting Chen, Chen-yu Wang and Yi-wei Yin should be considered joint
first author.

\textbf{*Corresponding author:}

Zheng Jiao, Professor

Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong
University

241 Huaihai West Road, Shanghai, China, 200030

E-mail: jiaozhen@online.sh.cn;

\textbf{Running head:} PPK review of Oxcarbazepine

\textbf{Keywords:} Oxcarbazepine; 10-hydroxycarbazepine; Population
pharmacokinetic; epilepsy; Nonlinear mixed effect modelling

\textbf{Number of words in main text:} 3290

\textbf{Number of words in abstract:} 202

\textbf{Number of tables:} three tables and one supplementary file

\textbf{Number of figures:} 4

\textbf{ORCID}

Zheng Jiao: https://orcid.org/0000-0001-7999-7162

Yue-ting Chen: https://orcid.org/0000-0001-9911-2181

Chen-yu Wang: https://orcid.org/0000-0003-1808-361X

Yin-yi Wei: https://orcid.org/0000-0002-1914-7577

Zi-ran Li: https://orcid.org/0000-0001-6740-6003

Min Zhu: https://orcid.org/0000-0001-6963-1220

\textbf{What is already known about this subject}

Oxcarbazepine is commonly used as monotherapy or adjunctive therapy for
partial seizures.\emph{In vivo} , it rapidly transforms to
10-hydroxycarbazepine,an active metabolite that deliveries majority
antiepileptic effect.

Due to the high pharmacokinetic variability of 10-hydroxycarbazepine,
many population pharmacokinetic models have been developed to optimise
the dosing~regimen~of~oxcarbazepine. However, the published population
pharmacokinetics information has not been reviewed.

\textbf{What this study adds}

\begin{itemize}
\tightlist
\item
  In this review, we identified weight, renal function, and
  co-administered medications as covariates that most likely to
  influence oxcarbazepine pharmacokinetics.
\item
  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.
\item
  Further studies are essential to evaluate oxcarbazepine
  pharmacokinetics in special populations such as infants.
\end{itemize}

\textbf{Abstract}

\textbf{Aim}This 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.

\textbf{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.

\textbf{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.

\textbf{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.

\textbf{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 (\textgreater{}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 \emph{in vivo} (16.05 vs. 215.52 \selectlanguage{greek}μ\selectlanguage{english}g\selectlanguage{ngerman}·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 (\textasciitilde{}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 AUC\textsubscript{0-168 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.

\textbf{2. Methods}

\textbf{2.1 Search Strategy}

The PubMed and Embase databases were used to systematically search for
articles on PPK of OXC published before 31 October 2020 followed the
principles of the Preferred Reporting Items for Systematic Reviews and
Meta-analyses (PRISMA) statement. The search terms used included
``oxcarbazepine'', ``oxcarbamazepine'', ``ocbz'', ``oxtellar'', or
``trileptal'' and ``population pharmacokinetic'', ``pharmacokinetic
modeling'', ``nonlinear mixed effect model'', ``NONMEM'', ``Pmetrics'',
``WINNONMIX'', ``ADAPT'', ``P-PHARM'', ``nlmixed'', ``NLME'',
``USC*PACK'', or ``MONOLIX''. Besides, references of all included
studies were searched.

All the relevant articles selected from the databases and reference
lists were screened to evaluate their eligibility for inclusion
according to the following criteria: target group of studies was human;
OXC was the study drug; PPK analysis was conducted in the study; and the
study was published in English. A study was excluded if it was a review
or external evaluation article; the data presented overlapped with
previous studies but with smaller sample sizes; or the PK parameters
were incomplete. Two independent authors screened the title and
abstracts as well as the full-text of each article to determine their
eligibility. Discrepancies were resolved by a third senior investigator.

\textbf{2.2 Evaluation of Literature Quality}

The quality of the PPK report was evaluated according to previous
guidelines of PK reports (Kanji et al. {[}17{]} and Jamsen et al.
{[}18{]}) that assist in transparent and complete reporting. A checklist
with 24 items was developed to summarise the key points of the report.
All items were categorised into five sections: the title and abstract,
background and introduction, methods, results, and discussion and
conclusion, according to their relevance to the sections of the research
report.

