Abstract
Zosuquidar is a potent and specific inhibitor of P-glycoprotein (P-gp). In preliminary experiments, blockade of P-gp for at least 12 h was required to reverse daunorubicin resistance. Because of the short half-life of zosuquidar, we performed a phase I trial of this drug as a 72-h infusion (CIV) in 16 patients during leukemic induction with daunorubicin and cytarabine. Study goals were to establish safety and determine the dose required for P-gp inhibition in NK cells and AML blasts. > 90% P-gp inhibition was achieved within 2h at a plasma threshold of 132 ng/ml zosuquidar. The recommended phase II dose of zosuquidar is 700 mg/day.
Publication types
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Clinical Trial, Phase I
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Multicenter Study
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
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Aged
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Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
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Antineoplastic Combined Chemotherapy Protocols / adverse effects
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Cytarabine / administration & dosage
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Cytarabine / adverse effects
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Daunorubicin / administration & dosage
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Daunorubicin / adverse effects
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Dibenzocycloheptenes / administration & dosage
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Dibenzocycloheptenes / adverse effects
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Drug Resistance, Multiple*
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Drug Resistance, Neoplasm*
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Female
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Humans
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Leukemia, Myeloid, Acute / drug therapy*
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Male
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Middle Aged
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Quinolines / administration & dosage
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Quinolines / adverse effects
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Time Factors
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Dibenzocycloheptenes
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Quinolines
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Cytarabine
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zosuquidar trihydrochloride
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Daunorubicin