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.
OBJECTIVE
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.


METHODS
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.
Calvo
Emiliano
E
Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
Tolcher
Anthony W
AW
Hammond
Lisa A
LA
Patnaik
Amita
A
de Bono
Johan S
JS
Eiseman
Irene A
IA
Olson
Stephen C
SC
Lenehan
Peter F
PF
McCreery
Heather
H
Lorusso
Patricia
P
Rowinsky
Eric K
EK
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D018739:Oncogene Proteins v-erbB / Q000037:antagonists & inhibitors*; D017434:Protein Structure, Tertiary; D013997:Time Factors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009025:Morpholines; D018739:Oncogene Proteins v-erbB; C420268:Canertinib