If there was a description in the paper that conforms to the criterion,
the scoring item will be counted as 1 point. If it was not reported,
zero points were given. Each identified study was evaluated based on
these criteria. Compliance of the included PPK studies was reported as a
proportion. The compliance rate was calculated as follows:

\begin{equation}
\text{compliance\ rate\ }\left(\%\right)=\frac{\text{sum\ of\ reported\ items}}{\text{sum\ of\ all\ items}}\times 100\%\nonumber \\
 \end{equation}

\textbf{2.3 Data Extraction}

A standardised data collection was used to extract the relevant
information from each eligible study as follows: patient
characteristics, such as age, weight, and laboratory~test, ; the study
design, such as research types, quantity of subjects and observations;
dose regimens; OXC formulation; and PPK study information such as data
analysis software and algorithm, model strategies, final PK parameters,
and tested and significant covariates.

\textbf{2.4 Study Comparison}

We developed virtual patients with different age: infants (10 kg,
1-year-old) taking 300 mg OXC every 12 h (q12h), children (30 kg, 10
years old) taking 300 mg OXC q12h, and adults (70 kg, 40 years old)
taking 600 mg OXC q12h. The concentration--time profiles in virtual
patients were drew on the basis of the restored PPK model and study
population in each included study. They received multiple doses of OXC
alone and achieve stable state. The sex of the virtual patient was
selected as male.

The identified covariates effect on clearance (CL) in the included
studies was analysed and showed by a forest map. The CL change less than
between 80\%-125\% was not considered to have a significant clinical
correlation {[}19{]}. For binary covariates such as co-administration
with medications, we use 0 for monotherapy and 1 for co-administration
with medications. For continuous covariates that were included in only
one model, we used the same range values as the study. For continuous
covariates included in multiple studies, we scaled them to the same
range for comparison. The effect of each covariate on CL was shown as
the ratio of CL in the range of the covariate divided by the typical CL
value in each study.

The simulation was conducted using NONMEM (version 7.4; ICON Development
Solutions, Ellicott City, MD, USA) software. R (version 3.5.1;
http://www.r-project.org/) was used to generate the concentration--time
plots and forest plots.

\textbf{3. Results}

\textbf{3.1 Study Identification}

A total of 155 articles were selected: 87 articles were selected from
PubMed; 67 articles from the Embase database; and one article from the
references of selected articles. After initial screening, 16 full-text
studies were assessed for eligibility. One study was excluded because
the final PK parameters were not presented {[}20{]}, and two were
excluded because of language {[}21, 22{]}. In addition, the study
conducted by Sallas et al. {[}23{]} was excluded because the study data
overlapped with that of Sugiyama et al. {[}24{]}. Finally, 12 articles
were included in the study (\textbf{Fig. 1} ).

\textbf{3.2 Evaluation of Literature Quality}

According to the guidelines, we summarised the quality of OXC PPK
studies based on 35 items, as outlined in \textbf{Table 1} . Compared
with that of the PPK articles published between 2005 and 2013, the
quality of PPK studies published between 2014 and 2019 significantly
improved {[}compliance rate median (range): 71.4\% (68.6\%--71.4\%) vs.
94.3\% (85.7\%--97.1\%){]}. Generally, prospective studies show better
compliance than retrospective studies; however, the prospective study by
Northam et al. {[}25{]} had a compliance rate of only 73.5\%. This may
be due to the lack of a standard reporting guide published at that time.

After the guidelines were published, the quality of PPK study reports
improved over time. Nonetheless, several studies still have compliance
rate of less than 60\%, which included deficiencies in the description
of sample, statistical methods and software, and methods for handling
missing data.

\textbf{3.3 Study Characteristics}

The included studies were published from 2005 to 2019. The total
quantity of subjects in included articles between 12 and 573. Most PPK
analysis was performed in patients with epilepsy {[}24, 26-33{]}, and
only Antunes et al. {[}34{]} enrolled healthy subjects. One study was
conducted only in infants {[}25{]}, seven studies were conducted in
children {[}24, 25, 27, 28, 30-32{]}, two studies included both children
and adults {[}26, 33{]}, and two studies only enrolled adults {[}29,
34{]}. Subjects in all the included studies were administered OXC
orally, with doses ranging from 75 to 1800 mg/d. In most studies, sparse
sampling was employed, with 1 to 4 samples collected per individual.
Detailed characteristics of all included studies were listed
in\textbf{Table 1} .

The PPK analyses were all conducted using population modelling software,
including NONMEM (Icon, Dublin, Ireland) {[}24-26, 29-31, 34, 35{]},
Phoenix NLME (Certara L.P. Pharsight, St. Louis, MO, USA) {[}26--28{]},
and Monolix (Lixoft, Antony, France) {[}32{]}. The most commonly used
algorithm was first-order conditional estimation with the \selectlanguage{greek}\emph{η-ε}
\selectlanguage{english}interaction.

