Imatinib is the first-line treatment for patients with gastrointestinal stromal tumors (GIST) after surgery. However, its pharmacokinetic profile varies remarkably between individuals and has not been well characterized in postoperative Chinese patients with GIST. Therefore, this study aimed to develop a population pharmacokinetic (PPK) model and recommend appropriate doses for different patients to achieve the target trough concentration in such a population. Patients and Methods: A total of 110 surgically treated GIST patients were enrolled, of which 85 were applied to conduct a PPK analysis with a nonlinear mixed-effect model and 25 for external validation of the model. Demographic and biomedical covariates, as well as six single nucleotide polymorphisms were tested to explore the sources of variation in pharmacokinetic parameters of imatinib. Monte Carlo simulations were performed to establish the initial dosing regimens. Results: A one-compartment model was established in postoperative GIST patients. The red blood cell count (RBC) and ABCG2 rs2231142 were observed to have a significant effect on the clearance of imatinib. The typical values estimated by the final model were 9.72 L/h for clearance (CL/F) and 229 L for volume of distribution (V/F). Different from the fixed dose regimen of 400 mg each day, patients carrying rs2231142 heterozygous type and with a lower level of RBC (2.9 × 10 12 /L), 300 mg imatinib daily is enough to achieve the target trough concentration. When RBC rises to 4.9 × 10 12 /L, 500 mg daily is recommended. For patients with rs2231142 GG genotype, 500 mg a day is required at RBCs of 3.9 × 10 12 /L and 4.9 × 10 12 /L. Conclusion: RBC and rs2231142 contribute to the pharmacokinetic variation of imatinib and personalized dose recommendations based on patient characteristics may be necessary.
Aim: To assess the role of genetic polymorphisms in postoperative imatinib concentrations and edema in patients with gastrointestinal stromal tumor. Methods: The relationships between genetic polymorphisms, imatinib concentrations and edema were explored. Results: Carriers of the rs683369 G-allele and rs2231142 T-allele had significantly higher imatinib concentrations. Grade ≥2 periorbital edemas were related to the carriership of two C-alleles in rs2072454 with an adjusted odds ratio of 2.85, two T-alleles in rs1867351 with an adjusted odds ratio of 3.42 and two A-alleles in rs11636419 with an adjusted odds ratio of 3.15. Conclusion: rs683369 and rs2231142 affect the metabolism of imatinib; rs2072454, rs1867351 and rs11636419 are related to grade ≥2 periorbital edemas.
Purpose Imatinib mesylate (IM) offers a significant survival benefit to patients with gastrointestinal stromal tumors (GIST). However, the clinical responses of IM vary drastically between individuals. Therefore, this study aimed to assess the role of genetic polymorphisms of metabolic enzymes, transporters and drug targets in IM plasma levels and adverse reactions in Chinese patients with GIST.Methods The dose-adjusted trough plasma levels (C0/D) of IM in 95 patients were quantified using two-dimensional liquid chromatography. Nine SNPs in six genes were detected. The relationships between C0/D, single nucleotide polymorphisms (SNPs) and adverse reactions were tested. Logistic regression was used to test the risk factors for IM-related grade ≥ 2 periorbital edema.Results A range of C0/D from 1.33 to 7.04 ng/mL·mg-1 for the 95 patients was found. G allele carriers (CG+GG) of SLC22A1 rs683369 and T allele carriers (GT+TT) of ABCG2 rs2231142 had significantly higher C0/D. For all grades of periorbital edema, an increase in incidence with age was found, while this differed from more severe periorbital edema. Grade ≥ 2 periorbital edema was related to the carriership of two C-alleles in EGFR rs2072454 with an adjusted OR of 2.85 (95% CI=1.10–7.40; P=0.032), two T-alleles in SLC22A1 rs1867351 with an adjusted OR of 3.42 (95% CI=1.32–8.88; P=0.010) and two A-alleles in CYP1A2 rs11636419 with an adjusted OR of 3.15 (95% CI=1.08–9.20; P=0.036). None of the nine SNPs was found to be related to gastrointestinal reactions.Conclusions Rs683369 and rs2231142 have an impact on the metabolism of IM; rs2072454, rs1867351, and rs11636419 are linked to grade ≥ 2 periorbital edema. These SNPs may be biomarkers for IM dose adjustment and IM-related grade ≥ 2 periorbital edema.
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