Pharmacokinetics (PK), safety and tolerability of atrasentan (ABT-627, ATN) in combination with docetaxel (DOC) in men with hormone refractory prostate cancer (HRPC)

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14512 Background: ATN (Xinlay) is an oral selective endothelin A receptor antagonist in Phase III clinical development for the treatment of HRPC. ATN is extensively metabolized by oxidation and glucuronidation. In vitro, CYP3A is the predominant isozyme involved in oxidative metabolism of ATN and DOC; ATN inhibits CYP3A with an IC50 of ∼3 μM (15-fold the mean plasma Cmax for 10 mg/d ATN). Methods: 11 men with HRPC received DOC 75 mg/m2 by 1-h IV infusion on day (D) 1 of each 21-D cycle (C), and ATN 10 mg po qd starting D8C1 and prednisone(Pred) 5 mg orally twice daily.Three oral doses of dexamethasone 8 mg were administered starting 12 hours before DOC. On coadministration days, ATN was taken at the start of the DOC infusion. PK were to be determined over 24 h following DOC alone (D1C1) and in combination with ATN (D1C2), and following ATN alone (D20C1) and in combination with DOC (D1C2). Plasma concentrations of ATN and DOC were determined using a validated LC/MS/MS method. Results: Preliminary PK results are summarized (N = 10, mean ± SD) in the table below. Some patients (pts) had D1C2 PK performed D1C4 (N = 4), D1C5 (N = 3) or not at all (N = 1). No unexpected adverse events (AE) were observed. One subject experienced neutropenic fever related to DOC. This resolved with treatment and ATN/DOC was resumed. Efficacy: 3/5 DOC naive and 2/6 DOC resistant pts had a >50% post treatment PSA decline. One DOC resistant pt demontrated post treatment calcicfication of liver metastases accompanied by a >45% PSA decline. Conclusions: No PK interaction was observed between ATN and DOC when coadministered at full standard single agent dosages implying 10 mg QD ATN did not alter CYP3A4 activity in gut or liver. Treatment with ATN/DOC was well tolerated and demonstrated activity in DOC resistant pts, further justifying a planned Southwest Oncology Group phase III study comparing ATN/DOC/Pred to DOC/Pred. [Table: see text] [Table: see text]

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.