Imatinib (IM) Pharmacokinetic (PK) Exposure and Its Correlation with Clinical Outcome in Patients with Chronic-Phase Chronic Myeloid Leukemia (CML-CP) for 400 Mg and 800 Mg Daily Doses (Tyrosine Kinase Dose Optimization Study [TOPS])
Authors: Guilhot François , Hughes Timothy P , Cortes Jorge , Wang Yanfeng , Hayes Michael , Gichangi Anthony , Druker Brian J. , Baccarani Michele 
Published: April 2020

Abstract
Background: Correlation between IM plasma level and clinical response has been previously reported [Larson et al., Picard et al.]. TOPS is an open-label, randomized, multicenter Phase III study investigating whether 800 mg of IM (400 mg twice daily) results in an improved efficacy compared with 400 mg daily IM in newly diagnosed, previously untreated CML-CP. This analysis reports IM trough plasma levels (Cmin) at both doses and their correlation with clinical response and safety parameters.
Methods: IM PK trough samples were collected at time 0 (predose), and following 1, 6, 9, and 12 month treatment for both 400 mg/day (mg/d) and 800 mg/d arms. Plasma concentrations of IM and CGP74588 (major metabolite) were determined by a validated LC/MS/MS (liquid chromatography and tandem mass spectrometry) method. Correlation of IM exposure with clinical response (major molecular response [MMR] rates and time to first MMR) was assessed by grouping patients into quartiles based on their measured IM Cmin levels in month 1. For correlation with frequency of adverse events [AEs], an average Cmin (aCmin) over 12 months corrected for dose intensity was used for the analysis. Correlations were assessed for the entire evaluable population and for each dose group separately.
Results: IM PK exposure was proportional to dose and stable over time. For the 400 mg/d dose (n=78–87), the median IM Cmin values at month 1, 6, 9, and 12 were 1190, 1060, 1210, and 1295 ng/mL, respectively; and for the 800 mg/d dose (n=148–167) the corresponding Cmin values for each month were 2720, 2340, 2170, and 2150 ng/mL, respectively. The intra-patient variability (CV%) was low and similar between the 400 mg/d and 800 mg/d doses, 25% and 27%, respectively. The inter-patient variability (CV%) was 38% for 400 mg/d and 58% for 800 mg/d. Despite this inter-patient variability there was a strong correlation between IM Cmin at month 1 (Table 1) and time to MMR or MMR at 3, 6, 9 and 12 months.
Table 1: MMR rates over 12 months based on month 1 IM C min quartiles for evaluable patients with PK data
MMR Rate* (%) Relative benefit (Fishers Exact Test p-value) Month of treatment (No. of evaluable patients) IM Cmin Q1 &lt;1165 ng/mL IM Cmin Q2-Q3 1165–3180 ng/mL IM Cmin Q4 &gt;3180 ng/mL Q2-Q3 vs Q1 Q4 vs Q1 *No. of patients achieving MMR/total number of patients evaluable at each visit Month 3 (218) 0/54 (0%) 15/108 (14%) 10/56 (18%) NA (0.0027) NA (0.0013) Month 6 (208) 8/51 (16%) 38/103 (37%) 22/54 (41%) 2.35 (0.0084) 2.60 (0.0052) Month 9 (212) 21/57 (37%) 60/103 (58%) 29/52 (56%) 1.58 (0.013) 1.51 (0.0561) Month 12(214) 21/56 (38%) 62/107 (58%) 30/51 (59%) 1.55 (0.0142) 1.57 (0.0338)
Based on the evaluable population at month 12, patients with higher Cmin at month 1 (&gt;1165 ng/mL, Q2-Q4) achieved MMR faster than patients with lower Cmin (&lt;1165 ng/mL, Q1) (P=0.0149). The MMR rate at 12 months was 58% for Q2-Q4 group and 38% for Q1 group (P=0.0263). In the 400 mg/d group, the MMR rate at month 12 was 24% for patients with Cmin below 851 ng/mL (Q1 for 400 mg/d), compared to 56% for patients with Cmin above 851 ng/mL (Q2-Q4; P=0.0207). In the 800 mg/d arm, the overall MMR at 12 month was 50%, and no significant differences were observed between different Cmin quartiles, although it should be noted that the majority of patients (88%) at this high dose level achieved a Cmin above 1165 ng/mL as compared with 52% for the 400 mg/d group. Using aCmin over 12 months as a rough estimate of exposure including dose changes, a slightly higher incidence of all grade AEs for the most frequently reported AEs such as rash, diarrhea, fatigue, and all cause edema, was observed in patients in the highest quartile but no significant differences in the frequency of grade 3/4 AEs were observed.
Conclusion: In TOPS, IM plasma trough level was proportional to dose and stable over time despite a high inter-patient variability which may have been attributable to dose changes. Patients with a IM Cmin in the lowest quartile showed a lower MMR rate at 12 months, whereas patients in the highest aCmin quartile showed a higher frequency of all grades of some AEs. The TOPS trial confirms previous observations that IM Cmin of approximately &lt;1000 ng/mL are associated with poorer outcomes. Monitoring IM levels can provide an added benefit to CML patients on IM to achieve the best clinical outcomes.