A phase I trial of continuous infusion of the multidrug resistance inhibitor zosuquidar with daunorubicin and cytarabine in acute myeloid leukemia.
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.
Lancet
Jeffrey E
JE
Hematologic Malignancies Program, H Lee Moffitt Cancer Center, Tampa, FL, USA.
Baer
Maria R
MR
Duran
George E
GE
List
Alan F
AF
Fielding
Robert
R
Marcelletti
John F
JF
Multani
Pratik S
PS
Sikic
Branimir I
BI
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D003630:Daunorubicin / Q000008:administration & dosage / Q000009:adverse effects; D003986:Dibenzocycloheptenes / Q000008:administration & dosage / Q000009:adverse effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003986:Dibenzocycloheptenes; D011804:Quinolines; D003561:Cytarabine; C095179:zosuquidar trihydrochloride; D003630:Daunorubicin