PMC8329375_01
Flowchart of the Monte Carlo (MC) simulation. Note. NMPA: The National Medical Products Administration, tau: the dosing interval, LTG: lamotrigine, VPA: valproate acid, IND: enzyme inducer, PK: pharmacokinetic, CL: total serum clearance, BW: total body weight, V
d: the apparent volume of distribution, k
a: the rate of absorption, F: the absolute bioavailability of the form of oral dosage, X
0: a single dose, t: the time of blood sampling, C
ss: steady-state serum concentrations, omegaCL: the inter-individual random error on CL, nj: the inter-individual variability in CL, CL
pop: the population mean CL, CL
j: the CL of the jth virtual patient.
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F1
All the parameters used as modeling inputs for the virtual populations as well as their assumed distributions were identical to those reported in Figure 1.
The evolution of the probability of target attainment (PTA) values (%) needed to reach steady-state serum concentrations (C
ss) within the target range (3-15 mg/L) and >=20 mg/L for different once-daily regimens (A,C) and twice-daily regimens (B,D) in different scenarios of concomitant therapy in adolescent Chinese epileptic patients weighing 60 kg, obtained by using Monte Carlo (MC) simulations. The solid node in the curve represents the result of a kind of assumed dosing regimen.
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F2
To verify the results of the MC simulation in Figure 2, MC simulations of the 10,000 virtual patients weighing the same as the patient considered in the case study were conducted to calculate the estimates of C ss of LTG for each of the regimens, corresponding to the patient's dosing titration regimens. Figure 2B, we see that the PTA values reached C ss within 3-15 mg/L for LTG dosing regimens of 125 mg/bid and 250 mg/bid as monotherapy were close to 100% and below 80%, respectively. Finally, the empirical LTG dosing regimen of 125 mg/bid was chosen by clinicians as the patient's maintenance doses after considering the efficacy, safety, and cost effectiveness.
Simulated mean steady-state concentrations (C
ss) (represented by blue dots) and the corresponding 10th and 90th percentiles (represented by pink dots), of the response to lamotrigine (LTG) for dosing regimens of 25 mg/bid to 125 mg/bid by adolescent Chinese patients with epilepsy weighing 60 kg in a 10,000-virtual patient Monte Carlo (MC) simulation. The 80% prediction interval, encompassing 80% of the simulated sample, adequately captured the measured LTG concentrations (represented by red squares) of a 15-year-old female epileptic Chinese patient weighing 60 kg. The patient's leukocytes (represented by orange triangles) decreased when the LTG concentration was increased, and had normalized when she was discharged. Note. LTG: the dosing titration regimens of LTG (mg/bid), VPA: the dosing titration regimens of the co-administered valproate acid (VPA) (g/qd), CVPA: the measured trough concentrations of VPA, PTAa: the probability of target attainment values (%) needed to reach C
ss within the range of 3-15 mg/L, PTAb: the probability of target attainment values (%) needed to reach C
ss >= 20 mg/L.
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F3
As is shown in Figure 3, the prediction interval between the 10th and 90th percentiles, encompassing 80% of the simulated sample (i.e., an 80% chance that the predicted value fell within this range), captured the patient's TDM data well, with all points lying between the upper and lower bounds of the prediction interval, indicating that the forecasted result was reliable.