Pharmacokinetics (PK) of PF-02341066, a dual ALK/MET inhibitor after multiple oral doses to advanced cancer patients.

Abstract

2596 Background: PF-02341066 (PF) is a selective, ATP-competitive, small molecule orally bioavailable inhibitor of the ALK and MET/HGF receptor tyrosine kinases being developed for the treatment of cancer. Methods: Preliminary PK data were collected for the first 80 cancer patients enrolled in the ongoing study A8081001, an open-label, multi- center phase I dose-escalation, safety, pharmacokinetic, and exploratory study (J Clin Oncol 27:15s, 2009). PF was administered orally to patients under fasting conditions in continuous 28-day cycles. Doses ranged from 50-200 mg QD and 200-300 mg BID. Serial blood samples were collected on lead-in Day 7, Cycle 1 Day 1, Cycle 1 Day 15, and/or Cycle 2 Day 1; and predose samples were collected on Days 1 and/or 15 of Cycles 2-5. Plasma concentrations of PF were determined using a validated analytical method. Results: Peak concentrations were reached at approximately 4 hours (hrs), followed by a multi-exponential decline with an average terminal half-life of 43 to 51 hrs across doses. PF AUC increased with median accumulation ratios ranging 1.7-3.4 after QD dosing and 4.0-5.9 after BID dosing, respectively. Repeated administration at 250 mg BID (maximum recommended dose for phase 2/3) for ≥15 days produced a median trough plasma concentration of 256 ng/mL (45 nM, free drug), exceeding the target efficacious levels for ALK and MET predicted from preclinical models. Subjects receiving doses ranging from 100-200 mg QD and 200 mg to 300 mg BID generally demonstrated linear PK, as evidenced by proportional increases in mean AUC. PF exposure was similar between Asian (N=13) and non-Asian (N=20) patients at 250 mg BID. Co-administration with a standard high-fat meal appeared not to change the geometric mean of AUC and Cmax of PF following single 250-mg PF doses. A 3.6-fold (90% CI: 2.7-4.9) increase in the single-dose oral midazolam AUC was observed following 28 days of PF dosing at 250 mg BID, suggesting that PF is a moderate CYP3A4 inhibitor. Conclusions: PF AUC generally increased proportionally with doses over the therapeutic dose range studied. PF AUC accumulated by 4.0-5.9-fold after multiple doses with a terminal half-life of 43-51 hrs. A high-fat meal did not appear to change PF PK. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Peter MacCullum Cancer Center, Pfizer