Home
Resources
Publications
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

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

Emiliano Calvo, Anthony W Tolcher, Lisa A Hammond, Amita Patnaik, Johan S de Bono, Irene A Eiseman, Stephen C Olson, Peter F Lenehan, Heather McCreery, Patricia Lorusso, Eric K Rowinsky

Clin Cancer Res. 2004 Nov 1;10(21):7112-20.

PMID: 15534081

Abstract:

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 pharmacokinetic 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 (Vd/F), and ka (mean +/- relative SD) were 280 L/hour +/- 33%, 684 L +/- 20%, and 0.35 hour(-1)+/- 69%, respectively. Cmax 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP289499452	CI-1033		289499-45-2	Price

As a specialist in analytical chemical Products, Alfa Chemistry offers consumers a wealth of raw materials and a full range of technologies and services.

QUICK LINKS

HEADQUARTERS

Tel:

Fax:

Email: