Administration of CI-1033, an irreversible Pan-erbB tyrosine kinase inhibitor, is feasible on a 7-day on, 7-day off schedule: A phase I pharmacokinetic and food effect study
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Calvo, E
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机构:Univ Texas, Inst Drug Dev, Canc Therapy & Res Ctr, Hlth Sci Ctr, San Antonio, TX 78229 USA
Calvo, E
Tolcher, AW
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机构:Univ Texas, Inst Drug Dev, Canc Therapy & Res Ctr, Hlth Sci Ctr, San Antonio, TX 78229 USA
Tolcher, AW
Hammond, LA
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Hammond, LA
Patnaik, A
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Patnaik, A
de Bono, JS
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de Bono, JS
Eiseman, IA
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Eiseman, IA
Olson, SC
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Olson, SC
Lenehan, PF
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Lenehan, PF
McCreery, H
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McCreery, H
LoRusso, P
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LoRusso, P
Rowinsky, EK
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机构:Univ Texas, Inst Drug Dev, Canc Therapy & Res Ctr, Hlth Sci Ctr, San Antonio, TX 78229 USA
Rowinsky, EK
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[1] Univ Texas, Inst Drug Dev, Canc Therapy & Res Ctr, Hlth Sci Ctr, San Antonio, TX 78229 USA
[2] Ann Arbor Labs, Pfizer Global Res & Dev, Ann Arbor, MI USA
Purpose: To determine the maximum tolerated dose of administrating CI-1033, an oral 4-anilinoquinazoline that irreversibly inhibits the tyrosine kinase domain of all erbB subfamilies, on an intermittent schedule, and assess the interaction of CI-1033 with food on the pharmaco fkinetic behavior. Experimental Design: Escalating doses of CI-1033 from a dose level of 300 mg/day for 7 days every other week were administered to patients with advanced solid malignancies. Plasma concentration-time data sets from all evaluable patients were used to develop a population pharmacokinetic model. Noncompartmental methods were used to independently assess the effect of a high-fat meal on CI-1033 absorption and bioavailability. Results: Twenty-four patients were treated with 69 twenty-eight day courses. The incidence of unacceptable toxicity, principally diarrhea and skin rash, was observed at the 300 mg/day dose level. At the 250 mg/day level, toxicity was manageable, and protracted administration was feasible. A one-compartment linear model with first-order absorption and elimination adequately described the pharmacokinetic disposition. CL/F, apparent volume of distribution (V-d/F), and k(a) (mean +/- relative SD) were 280 L/hour +/- 33%, 684 L +/- 20%, and 0.35 hour(-1) +/- 69%, respectively. C-max values were achieved in 2 to 4 hours. Systemic CI-1033 exposure was largely unaffected by administration of a high-fat meal. At 250 mg, concentration values exceeded IC50 values required for prolonged pan-erbB tyrosine kinase inhibition in preclinical assays. Conclusions: The recommended dose on this schedule is 250 mg/day. Its tolerability and the biological relevance of concentrations achieved at the maximal tolerated dose warrant consideration of disease-directed evaluations. This intermittent treatment schedule can be used without regard to meals.