Most studies described the PK of MHD as a one-compartment model with
first-order absorption and elimination. Rodrigues et al. {[}32{]}
described the PK of OXC and its active metabolite MHD with a
two-compartment model with first-order absorption and elimination.
Antunes et al. {[}34{]} described the PK of OXC and its active
metabolite enantiomers using a two-compartment model with transit
absorption and first-order elimination.

All studies used either internal or external evaluation. The commonly
method of external evaluation is the goodness-of-fit plot, while the
second popular method was the visual predictive check. Although a
normalised prediction distribution error (NPDE) has better properties
{[}36{]}, it is not commonly used {[}29, 30, 32, 34{]}. Four studies
performed an external evaluation using an independent dataset, all of
which showed acceptable predictability {[}28, 30, 31, 33{]}.

\textbf{3.4 Study Comparison}

There were no obvious differences in the PK of OXC due to
ethnicity.\textbf{Fig. 2} shows concentration-time profiles of all
studies that are simulated with virtual infant (a), children (b) and
adult (c) patients. The model established by Peng et al. {[}27{]} which
presented lower CL, displayed a much higher trough concentration
(C\textsubscript{trough}) than others (CL: 0.016 vs. 0.035--0.073
L/h/kg). On the contrary, the PPK model established by Yu et al.
{[}33{]} which presented a higher CL, showed a considerably lower
C\textsubscript{trough} than others (CL: 0.084 vs. 0.035--0.073 L/h/kg).

The estimated median CL was 0.078 L/h/kg for infants (10 kg, 1 year)
{[}25{]}, 0.058 (range: 0.016--0.084) L/h/kg for children (30 kg, 10
years) {[}24, 26-28, 30-33{]}, and 0.033 (range: 0.029--0.0599) L/h/kg
for adults (70 kg, 40 years) {[}26, 29, 33-35{]}. The median CL per kg
in infants and children was higher than that in adults. Furthermore,
children had a larger variability in CL than adults (0.016--0.084 L/h/kg
vs. 0.029--0.06 L/h/kg).

Moreover, the median Vd per kg in infants and children was higher than
that in adults. The determined median Vd was 1.38 L/kg for infants, 0.78
(range: 0.47--2.16) L/kg for children, and 0.45 (range: 0.2--1.48) L/kg
for adults.

The final PK parameters included in our review are summarised
in\textbf{Table 3} . The between-subject variability (BSV) was
determined from exponential models in all included studies. The median
(range) BSV was as follows: CL, 16.84\% (11.09\%--34.21\%); Vd, 35.35\%
(6.88\%--104.4\%); and Ka, 24.05\% (8.27\%--39.82\%). The residual
unexplained variability (RUV) was described using the proportional
model: 12.05\% (4\%--32\%) or additive model: 3.396 mg/L (0.93--0.512
mg/L).

All PPK analysis intended to explain the BSV of MHD PK by investigating
possible covariates. The covariates investigated and identified in each
study are visually shown in \textbf{Fig. 3} . The commonly investigated
covariates included weight, sex, age, co-administered medications, body
surface area, and estimated glomerular filtration rate (eGFR). The
identified covariates for CL included weight, co-administered
medications, eGFR, dose. All the investigated and identified covariates
in the PPK model are summarised in \textbf{Table S1} .

It was found that eGFR significantly affected MHD CL, according to the
observations from Lin et al. {[}29{]}. In patients with impaired renal
function (eGFR: 20--80 mL/min), the CL was 34.8\% (9.4\%--64.2\%) lower
than those with normal renal function.

There was one study identified dose could affect CL, which may indicate
a nonlinear elimination of MHD {[}27{]}. However, these effects may on
account of the dose adjustment in clinical practice according to the TDM
process, which can be misinterpreted as nonlinearity in the system
{[}37{]}. Therefore, further in-depth study on the possible PK of MHD is
necessary.

The influence of all included covariates on CL is shown in \textbf{Fig.
4} . The ranges of continuous covariates that were scaled are as
follows: the weight of adults was set at 40--100 kg and that of children
was set at 16--40 kg. The age was set as 18--75 years. The range of eGFR
and alanine aminotransferase (ALT) were set as 20--120 mL/min and 5--150
U/L, respectively. The dose of OXC was set as 75--1350 mg/kg/d.

