Cefixime allows greater dose escalation of oral irinotecan: a phase I study in pediatric patients with refractory solid tumors.
OBJECTIVE
Irinotecan is active against a variety of malignancies; however, severe diarrhea limits its usefulness. In our phase I study, the intravenous formulation of irinotecan was administered orally daily for 5 days for 2 consecutive weeks (repeated every 21 days) to children with refractory solid tumors. Our objectives were to determine the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of oral irinotecan and to evaluate whether coadministration of cefixime (8 mg/kg/d beginning 5 days before irinotecan and continuing throughout the course) ameliorates irinotecan-induced diarrhea.


METHODS
In separate cohorts, irinotecan doses were escalated from 15 to 45 mg/m2/d without cefixime and then from 45 to 60 and 75 mg/m2/d with cefixime.


RESULTS
Without cefixime, diarrhea was dose limiting at irinotecan 45 mg/m2/d. Myelotoxicity was not significant at any dose. The MTD was 40 mg/m2/d without cefixime but 60 mg/m2/d with cefixime. Systemic exposure to SN-38 at the MTD was significantly higher with cefixime than without cefixime (mean SN-38 area under the curve: 19.5 ng x h/mL; standard deviation [SD], 6.8 ng x h/mL v 10.4 ng x h/mL; SD, 4.3 ng x h/mL, respectively; P = .030).


CONCLUSIONS
Cefixime administered with oral irinotecan is well tolerated in children and allows greater dose escalation of irinotecan. Because diarrhea is a major adverse effect of both intravenous and oral irinotecan, further evaluation of the use of cefixime to ameliorate this adverse effect is warranted.
Furman
Wayne L
WL
Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN 38105-2794l, USA. wayne.furman@stjude.org
Crews
Kristine R
KR
Billups
Catherine
C
Wu
Jianrong
J
Gajjar
Amar J
AJ
Daw
Najat C
NC
Patrick
Christian C
CC
Rodriguez-Galindo
Carlos
C
Stewart
Clinton F
CF
Dome
Jeffrey S
JS
Panetta
John C
JC
Houghton
Peter J
PJ
Santana
Victor M
VM
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D020682:Cefixime / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D003967:Diarrhea / Q000139:chemically induced / Q000517:prevention & control*; D005243:Feces / Q000201:enzymology; D005260:Female; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D007783:Lactones / Q000493:pharmacokinetics; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D012720:Severity of Illness Index
D000972:Antineoplastic Agents, Phytogenic; D007783:Lactones; D000077146:Irinotecan; D020682:Cefixime; D005966:Glucuronidase; D002166:Camptothecin