Association of the Trough, Peak/Trough Ratio of Imatinib, Pyridine–N-Oxide Imatinib and ABCG2 SNPs 34 G>A and SLCO1B3 334 T>G With Imatinib Response in Egyptian Chronic Myeloid Leukemia Patients

Abstract

Imatinib mesylate (IM) is highly efficacious in the treatment of chronic myeloid leukemia (CML). Therapeutic drug monitoring and pharmacogenetic screening are affirmed for better management of IM therapy. The goal of this study was to gain a greater mechanistic understanding of the factors controlling variability in IM level and its relation to the response. One hundred and two patients with CML at chronic phase were recruited in this study. Blood samples were withdrawn at least 30 days after drug administration, and trough and peak concentrations of imatinib, N-des-methyl imatinib, and pyridine-N-oxide imatinib were determined by HPLC/MS/MS. Genetic polymorphism of the genes ABCG2 SNPs 34 G>A and 421C >A; ABCB1 SNPs 2677 G>A/T, 1236 C>T, 3435 C>T; SLCO1B3 SNPs 334 T>G and CYP3A5 were studied using PCR-RFLP technique. Our study presented significant higher trough IM (1,281 ± 578 ng/ml), lower Peak/Trough ratio, clearance (Cl), and elimination rate constant, k e , among patients who achieved favorable responses ( N = 64) than those for patients who suffered unfavorable response ( N = 37). The P/T ratio was the only significant independent factor affecting response, as the P/T ratio increased by one, the risk of unfavorable response increased by more than double as compared to favorable response with 95% CI (1.28–3.92, P = 00.005). Moreover, like the results of IM, the trough concentration of Pyridine-N-oxide imatinib was significantly higher ( P = 0.01) and its P/T ratio was significantly lower ( P = 0.008) in patients achieved favorable response than those without. The wild GG genotype of the ABCG2.34 G>A gene was associated with favorable response ( P = 0.01), lower Cl, K e and high plasma IM trough level than both (AA+GA) genotypes. ABCG2.421C >A (CC) genotype had a significantly higher plasma peak of IM, N-des-methyl imatinib and higher C ss . The GG and TG alleles of the SLCO1B3.334 T>G gene were significantly correlated to favorable response, while the wild allele TT was linked to unfavorable response ( P = 0.03). In conclusion, the trough and P/ T ratio for both IM and Pyridine-N-oxide imatinib, in addition to Polymorphism of ABCG2 SNPs 34 G>A and SLCO1B3.334 T>G gene, is a good predictor for response of IM in CML Egyptian patients.

Determination of the Cut-off Value for Imatinib Plasma Levels Linked to Occurrence of Bone Pain in CML Patients

“…Our earlier research showed that a high imatinib trough is linked with a strong response to the drug, and that the genotypes ABCG2.34 G > A and SLCO1B3.334 T > G were associated with a good imatinib response in Egyptian CML patients. 20 In this study, for individuals who had the wild homogenous allele TT SLCO1B3.334 T > G, we discovered that the imatinib trough concentration was 520 ng/mL higher in them than in those with the heterozygous GA allele and the variant type. This supports our previous finding that patients with the wild variant of SLCO1B3.334 T > G have favorable response to imatinib.…”

“…This supports our previous finding that patients with the wild variant of SLCO1B3.334 T > G have favorable response to imatinib. 20 According to earlier research on the immunosuppressant medication Mycophenolic acid, SLCO1B3 334T > G was shown to be strongly linked to adverse outcomes, although heterozygous carriers of SLCO1B3 334T > G had a lower chance of experiencing gastrointestinal side effects than wild-type people. 40 …”

“…This study was based on data from 102 patients, obtained from our previously published dataset. 20 This study was conducted at the Hematological Outpatient Clinic of the National Cancer Institute at Cairo University. Patients were diagnosed with CML, at least 18 years old, and were receiving imatinib therapy for at least 30 days (to reach a steady state).…”

“…As mentioned in our previous work, 20 whole blood samples were drawn and placed in tubes that contained EDTA just prior to administering the medication (trough samples) and 2 hours after imatinib administration (peak sample). Injecting 10 µL of plasma into the LC/MS/MS system after it was analyzed using HPLC autosampler bottles.…”

“…As well as the previous genetic polymorphism data for those patients that was extracted from our previous study. 20 …”