Ten of all studies that investigated impact of the weight indicated that
it was associated with the CL of MHD {[}24, 26-32, 34, 35{]}. Weight had
a significant influence on CL. Our finding showed that the CL of
patients with different weight could range from 0.54 to 1.8 times
compared to the typical patient (children: 30kg, adults: 70kg).
Co-administration with EIAEDs also significantly affected CL in children
and adults, which approximately increased 1.17 to 1.63 times {[}24-26,
28, 32{]}; in four studies, the clinical significance of the impact of
EIAED co-administration on CL was more than 20\% {[}24-26, 32{]}. eGFR
was identified to significantly affect the CL of adults with a range of
0.33 to 1.24 times {[}29{]} compared to a typical patient with an eGFR
of 90 mL/min. ALT was also found to have a significant impact on CL in
children, with a range of 0.73 to 1.35 times compared to a typical
patient with an ALT level of 30 U/L {[}33{]}.

Four studies conducted a model-based simulation to show the influence of
covariates on the PK profile and optimize the dosage regimen to achieve
the target MHD concentrations of 3 and 35 mg/L recommended by the
current guideline {[}29-32{]}. For adults and paediatric patients, all
the four studies recommended adjusting the dosage {[}29-32{]}. Chen et
al. {[}31{]} and Rodrigues et al. {[}32{]} had a similar recommended
dose range for paediatric patients based on their weight. However, Lin
et al. {[}30{]} recommended a lower dose than others, which may be
explained by the lower CL in their study than others (0.04 L/h/kg vs.
0.059/0.057 L/h/kg). Meanwhile, Rodrigues et al. {[}32{]} also
recommended increasing the maintenance dose by 50\% above the
recommended maintenance dose for children treated with EIAEDs.

\textbf{4. Discussion}

To our knowledge, this is the first review that summarised data
concerning previously published PPK models of OXC and its active
metabolite MHD. We found considerable PK differences between children
and adults. We also provided evidence regarding adjustment of the dose
regimen according to weight, co-administration with EIAEDs, and eGFR.

The PK of MHD showed no significant differences due to ethnicity.
According to the PPK studies, there were similar PK profiles in adults.
The weight-standardised CL in Caucasians (median: 0.045, range:
0.029--0.060 L/h/kg) was similar to that in Asians (median: 0.036,
range: 0.033--0.039 L/h/kg) (P \textgreater{} 0.05). Likewise, most PPK
studies performed in paediatric patients also displayed comparable PK
profiles. Moreover, Sugiyama et al. {[}24{]} directly compared the PK of
MHD among Caucasian, Black, and Asian populations and found no obvious
differences among these sub-populations. Nevertheless, studies conducted
in Chinese populations showed larger variabilities than other
ethnicities (0.016--0.084 L/h/kg vs. 0.043--0.078 L/h/kg). The reason
for this is unclear and may require still exploration.

The PK of MHD displayed considerable difference among infant, children,
and adult patients. Adults generally displayed lower CL per kg than the
infants and children, consistent with the classical PK investigations
{[}38{]}. This difference may be attributed to the lower body fat/lean
mass ratio, higher kidney blood flow, and higher total body water in
children {[}39{]}. Furthermore, children had a wider weight-standardised
CL range than adults, which is attributed to the maturity of the liver
and inefficient UGT enzyme capacity {[}40, 41{]}. A higher CL resulted
in a lower concentration of MHD. Therefore, a higher dosage could be
used in paediatric patients~to achieve the target steady-state
concentration of MHD {[}23{]}.

Recently, OXC was increasingly off-label used to treat epileptic
seizures in infants {[}39{]} owing to its linear PK, better safety, and
well-tolerated profile {[}6{]}. Pi\selectlanguage{ngerman}ña-Garza et al. {[}42{]} reported that
OXC is relatively safe and effective in the treatment of infant
seizures. To date, only one PPK study has been conducted in paediatric
patients aged 0.2 to 3.75 years {[}25{]}; therefore, clinical data of
OXC in the treatment of infants are limited. To ensure better efficacy
and safety in infants, further studies are necessary to explore the
covariates that affect the variability of OXC.

