Population Pharmacokinetic Analysis And Application Of Adjuvant Imatinib In The Treatment Of Gastrointestinal Stromal Tumors

Imatinib is the first-line treatment for patients with gastrointestinal stromal tumors（GIST）and significantly improves the prognosis of patients.However,its pharmacokinetic parameters are influenced by many factors and vary remarkably between individuals,and has not been well characterized in postoperative Chinese patients with GIST.Population pharmacokinetics（PPK）combines statistical methods with the basic principles of pharmacokinetics,allowing quantitative description of the sources of pharmacokinetic variation and serving as guidance for the development of individualized dosing regimens.This study aims to establish a PPK model and provide a basis for the rational use of imatinib.Objectives1.To investigate the effects of genetic polymorphisms of CYP1A2,SLC22A1,SLCO1A2,ABCG2,RET,and EGFR on imatinib plasma levels and adverse effects in postoperative GIST patients.2.To construct a PPK model of adjuvant imatinib in treating GIST based on pharmacogenomics,and then perform internal evaluation and external validation of the final model,followed by utilizing the model to generate individualized initial dosing.Methods1.The blood samples were prospectively collected from postoperative GIST patients who received adjuvant imatinib at the First Affiliated Hospital of Nanchang University from January 2021 to September 2022.2.The two-dimensional liquid chromatography was applied to determine the plasma concentrations of imatinib,and the Mass ARRAY technique was used to genotype nine single nucleotide polymorphisms（SNPs）,namely CYP1A2 rs11636419;SLC22A1rs1867351,rs683369 and rs2282143;SLCO1A2 rs10841803;ABCG2 rs2231142;RET rs1800860;EGFR rs2072454 and rs2227983.3.The associations of different SNP typing with imatinib C₀/D and adverse reactions were analyzed using statistical methods.4.The nonlinear mixed-effect model（NONMEM）was adopted to establish a PPK model of adjuvant imatinib in treating patients with GIST,and the effects of demographic data,laboratory inspection items（blood cell counts and liver and kidney function indicators）and different SNP typing on pharmacokinetic parameters of imatinib were quantitatively measured.5.After the final model was internally evaluated and externally validated,Monte Carlo simulations were performed to generate individualized dose recommendations of imatinib for patients with GIST showing different characteristics.Results1.A total of 95 postoperative GIST patients were enrolled in the analysis group with imatinib C₀/D ranging from 1.33–7.04 ng/mL·mg^-1.Among the nine candidate SNPs,it was found that patients with the rs683369 CC genotype(3.57±1.21 ng/mL·mg^-1)appeared to have lower imatinib trough plasm levels than G allele carriers(4.32±1.60ng/mL·mg^-1).The C₀/D of imatinib appeared higher in patients with the rs2231142mutant T allele(3.98±1.36 ng/mL·mg^-1)than that in wild-type GG genotype patients(3.40±1.21 ng/mL·mg^-1).Grade≥2 periorbital edemas were related to the carriership of two C-alleles in rs2072454 with an adjusted OR of 2.85（95%CI=1.10–7.40;P=0.032）,two T-alleles in rs1867351 with an adjusted OR of 3.42（95%CI=1.32–8.88;P=0.010）and two A-alleles in rs11636419 with an adjusted OR of 3.15（95%CI=1.08–9.20;P=0.036）.2.A total of 110 patients were included in the PPK modeling group according to predetermined inclusion and exclusion criteria,of which 85 patient data were used to establish the model and the other 25 patient data were used to validate the model predictive performance externally.The red blood cell count（RBC）and ABCG2rs2231142 were observed to have a significant effect on the clearance of imatinib.A one-compartment model with first-order absorption and first-order elimination was established and the final model was expressed as:CL/F（L/h）=9.72×（RBC/3.7）^0.49×0.879 ^heterozygous×0.976 ^homozygous;V/F（L）=229.The goodness-of-fit（GOF）diagnostic plot showed that the final model fits well;Bootstrap results indicated that the parameter typical values estimated by the model were equal or similar to the median of the parameter values aggregated from the bootstrap datasets and were all within the 95%CI（2.5%–97.5%）,and the robustness of the model was 99.0%,suggesting that the model was stable;The visual predictive check（VPC）showed that the 5th,50th,and95th percentiles of observed values fell within the 95%CI of the corresponding simulated data,which shows that the predictability of the final model is acceptable.Additionally,the mean prediction error（MPE）was-11.9%and the mean absolute prediction error（MAPE）was 17.9%in the external validation,both of which were all within the pre-defined acceptable criteria（MPE%≤±20%,MAPE%≤30%）.3.Different from the fixed dose regimen of 400 mg each day,the Monte Carlo simulations demonstrated that patients carrying rs2231142 heterozygous type and with a lower level of RBC(2.9×10¹²/L),300 mg imatinib daily is enough to achieve the target trough concentration.When RBC rises to 4.9×10¹²/L,500 mg daily is recommended.For patients with rs2231142 GG genotype,500 mg a day is required at RBCs of 3.9×10¹²/L and 4.9×10¹²/L.According to the SNP typing results of the studied population,the proportion of patients with the rs2231142 TT genotype was small,and such patients would be expected to require a dose of 500 mg daily to achieve satisfactory concentrations at RBCs of 3.9×10¹²/L and 4.9×10¹²/L.Conclusions1.SLC22A1 rs683369 and ABCG2 rs2231142 may significantly affect the plasma levels of imatinib,and more severe periorbital edema due to imatinib was associated with EGFR rs2072454,SLC22A1 rs1867351 and CYP1A2 rs11636419.2.The PPK model developed in this study eventually incorporated rs2231142 and RBC covariates,and both the internal evaluations（GOF,Bootstrap,and VPC）and external validation results all suggested that the final model featured high stability,reliability and predictive accuracy.According to the model,individualized initial dose recommendations were given in accordance with the different characteristics of patients.