Pharmacokinetic and safety study of weekly irinotecan and oral capecitabine in patients with advanced solid cancers.
BACKGROUND
Capecitabine and irinotecan have demonstrated in vitro synergistic anti-cancer activity, and both are substrates for carboxyl esterases (CES). We conducted a study to identify a safe dose and potential drug-drug interactions of this combination.


METHODS
This was an open-label phase I dose escalation trial. Irinotecan was given as a 30 min infusion on days 1 and 8, and capecitabine on days 1-14 of a 21-day cycle. Plasma for pharmacokinetic analyses was drawn on days 1 and 8.


RESULTS
Forty-seven patients with advanced solid tumors received 202 cycles of chemotherapy in 6 dose cohorts. At the highest dose tested, 1 of 3 patients developed fatal neutropenia and gram-negative sepsis. At dose level 5 (100/2000), 2 of 28 patients developed cycle 1 DLT-grade 3 diarrhea/vomiting, and grade 3 diarrhea. Responses were observed in 9 of 35 (5 of 9 ovarian cancer) evaluable patients. The AUC((0-last)) of irinotecan, SN-38G, and APC were similar on days 1 and 8. However, SN-38 T(max) was longer on Day 8 (0.88 h vs. 1.23 h, p = 0.012). While SN-38 AUC((0-last)) was lower on day 8 by 35%, this was not statistically significant (p = 0.123).


CONCLUSIONS
Capecitabine results in a significantly delayed conversion of irinotecan to SN-38, suggesting drug-drug interaction at the level of CES. This suggests caution should be used when irinotecan is combined with substrates of CES, and warrants further study. The combination of irinotecan and capecitabine is safe and well tolerated at 100/2000, and warrants further evaluation in ovarian and breast cancer.
Goel
Sanjay
S
Department of Oncology, Albert Einstein College of Medicine and Cancer Center, Bronx, NY 10461, USA. sgoel@montefiore.org
Desai
Kavita
K
Karri
Sirisha
S
Gollamudi
Radharani
R
Chaudhary
Imran
I
Bulgaru
Anca
A
Kaubisch
Andreas
A
Goldberg
Gary
G
Einstein
Mark
M
Camacho
Fernando
F
Baker
Sharyn
S
Mani
Sridhar
S
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood; D000069287:Capecitabine; D043182:Carboxylesterase / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D016896:Treatment Outcome
C100720:RPR 121056; C106003:SN38-Glu; D003841:Deoxycytidine; D000069287:Capecitabine; D000077146:Irinotecan; D043182:Carboxylesterase; D005472:Fluorouracil; D002166:Camptothecin