Previous PPK studies found that EIAEDs could significantly increase the
CL of MHD. This is consistent with the PK study performed by McKee et
al. {[}43{]}, who found that CBZ and phenytoin (PHT) decreased the AUC
of MHD by 40\% and 29\%, respectively. As MHD is primarily cleared via
glucuronic acid conjugation, EIAEDs may play a more important role
through the induction of UGT-mediated glucuronidation to decrease serum
MHD concentration {[}35{]}. Lower exposure could increase the risk of
seizures {[}44{]}; therefore, the dose of OXC may be increased when
co-administered with EIAEDs.

Renal function may also influence the CL of MHD because OXC and MHD are
almost completely excreted by the kidney (94\%--97.7\%) {[}5{]}. Lin et
al. {[}29{]} found that MHD CL decreased by 64.2\% when the eGFR
decreased to 20 mL/min and recommended dose adjustment according to eGFR
in adult patients. When the eGFR is normal, at approximately 90--120
mL/min, the recommended dose is 225 or 300 mg q12h {[}29{]}.When the
eGFR is less than 30 mL/min, the recommended dose is 75 mg q12h. This
was similar to the OXC label recommendation that indicated that patients
with impaired renal function (creatinine clearance \textless{}30 mL/min)
should initiate OXC at one-half of the dose of 300 mg/day q12h.
Therefore, to ensure a safe dose for adults with renal dysfunction, a
more detailed dose recommendation may be required. However, there are
also PPK studies that did not identify eGFR as a covariate {[}24, 33{]}.
This may be because of the low proportion of study cohorts with low eGFR
levels. Thus, patients with renal impairment on MHD clearance warrant
further investigation to optimise their dosing regimen.

There were many unknown variabilities in children that could not be
explained by previously reported PPK models. In the included studies,
children had a larger RUV (additive model 0.93--5.12 mg/L; proportional
model 4\%--32\%) than adults (RUV: additive model 2.38--3.80 mg/L;
proportional model 1.7\%--24.5\%). Moreover, the practice guideline for
the TDM of AEDs indicated the benefits of TDM for children such as
diagnosis of clinical toxicity and guide dosage adjustment {[}45{]}.
Thus, TDM monitoring is more crucial for paediatric patients taking OXC.

As the literature search in this study was restricted to English
language, studies published in other languages may have been missed.
Based on this meta-analysis, it can be suggested that there are still
several gaps regarding MHD that can be explored. Further studies that
evaluate MHD pharmacodynamics in patients with epilepsy and PK in
infants are essential to optimise the clinical dosing regimen across
patients of different ages.

\textbf{5. Conclusions}

The PPK studies of OXC have been extensively reviewed. The PK of MHD has
a large difference between children and adults. Furthermore, children
have a larger variability in PK than adults. This review showed that to
optimise the dosing regimen of OXC, the weight, identity of
co-administered drugs, and renal function of patients should be
considered.

\textbf{Acknowledgments:}

The authors would like to sincerely thank \emph{Dr. Vincent Jullien}from
Service de Pharmacologie, Hôpital européen Georges Pompidou, France;
\emph{Yang Wang} and \emph{Jing Peng} from Department of Pharmacy, Wuhan
Children's Hospital, China; \emph{Yunli Yu} from Department of Clinical
Pharmacology, The Second Affiliated Hospital of Soochow University,
China for providing details about the research and active discussions on
the coding. We would like to thank \emph{Hai-ni Wen} MPharm from
Shanghai Chest Hospital; and Ph.D. candidate\emph{Xiao-qin Liu} from
Department of Pharmacy, Huashan Hospital, Fudan University, China for
their critical comments. We would also like to thank Editage
(www.editage.cn) for English language editing.

\textbf{Funding} \textbf{:}Not applicable

\textbf{Conflicts of interest}

Yue-ting Chen, Chen-yu Wang, Yi-wei Yin, Zi-ran Li, Wei-wei Lin, Min Zhu
and Zheng Jiao declare that they have no conflict of interest.

\textbf{Authorcontributions}

\textbf{Yue-ting Chen:} Data curation, Writing- Original draft
preparation, Writing- Reviewing and Editing,
Visualization;\textbf{Chen-yu Wang:} Data curation, Writing- Reviewing
and Editing;\textbf{Yi-Wei Yin:}Writing- Reviewing and Editing,
Supervision; \textbf{Zi-ran Li:} Software, Writing- Reviewing and
Editing; \textbf{Wei-wei Lin:} Software, Validation, Writing- Reviewing
and Editing; \textbf{Min Zhu:} Software;\textbf{Zheng Jiao:}
Conceptualization, Methodology, Writing- Reviewing and Editing,
Supervision.

\textbf{Data availability statement:} Not applicable.

\textbf{Reference}

1. Schwabe S. Oxcarbazepine: clinical development
program.\emph{Epilepsia} . 1994;35 Suppl 5:S51-3.
doi:10.1111/j.1528-1157.1994.tb05968.x

2. Wellington K, Goa KL. Oxcarbazepine: an update of its efficacy in the
management of epilepsy. \emph{CNS Drugs} . 2001;15(2):137-63.
doi:10.2165/00023210-200115020-00005

3. Schachter SC. Oxcarbazepine: current status and clinical
applications. \emph{Expert Opin Investig Drugs} . Jul 1999;8(7):1103-12.
doi:10.1517/13543784.8.7.1103

4. Maiti R, Mishra BR, Sanyal S, Mohapatra D, Parida S, Mishra A. Effect
of carbamazepine and oxcarbazepine on serum neuron-specific enolase in
focal seizures: A randomized controlled trial. \emph{Epilepsy Res} . Dec
2017;138:5-10. doi:10.1016/j.eplepsyres.2017.10.003

5. Schütz H, Feldmann KF, Faigle JW, Kriemler HP, Winkler T. The
metabolism of 14C-oxcarbazepine in man. \emph{Xenobiotica} . Aug
1986;16(8):769-78. doi:10.3109/00498258609043567

6. May TW, Korn-Merker E, Rambeck B. Clinical pharmacokinetics of
oxcarbazepine. \emph{Clin Pharmacokinet} . 2003;42(12):1023-42.
doi:10.2165/00003088-200342120-00002

7. Di Girolamo G, Opezzo JA, Schere D, Gonzalez CD, Moncalvo JJ. Parent
drug and/or metabolite? Which of them is most appropriate to establish
bioequivalence of two oral oxcarbazepine formulations in healthy
volunteers? \emph{Expert Opin Pharmacother} . Jul 2007;8(10):1415-23.
doi:10.1517/14656566.8.10.1415

8. Lu Y, Fang Y, Wu X, Ma C, Wang Y, Xu L. Effects of UGT1A9 genetic
polymorphisms on monohydroxylated derivative of oxcarbazepine
concentrations and oxcarbazepine monotherapeutic efficacy in Chinese
patients with epilepsy. \emph{Eur J Clin Pharmacol} . Mar
2017;73(3):307-315. doi:10.1007/s00228-016-2157-3

9. van Heiningen PN, Eve MD, Oosterhuis B, et al. The influence of age
on the pharmacokinetics of the antiepileptic agent
oxcarbazepine.\emph{Clin Pharmacol Ther} . Oct 1991;50(4):410-9.
doi:10.1038/clpt.1991.158

10. Patsalos PN, Elyas AA, Zakrzewska JM. Protein binding of
oxcarbazepine and its primary active metabolite, 10-hydroxycarbazepine,
in patients with trigeminal neuralgia. \emph{Eur J Clin Pharmacol} .
1990;39(4):413-5. doi:10.1007/bf00315422

11. Flesch G. Overview of the clinical pharmacokinetics of
oxcarbazepine. \emph{Clin Drug Investig} . 2004;24(4):185-203.
doi:10.2165/00044011-200424040-00001

12. Rouan MC, Lecaillon JB, Godbillon J, et al. The effect of renal
impairment on the pharmacokinetics of oxcarbazepine and its
metabolites.\emph{Eur J Clin Pharmacol} . 1994;47(2):161-7.
doi:10.1007/bf00194967

13. Sachdeo R, Beydoun A, Schachter S, et al. Oxcarbazepine (Trileptal)
as monotherapy in patients with partial seizures. \emph{Neurology} . Sep
11 2001;57(5):864-71. doi:10.1212/wnl.57.5.864

14. Bring P, Ensom MH. Does oxcarbazepine warrant therapeutic drug
monitoring? A critical review. \emph{Clin Pharmacokinet} .
2008;47(12):767-78. doi:10.2165/0003088-200847120-00002

15. Sheiner LB, Rosenberg B, Melmon KL. Modelling of individual
pharmacokinetics for computer-aided drug dosage. \emph{Comput Biomed
Res} . Oct 1972;5(5):411-59. doi:10.1016/0010-4809(72)90051-1

16. Sasaki T, Tabuchi H, Higuchi S, Ieiri I. Warfarin-dosing algorithm
based on a population pharmacokinetic/pharmacodynamic model combined
with Bayesian forecasting. \emph{Pharmacogenomics} . Aug
2009;10(8):1257-66. doi:10.2217/pgs.09.65

