Pharmacokinetics of ARRY-543 from a Phase 1 study in cancer patients

C164 Background: ARRY-543 is an ATP-competitive, selective, reversible inhibitor of EGFR and ErbB2 that is being developed for the treatment of cancer. The safety and pharmacokinetics (PK) of ARRY-543 have been assessed in patients as part of a Phase I open-label study with escalating QD and BID dosing.
 Methods: ARRY-543 was administered to successive cohorts of patients with solid tumors. All patients received a single oral dose followed by a one week observation period. Daily dosing (QD or BID) started on Day 8 with the cycle ending on Day 36. Blood samples were collected on Day 1 of dosing (single dose) and on Day 22 (at steady-state). Plasma concentrations of ARRY-543 were quantitated using a validated LC-MS/MS method with a quantitation range of 5 ng/mL to 40 µg/mL (Keystone Analytical, North Wales, PA). The mean inter-batch values for precision and accuracy of analysis were 5.9% and 1.7%, respectively.
 Results: As of July 2007, single dose (n=40) and steady-state (n=33) PK has been assessed at dose levels of 50, 100, 200, 300, and 400 mg. Following single doses of ARRY-543, there was a dose-proportional increase in mean C max and AUC inf values over the dose range studied. Following a 400 mg dose, the mean (± SD) C max value was 2.01 ± 1.04 µg/mL, and the mean AUC inf value was 21.6 ± 17.0 µg-hr/mL. The mean T max value tended to increase somewhat from 1.5 to 3.6 hours post-dose with increasing doses, whereas the mean t 1/2 value was similar for all dose levels (6.6 ± 1.5 hours). Following QD dosing, exposure increased in a dose-proportional manner with a maximum mean AUC 24hr value of 34.2 µg-hr/mL for the 400-mg QD cohort (n=3). The mean accumulation ratio for all QD cohorts was 1.46 ± 0.23. Following BID dosing, exposure increased in a linear, but somewhat greater than dose-proportional, manner. The mean daily steady-state plasma AUC increased from 13.5 to 40.9 to 71.3 µg-hr/mL at doses of 100, 200 and 300 mg BID, respectively. Preliminary data at the 400 mg BID dose shows continued increases in AUC, with a value of 125 µg-hr/mL. At the 300 mg BID dose level, the mean C max and C trough values were 4.53 and 2.06 µg/mL, respectively, giving a mean peak-to-trough value of 2.2 and a mean accumulation ratio of 1.9. Dosing at 300 mg BID was well-tolerated even though the predicted mean plasma concentrations of ARRY-543 were maintained continually at > 2 µg/mL for 28 days. Preliminary evidence of activity was stable disease, with eight of fifteen patients in the 100-300 mg BID cohorts remaining on therapy for 12 - 32+ weeks.
 Conclusions: ARRY-543 has shown excellent pharmacokinetic properties in the Phase 1 study. The systemic exposure of ARRY-543 increased dose-proportionally over the range of 50 to 400 mg with no indication of reaching the maximum absorbable dose. The t 1/2 value remained constant with increasing dose. At steady-state, following continuous BID dosing at 300 mg, the drug was well tolerated, and plasma concentrations were maintained at > 2 µg/mL with a small peak-to-trough ratio.

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