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 > 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]. Piña-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 <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.