| Objective:Levetiracetam（LEV）is a second-generation broad-spectrum antiepileptic drugs（AEDs）with substantial evidence of efficacy and safety in the treatment of epilepsy in pregnancy,and is recommended for the treatment of patients with epilepsy of childbearing age and pregnancy.A series of physiological changes including the increase of body weight and hemodynamics in pregnant women can significantly change the pharmacokinetic behavior of LEV,decrease the serum concentration of LEV and increase the risk of seizures.Individualized treatment is needed for patients with epilepsy during pregnancy.The purpose of this study was to characterize the systematic pharmacokinetic changes of LEV from pre-pregnancy to postpartum,to quantitatively investigate the factors affecting the pharmacokinetic changes of LEV during pregnancy,to establish a population pharmacokinetic model of LEV in patients with epilepsy during pregnancy,and to develop an individualized dosing regimen of LEV based on the established model so as to provide reference for clinical individualized treatment.Methods:1.Pharmacokinetic changes of LEV in patients with epilepsy during pregnancyThe clinical data of patients with epilepsy during pregnancy who were admitted to Shengjing Hospital of China Medical University from January 2017 to July 2022 and had regular therapeutic drug monitoring of LEV were collected retrospectively.The pharmacokinetic behavior of LEV was characterized by calculating the apparent clearance rate（CL/F）from pre-pregnancy to postpartum.The dosing regimens of LEV in patients with epilepsy during pregnancy were analyzed,and the effects of concomitant AEDs on the pharmacokinetics of LEV during pregnancy were explored.SPSS software version 26.0 was used for statistical analysis.2.Population pharmacokinetics model and dosing regimens optimization of LEV in patients with epilepsy during pregnancySerum concentration data of LEV and clinical data of patients with epilepsy admitted to our hospital from January 2017 to July 2022 were retrospectively analyzed.The nonlinear mixed effect model（NONMEM）was used to establish the population pharmacokinetic model of LEV in patients with epilepsy during pregnancy to investigate the effects of demographic characteristics,concomitant medications,physiology and biochemistry on the pharmacokinetic parameters of LEV.The standard goodness-of-fit plots,normalized prediction distribution error and bootstrap method were performed to evaluate the stability and predictive performance of the final model.Monte Carlo simulation was carried out based on the final model to develop the optimal individualized dosing regimens for LEV during pregnancy.Meanwhile,the LEV dose prediction model was established based on the final model,and its predictive ability was verified.Results:1.Pharmacokinetic changes of LEV in patients with epilepsy during pregnancyIn this study,the clinical data of 52 patients with epilepsy during pregnancy were screened,of which 18 patients were excluded because they were not satisfied with the inclusion criteria.A total of 20 patients with LEV monotherapy and 14 patients with LEV combined with medication were included.An analysis of 161 blood concentration monitoring data of 20 patients with epilepsy during pregnancy treated with LEV monotherapy showed that the CL/F of LEV during pregnancy increased significantly,increased by 96.60%（P<0.001）during the first trimester,142.18%（P<0.001）during the second trimester and 134.69%（P<0.001）during the third trimester compared with the pre-pregnancy levels.The CL/F decreased rapidly after delivery and returned to the pre-pregnancy levels about 6 weeks after delivery.There were differences in the dose of LEV in different pregnancy trimesters.The LEV dose in the second and third pregnancy was significantly higher than that in pre-pregnancy,increased by 59.91%（P=0.030）and97.87%（P<0.001）respectively.The concomitant medication with enzyme-induced AEDs can induce LEV metabolism and increase its CL/F.2.Population pharmacokinetics model and dosing regimens optimization of LEV in patients with epilepsy during pregnancyA total of 43 patients with epilepsy during pregnancy taking LEV therapy were included in this study,of which 37 patients with a total of 166 blood concentration data were fitted using NONMEM software and 6 patients with a total of 38 blood concentration data were used for model validation.The structural model was constructed by one-compartment model with first-order absorption and first-order elimination.The inter-individual variation and residual variation were estimated by exponential model and proportional model respectively.The final model was established as CL/F（L/h）=3.82×（TBW/65）0.939×1.22（Trimester=2）×1.15（Trimester=3）;V/F（L）=42（Fixed）.The typical population value of LEV CL/F during pregnancy is 3.82 L/h.The evaluation results show that the final model has good stability and predictive performance.Monte Carlo simulations indicate that dosing regimens for LEV should be individualized based on the patient’s weight and trimester of pregnancy to increase the probability of achieving target concentrations.Validation of the LEV individualized dose prediction model revealed that the relative prediction error was within±20%for 89%of the blood samples,indicating a high degree of accuracy and precision of the LEV dose prediction model.Conclusion:The pharmacokinetic behavior of LEV during pregnancy changed significantly and displayed marked inter-individual variation,and the CL/F reached its peak in the second trimester.The first LEV population pharmacokinetic in patients with epilepsy during pregnancy was established in this study,and an individualized dose prediction model for LEV was established based on this model.Validation shows that the model is stable and has good predictive performance,which can be used for the clinical individualized treatment.A Monte Carlo simulation was used to develop an individualized dosing regimen for LEV in patients with epilepsy during pregnancy,providing a basis for individualized treatment of LEV in this population. |
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