A Phase I Study of the P-Glycoprotein Antagonist Tariquidar in Combination with Vinorelbine

• Published in: Clinical cancer research 2009-05, Vol.15 (10), p.3574-3582
• Main Authors: ABRAHAM, Jame, EDGERLY, Maureen, VAN TELLINGEN, Olaf, BATES, Susan E, FOJO, Tito, WILSON, Richard, CHEN, Clara, RUTT, Ann, BAKKE, Susan, ROBEY, Rob, DWYER, Andrew, GOLDSPIEL, Barry, BALIS, Frank
• Format: Article
• Language: English
• Subjects: ABC transporters; ABCB1; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Agents, Phytogenic - adverse effects; Antineoplastic Agents, Phytogenic - pharmacokinetics; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; Biological and medical sciences; Dose-Response Relationship, Drug; Drug Interactions; drug resistance; Humans; MDR1; Medical sciences; Metabolic Clearance Rate; Middle Aged; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Neutropenia - chemically induced; P-glycoprotein; Pgp antagonists; Pharmacology. Drug treatments; Quinolines - adverse effects; Quinolines - pharmacokinetics; stem cells; tariquidar; Vinblastine - adverse effects; Vinblastine - analogs & derivatives; Vinblastine - pharmacokinetics; Vinorelbine; XR9576; Young Adult; Zosuquidar
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-0938

Purpose: 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. Experimental Design: Patients first received tariquidar alone to assess effects on the accumulation of 99m Tc-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. Results: Twenty-six patients were enrolled. Vinorelbine 20 mg/m 2 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 (2), constipation (2), fatigue (3), myalgia (2), pain (4) and dehydration, depression, diarrhea, ileus, nausea, and vomiting, (all once). A 150-mg dose of tariquidar: (1) reduced liver 99m Tc-sestamibi clearance consistent with inhibition of liver Pgp; (2) increased 99m Tc-sestamibi retention in a majority of tumor masses visible by 99m Tc-sestamibi; and (3) 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. Conclusions: 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.