Phase I pharmacokinetic, food effect, and pharmacogenetic study of oral irinotecan given as semisolid matrix capsules in patients with solid tumors.
OBJECTIVE
To characterize the maximum-tolerated dose, recommended dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and food effect of orally administered irinotecan formulated as new semisolid matrix capsules.


METHODS
Irinotecan was given orally in fasted patients once daily for 5 consecutive days and repeated every 3 weeks. Patients were randomly assigned to take the drug along with a high-fat, high-calorie breakfast for the administration at day 1 of the first or second cycle. Dosages tested were 70 and 80 mg/m(2)/day.


RESULTS
Twenty-five patients received 101 cycles of therapy (median two cycles, range 1-15). During the first cycle, grade 3 delayed diarrhea and grade 3 fever were the DLTs at the dosage of 80 mg/m(2)/day in three out of five patients. Hematologic and nonhematologic toxicities were mild to moderate. Exposure to the active metabolite SN-38 was relatively high compared with i.v. infusion, but no relevant accumulation was observed. Food had no significant effect on irinotecan pharmacokinetics. One confirmed partial remission and 10 disease stabilizations were observed in previously treated patients. No association was found between the UGT1A1*28 genotype and the risk of severe irinotecan-induced toxicity.


CONCLUSIONS
For oral irinotecan, a dose of 70 mg/m(2)/day for 5 consecutive days every 3 weeks is recommended for further studies. Delayed diarrhea was the main DLT, similar to that observed with intravenously administered irinotecan. This study confirms that oral administration of irinotecan is feasible and may have favorable pharmacokinetic characteristics.
Soepenberg
Otto
O
Daniel den Hoed Cancer Center, Department of Medical Oncology, Erasmus University Medical Center Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands. o.soepenberg@erasmusmc.nl
Dumez
Herlinde
H
Verweij
Jaap
J
de Jong
Floris A
FA
de Jonge
Maja J A
MJ
Thomas
José
J
Eskens
Ferry A L M
FA
van Schaik
Ron H N
RH
Selleslach
Johan
J
Ter Steeg
Judith
J
Lefebvre
Patricia
P
Assadourian
Sylvie
S
Sanderink
Ger-Jan
GJ
Sparreboom
Alex
A
van Oosterom
Allan T
AT
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D002214:Capsules; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D003967:Diarrhea / Q000139:chemically induced; D004041:Dietary Fats / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D013921:Thrombocytopenia / Q000139:chemically induced; D013997:Time Factors; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced; D000099148:UGT1A1 Enzyme
D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D002214:Capsules; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D004041:Dietary Fats; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme; C104464:CYP3A protein, human