17. Kanji S, Hayes M, Ling A, et al. Reporting Guidelines for Clinical
Pharmacokinetic Studies: The ClinPK Statement. \emph{Clin Pharmacokinet}
. Jul 2015;54(7):783-95. doi:10.1007/s40262-015-0236-8

18. Jamsen KM, McLeay SC, Barras MA, Green B. Reporting a population
pharmacokinetic-pharmacodynamic study: a journal's
perspective.\emph{Clin Pharmacokinet} . Feb 2014;53(2):111-22.
doi:10.1007/s40262-013-0114-1

19. Burns DR, Elswick RK, Jr. Equivalence testing with dental clinical
trials. \emph{J Dent Res} . Jun 2001;80(6):1513-7.
doi:10.1177/00220345010800060701

20. Ahmad A, Garnett WR. Carbamazepine extended-release capsules vs.
oxcarbazepine: computer simulations of the effect of missed doses on
drug plasma concentrations. \emph{Curr Med Res Opin} . Sep
2005;21(9):1363-8. doi:10.1185/030079905x59120

21. Ling J, Qian LX, Ding JJ, Jiao Z. {[}Effects of multiple-trough
sampling design and algorithm on the estimation of population and
individual pharmacokinetic parameters{]}. \emph{Yao Xue Xue Bao} . May
2014;49(5):686-94.

22. Liu M, Ma CL, Jiao Z, Gao YC, Liu YX, Wu XY. Population
pharmacokinetics of oxcarbazepine in Chinese epilepsy patients.
Article.\emph{Yaoxue Xuebao} . 2018;53(8):1318-1323.
doi:10.16438/J.0513-4870.2018-0187

23. Sallas WM, Milosavljev S, D'Souza J, Hossain M. Pharmacokinetic drug
interactions in children taking oxcarbazepine. \emph{Clin Pharmacol
Ther} . Aug 2003;74(2):138-49. doi:10.1016/s0009-9236(03)00124-3

24. Sugiyama I, Bouillon T, Yamaguchi M, Suzuki H, Hirota T, Fink M.
Population pharmacokinetic analysis for 10-monohydroxy derivative of
oxcarbazepine in pediatric epileptic patients shows no difference
between Japanese and other ethnicities. \emph{Drug Metab Pharmacokinet}
. Apr 2015;30(2):160-7. doi:10.1016/j.dmpk.2014.12.002

25. Northam RS, Hernandez AW, Litzinger MJ, et al. Oxcarbazepine in
infants and young children with partial seizures. \emph{Pediatr Neurol}
. Nov 2005;33(5):337-44. doi:10.1016/j.pediatrneurol.2005.05.011

26. Park KJ, Kim JR, Joo EY, et al. Drug interaction and pharmacokinetic
modeling of oxcarbazepine in korean patients with epilepsy. \emph{Clin
Neuropharmacol} . Jan-Feb 2012;35(1):40-4.
doi:10.1097/WNF.0b013e31824150a5

27. Peng J, Zhang HN, Liu ZS, Xu H, Wang Y. Population pharmacokinetics
of oxcarbazepine active metabolite in Chinese children with
epilepsy.\emph{Int J Clin Pharmacol Ther} . Aug 2014;52(8):684-92.
doi:10.5414/cp202078

28. Wang Y, Zhang HN, Niu CH, et al. Population pharmacokinetics
modeling of oxcarbazepine to characterize drug interactions in Chinese
children with epilepsy. \emph{Acta Pharmacol Sin} . Oct
2014;35(10):1342-50. doi:10.1038/aps.2014.76

29. Lin WW, Wang CL, Jiao Z, et al. Glomerular Filtration Rate Is a
Major Predictor of Clearance of Oxcarbazepine Active Metabolite in Adult
Chinese Epileptic Patients: A Population Pharmacokinetic
Analysis.\emph{Ther Drug Monit} . Oct 2019;41(5):665-673.
doi:10.1097/ftd.0000000000000644

30. Lin WW, Li XW, Jiao Z, et al. Population pharmacokinetics of
oxcarbazepine active metabolite in Chinese paediatric epilepsy patients
and its application in individualised dosage regimens. \emph{Eur J Clin
Pharmacol} . Mar 2019;75(3):381-392. doi:10.1007/s00228-018-2600-8

