A phase I study of the P-glycoprotein antagonist tariquidar in combination with vinorelbine.
A phase I study of the P-glycoprotein antagonist tariquidar in combination with vinorelbine.
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DOI：
10.1158/1078-0432.ccr-08-0938
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发表时间：
2009-05-15
期刊：
影响因子：
--
通讯作者：
Fojo T
中科院分区：
文献类型：
--
作者：
Abraham J;Edgerly M;Wilson R;Chen C;Rutt A;Bakke S;Robey R;Dwyer A;Goldspiel B;Balis F;Van Tellingen O;Bates SE;Fojo T
P-glycoprotein (Pgp) antagonists have had unpredictable pharmacokinetic interactions requiring reductions of chemotherapy. We report a phase I study using tariquidar (XR9576), a potent Pgp antagonist, in combination with vinorelbine. Patients first received tariquidar alone to assess effects on the accumulation of 99mTc-sestamibi in tumor and normal organs and rhodamine efflux from CD56+ mononuclear cells. In the first cycle, vinorelbine pharmacokinetics was monitored after the day 1 and 8 doses without or with tariquidar. In subsequent cycles, vinorelbine was administered with tariquidar. Tariquidar pharmacokinetics was studied alone and with vinorelbine. Twenty-six patients were enrolled. Vinorelbine 20 mg/m2 on day 1 and 8 was identified as the maximum tolerated dose (neutropenia). Nonhematologic grade 3/4 toxicities in 77 cycles included the following: abdominal pain (4 cycles), anorexia, constipation, fatigue, myalgia, pain and dehydration, depression, diarrhea, ileus, nausea, and vomiting, (all once). A 150-mg dose of tariquidar: reduced liver 99mTc-sestamibi clearance consistent with inhibition of liver Pgp; increased 99mTc-sestamibi retention in a majority of tumor masses visible by 99mTc-sestamibi; and blocked Pgp-mediated rhodamine efflux from CD56+ cells over the 48 hours examined. Tariquidar had no effects on vinorelbine pharmacokinetics. Vinorelbine had no effect on tariquidar pharmacokinetics. One patient with breast cancer had a minor response, and one with renal carcinoma had a partial remission. Tariquidar is a potent Pgp antagonist, without significant side effects and much less pharmacokinetic interaction than previous Pgp antagonists. Tariquidar offers the potential to increase drug exposure in drug-resistant cancers.
