Imatinib PK: Observations From the TIDEL II Study
Authors: White Deborah L. , Saunders Verity , Andrew Menelaou , Rofe Allan , Slader Cassandra , Yeung David T. , Osborn Michael , Mills Anthony K. , Grigg Andrew , Hughes Timothy 
Published: October 2019

Abstract
Abstract 2288
Previous studies have demonstrated that the achievement of an imatinib (IM) trough level of 1000ng/ml in CP-CML patients is associated with a better response. The aim of this sub-study was to perform a detailed assessment of IM plasma levels in the TIDEL II trial, in which patients are treated with IM 600mg/day upfront with subsequent dose escalation to 400mg BID, or switch to nilotinib if pre-determined molecular milestones are not met. Patients failing to achieve a trough level of >1000ng/ml 22 days after the commencement of IM were scheduled to dose escalate to 400mg BID or maximum tolerated dose (MTD).
105 patients were enrolled in Cohort I of this trial. Plasma for trough IM PK testing was collected at day 8 and day 22, then at 3, 6, and 12 months, and IM levels were measured via HPLC. The median IM PK at day 22 was 1550ng/ml (R 0–4680) (Table 1). 21% (22/103 evaluable) of patients failed to achieve 1000g/ml at day 8, 20% (21/103) at day 22, 20% (18/91) at 3 mths, 29% (23/80) at 6 mths and 24% (13/55) at 12 mths. Overall 56/103 patients (54%) failed to achieve plasma IM levels of >1000ng/ml at least once over the study period. In the majority of cases these reductions in IM level were transient. However, detection of an IM level <1000ng/mL beyond day 22 was associated with a concomitant rise (median 1.9 fold; R: 0.6–122.5 fold) in BCR-ABL levels in 22/36 patients, and was sufficient in 40% of cases to trigger mutation analysis. The Y253H mutation was the only mutation found in one patient who had repeated low drug levels. In 3/9 patients the low drug level was associated with a loss of MMR, which was re-established when drug levels rose above 1000ng/ml again. In 3/8 patients in CCyR at the time of PK fall, CCyR was lost, and 2 of these 3 patients were removed from study for compliance. 16/21 patients who had an IM level <1000ng/ml at day 22 dose escalated to 800mg (median 2.25 mths after commencement. R:1-3). 14/16 achieved IM levels >1000ng/ml when reassessed 22 days later. There was a significant difference in BCR-ABL levels at 2 months between this cohort of patients (median 10.7% (IS) Range 0.5–79%) and those who achieved ≥1000ng/ml at day 22 (median 3.01% (IS) Range 0–52.5%. p=0.028). However by 6 months, when all 16 low PK patients had been dose escalated for at least 3 months there was no significant difference between the two cohorts (<1000ng/ml @ day 22 – median BCR-ABL – 0.149% Range 0–9.9% vs ≥1000ng/ml 0.153% Range 0–16.4%. p=0.944) supporting the efficacy of this approach. Furthermore at 3 and 6 mths post escalation there was no significant difference in PK between these 16 patients and those who achieved 1000ng/ml at day 22 (p=0.469 and 0.738 respectively) (Table 1). Twelve patients were dose reduced to 400mg for intolerance (median 3 mths after commencement; R:1-9). For these patients, IM levels at day 22 were significantly higher (median 2110ng/ml; R:920–3860ng/ml) than for all other patients (median 1500; R:0-4680ng/ml, p=0.036). All patients who dose reduced demonstrated a subsequent decrease in IM level (Table 1).
assessed at 3, 6 and 12 months after therapy change
In summary, there is wide interpatient variation in IM levels in patients on 600mg/day. Dose escalation generally resulted in increased IM levels, and improved response. Intolerance is associated with higher IM levels, however high IM levels are not exclusively observed in patients with intolerance. Plasma IM levels <1000ng/ml occurred in approximately half of the patients at least once over the follow up period. Patients whose IM level fell below 1000ng/ml after day 22 often had an associated significant rise in BCR-ABL. Therefore, routine IM plasma testing provides an informative adjunct to BCR-ABL monitoring to guide subsequent treatment decisions.
Table: Comparative trough IM levels in patients on 600mg/day, those dose escalated, and those dose reduced. Trough IM Plasma Level (ng/ml) median (Range) n= Day 8 Day 22 3mth 6 mth 12 mth All 1430(110–4070) 101 1550(0–4680) 103 1580(110–4940) 73 1505(0–4550) 70 1440(220–4870) 47 Dose increase D22* 1690(1210–3100) 16 1660(120–2800) 16 1550(0–3010) 9 Dose decrease* 1060(360–1850) 7 880(0–1900) 9 1535(860–2570) 6

Disclosures:
White: Novartis: Honoraria, Research Funding; BMS: Research Funding. Slader: Novartis Pharmaceuticals: Employment, Equity Ownership. Osborn: Novartis Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. Mills: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria.