| Chronic myeloid leukemia is a clonal hematopoietic stem cell disorder characterized by Philadelphia chromosome(Ph chromosome). The abnormality results from the reciprocal translocation that fuses the abl gene from chromosome 9 to the bcr gene from chromosome 22. The protein encoded by the fusion gene(BCR-ABL) is thought to play a crucial role in the development of CML due to its continuous actived tyrosine kinase activity, which may increase proliferation and inhibit apoptosis.Imatinib mesylate(Glivec) is the first 2-phenylaminopyrimidine-type inhibitor of BCR–ABL kinase approved as front-line therapy for CML, which competitively inhibits the binding of ATP to the ATP binding pocket of BCR–ABL. Many large-scale clinical researches have proved the great success of Glivec in treatment of imatinib. However,most Chinese patients can not afford it because of its high price.Generic imatinib mesylate capsules made by Chia- ai Tianqing Pharmaceutical Group presented similar pharmacokinetic parameters with brand imatinib in healthy volunteers and has been approved by China Food and Drug Administration for front-line treatment of CML in June 26 th, 2013.To further evaluate safety and efficacy, characteristics of plasma drug concentration of generic imatinib and also its bioequivalence with brand imatinib, the study was performed in 21 newly diagnosed Chinese CML-CP patients. Results were shown as followings: 1) Pharmacokinetic parameters showed no significant difference between generic imatinib and brand imatinib. The 90% CIs of the generic drug/glivec ratios for the natural log-transformed values of Cmax and AUC0–t for either imatinib or CGP-74588 met the predetermined criteria for bioequivalence. The relative bioavailability of generic drug to Glivec for imatinib and CGP-74588 in single dose administration was 102.5% and 103.6%, respectively. Correspondingly, in multiple dose administration, it was 105.5% and 103.4%, respectively, which met the CFDA regulatory criteria for bioequivalence(80%–125% for AUC and 70%–143% for Cmax). 2) CCy R rate of the 21 patients at 3 months,6 months,and 12 months was 43%, 67% and 75%, respectively. Patients with better early molecular response(EMR), namely BCR-ABL transcripts ≤10% at 3 months and ≤1% at 6 months, showed better CCy R rate at 12 months(87% vs 40% at 3 months,P=0.000; 83% vs 60% at 6 months,P=0.003). EFS rate at 12 months was 86%. 3) Drug-related adverse events were mostly 1/2 grade and tolerable. The common non-hematological events included edema(81%), nausea and vomiting(52%), and muscle pain(43%). All grades of hematological events were neutropenia(57%), anemia(57%), and thrombocytopenia(48%). 4)The mean plasma trough level of imatinib and its metabolism(CGP-74588) was 1185.07 ± 417.91ng/ml and 251.53 ± 76.50ng/ml, respectively. Plasma trough level of imatinib and its metabolism was not significantly related to age, weight and BSA. Patients with plasma trough level more than 1000 ng/ml tended to have higher CMR/MMR rate(42% vs 0%, P<0.05).In conclusion, generic imatinib and brand imatinib were bioequivalent and similar in safety and efficacy. Plasma trough levels of generic imatinib varied a lot in different patients and was partially related to clinical response. The generic imatinib might provide a well-tolerated, effective and more economical strategy for CML patients. |
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