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. 2020 Aug 19:10:1348.
doi: 10.3389/fonc.2020.01348. eCollection 2020.

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

Mervat M Omran  1 , Raafat Abdelfattah  2 , Heba S Moussa  3 , Nelly Alieldin  4 , Samia A Shouman  1
Affiliations

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

Mervat M Omran et al. Front Oncol. .

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 Blood samples were withdrawn at least 30 days after drug administration, and trough and peak concentrations of imatinib, N-des-methyl imatinib, and pyridine-N-oxide imatinib were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, ke, 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, Ke 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 Css. 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.

Keywords: ABCG2; CML; P/T ratio; SNP; imatinib; pyridine-N-oxide imatinib; response.

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Figures

Figure 1
Figure 1
Relations express the relation between response and pharmacokinetic parameters. (A) Plasma IM trough concentration (ng/ml) (P = 0.006), (B) IM peak/trough ratio (P/T) (P = 0.001), (C) Elimination rate constant (Ke) (P = 0.001), (D) IM clearance (ml/min) (P = 0.004), (E) Plasma trough of Pyridine-N-oxide imatinib (P = 0.01), and (F) Peak/Trough ratio (P/T) Pyridine-N-oxide imatinib (P = 0.008).
Figure 2
Figure 2
Relation of relative frequency of the gene variant ABCG2. 34 G>A and SLCO1B3. 334 T>G with response. (A) ABCG2. 34 G>A gene, (B) SLCO1B3. 334 T>G gene.
Figure 3
Figure 3
Relation of the genotype variant ABCG2. 34 G>A gene with pharmacokinetic parameters. (A) IM clearance (P = 0.02), (B) Ke, elimination rate constant (P = 0.005), (C) IM trough plasma concentration (P = 0.01).
Figure 4
Figure 4
Relation of the genotype variant ABCG2. 421C >A with pharmacokinetic parameters. (A) Plasma IM peak concentration (ng/ml) (P = 0.03), (B) IM steady state concentration (ng/ml) (P = 0.05), (C) Peak of N-des-methyl IM (ng/ml) (P = 0.02).
Figure 5
Figure 5
Relation of ABCB1. 3435C>T and 1236 C>T gene with pharmacokinetics of Imatinib. (A) Association of ABCB1. 3435C>T with the steady state concentration (ng/ml) (P = 0.038). (B) Association of ABCB1. 1236 C>T gene with trough concentration of N-des-methyl imatinib (ng/ml) (P = 0.004).
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