Tyrosine kinase inhibitor enhances the bioavailability of oral irinotecan in pediatric patients with refractory solid tumors.
OBJECTIVE
To assess the maximum-tolerated dosages (MTDs), and dose-limiting toxicities (DLTs) of the epidermal growth factor receptor inhibitor gefitinib and of intravenous (IV) irinotecan when administered together in children with refractory solid tumors. To assess the effect of gefitinib on the pharmacokinetics of IV irinotecan and on the bioavailability of a single oral dose of irinotecan.


METHODS
IV irinotecan (15 or 20 mg/m(2)) was given daily for 5 days of 2 consecutive weeks. Oral gefitinib (150 or 112.5 mg/m(2)) was concomitantly given daily for 12 or 21 days. A single oral dose of irinotecan was given on day 9 of course 2 to allow pharmacokinetic analysis.


RESULTS
The study enrolled 29 patients with recurrent solid tumors. The 21-day regimen of oral gefitinib with irinotecan was not tolerated. Diarrhea was the most common DLT. The MTD of the combination regimen was 15 mg/m(2)/d of IV irinotecan for 5 days of 2 consecutive weeks and 112.5 mg/m(2)/d of gefitinib given for 12 days. Gefitinib increased the bioavailability of oral irinotecan by four-fold over that observed in historical controls (median, 0.09 v 0.42; P < .000001), reducing the apparent clearance (an inverse measure of exposure) of irinotecan and SN-38 by 37% and 38%, respectively (P < .0001). A partial response was observed in a patient with refractory Ewing sarcoma.


CONCLUSIONS
IV irinotecan given with 12 days of oral gefitinib is well tolerated in children. We observed one partial response. Gefitinib significantly enhances the bioavailability of oral irinotecan. This combination warrants further investigation, particularly with orally administered irinotecan.
Furman
Wayne L
WL
Department of Oncology, St Jude Children's Research Hospital, 262 Danny Thomas Pl, Memphis, TN 38105-3678, USA. wayne.furman@stjude.org
Navid
Fariba
F
Daw
Najat C
NC
McCarville
M Beth
MB
McGregor
Lisa M
LM
Spunt
Sheri L
SL
Rodriguez-Galindo
Carlos
C
Panetta
John C
JC
Crews
Kristine R
KR
Wu
Jianrong
J
Gajjar
Amar J
AJ
Houghton
Peter J
PJ
Santana
Victor M
VM
Stewart
Clinton F
CF
D000284:Administration, Oral; D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics; D001682:Biological Availability; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D004357:Drug Synergism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018675:Toxicity Tests; D055815:Young Adult
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077146:Irinotecan; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib; D002166:Camptothecin
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