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.