31. Chen CY, Zhou Y, Cui YM, Yang T, Zhao X, Wu Y. Population
pharmacokinetics and dose simulation of oxcarbazepine in Chinese
paediatric patients with epilepsy. \emph{J Clin Pharm Ther} . Apr
2019;44(2):300-311. doi:10.1111/jcpt.12792

32. Rodrigues C, Chiron C, Rey E, et al. Population pharmacokinetics of
oxcarbazepine and its monohydroxy derivative in epileptic
children.\emph{Br J Clin Pharmacol} . Dec 2017;83(12):2695-2708.
doi:10.1111/bcp.13392

33. Yu Y, Zhang Q, Xu W, Lv C, Hao G. Population pharmacokinetic
modeling of oxcarbazepine active metabolite in Chinese patients with
epilepsy. \emph{Eur J Drug Metab Pharmacokinet} . Aug 2016;41(4):345-51.
doi:10.1007/s13318-015-0266-5

34. Antunes NJ, van Dijkman SC, Lanchote VL, et al. Population
pharmacokinetics of oxcarbazepine and its metabolite
10-hydroxycarbazepine in healthy subjects. \emph{Eur J Pharm Sci} . Nov
15 2017;109s:S116-s123. doi:10.1016/j.ejps.2017.05.034

35. Wegner I, Edelbroek P, de Haan GJ, Lindhout D, Sander JW. Drug
monitoring of lamotrigine and oxcarbazepine combination during
pregnancy. \emph{Epilepsia} . Dec 2010;51(12):2500-2.
doi:10.1111/j.1528-1167.2010.02771.x

36. Comets E, Brendel K, Mentré F. Computing normalised prediction
distribution errors to evaluate nonlinear mixed-effect models: the npde
add-on package for R. \emph{Comput Methods Programs Biomed} . May
2008;90(2):154-66. doi:10.1016/j.cmpb.2007.12.002

37. Ahn JE, Birnbaum AK, Brundage RC. Inherent correlation between dose
and clearance in therapeutic drug monitoring settings: possible
misinterpretation in population pharmacokinetic analyses. \emph{J
Pharmacokinet Pharmacodyn} . Dec 2005;32(5-6):703-18.
doi:10.1007/s10928-005-0083-6

38. Perucca E. Pharmacokinetic variability of new antiepileptic drugs at
different ages. \emph{Ther Drug Monit} . Dec 2005;27(6):714-7.
doi:10.1097/01.ftd.0000179847.37965.4e

39. Perucca E. Clinical pharmacokinetics of new-generation antiepileptic
drugs at the extremes of age. \emph{Clin Pharmacokinet} .
2006;45(4):351-63. doi:10.2165/00003088-200645040-00002

40. Choonara IA, McKay P, Hain R, Rane A. Morphine metabolism in
children. \emph{Br J Clin Pharmacol} . Nov 1989;28(5):599-604.
doi:10.1111/j.1365-2125.1989.tb03548.x

41. de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Glucuronidation
in humans. Pharmacogenetic and developmental aspects. \emph{Clin
Pharmacokinet} . Jun 1999;36(6):439-52.
doi:10.2165/00003088-199936060-00005

42. Piña-Garza JE, Espinoza R, Nordli D, et al. Oxcarbazepine adjunctive
therapy in infants and young children with partial
seizures.\emph{Neurology} . Nov 8 2005;65(9):1370-5.
doi:10.1212/01.wnl.0000186800.18456.72

43. McKee PJ, Blacklaw J, Forrest G, et al. A double-blind,
placebo-controlled interaction study between oxcarbazepine and
carbamazepine, sodium valproate and phenytoin in epileptic
patients.\emph{Br J Clin Pharmacol} . Jan 1994;37(1):27-32.
doi:10.1111/j.1365-2125.1994.tb04234.x

44. French JA, Baroldi P, Brittain ST, Johnson JK. Efficacy and safety
of extended-release oxcarbazepine (Oxtellar XR\selectlanguage{english}) as adjunctive therapy
in patients with refractory partial-onset seizures: a randomized
controlled trial. \emph{Acta Neurol Scand} . Mar 2014;129(3):143-53.
doi:10.1111/ane.12207

45. Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic
drugs--best practice guidelines for therapeutic drug monitoring: a
position paper by the subcommission on therapeutic drug monitoring, ILAE
Commission on Therapeutic Strategies. \emph{Epilepsia} . Jul
2008;49(7):1239-76. doi:10.1111/j.1528-1167.2008.01561.x

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