Effects Of Carfilzomib (Cfz) On Pharmacokinetics Of Midazolam (Mdz) In Subjects With Solid Tumors

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Introduction: CFZ is a novel, highly selective epoxyketone proteasome inhibitor that has demonstrated durable single-agent antitumor activity in patients (pts) with relapsed or refractory myeloma and solid tumors. PX-171-008 was an open-label, Phase 1b, non-randomized, fixed sequence study to determine the effect of CFZ on the PK of MDZ, a sensitive substrate of human cytochrome P450 3A4. Methods: During Period 1, pts received a single, 2 mg oral dose of MDZ. In Period 2 the same pts received 27 mg/m2 CFZ IV push on Days 1, 2, 8, 9, 15, and 16 of a single 28-day cycle. Oral MDZ was given immediately following CFZ on Days 1 and 16. The primary endpoint was to evaluate the PK of MDZ in the presence or absence of CFZ. The extent of CYP 3A4/5 interaction was evaluated based on fold-change in AUC for MDZ. ICH Guideline for extent of interaction: Strong = > 5-fold change, Moderate 2-5-fold, Weak = 1.25-2. Safety was evaluated by assessment of adverse events (AEs), clinical laboratory tests, physical exams, vital signs, and an ECG. Results: 18 pts (12 female, 6 male) were enrolled. Of these, 12 completed and were eligible for full PK analysis, 5 terminated prior to receiving all 6 doses of CFZ and were included only in the day 1 PK analysis, and 1 discontinued prior to receiving any doses of CFZ and was excluded from all PK and safety analysis. All 17 pts included in the PK analysis had significant exposure to CFZ on Day 1. The results suggest that CFZ does not clinically interact with oral MDZ (not even qualifying as a weak inhibitor of CYP3A4). PK parameters are summarized below. ![Figure][1] All pts experienced at least 1 AE. The most common were fatigue (52.9%), nausea (52.9%), dyspnea (35.3%), anxiety (23.5%), headache (23.5%), and vomiting (23.5%). AEs were primarily Grade 1/2 in severity and were similar to the safety profile in other CFZ studies. Conclusions: Administration of CFZ did not result in a clinically significant impact on the PK of MDZ. The observed safety profiles were similar to those previously reported for each drug. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1298. doi:10.1158/1538-7445.AM2011-1298 [1]: pending:yes