3.4 Study Comparison
There were no obvious differences in the PK of OXC due to ethnicity.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
(Ctrough) 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
Ctrough 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 inTable 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 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 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 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.