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.
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.
Authors: Nasser Hanna; Paul A Bunn; Corey Langer; Lawrence Einhorn; Troy Guthrie; Thaddeus Beck; Rafat Ansari; Peter Ellis; Michael Byrne; Mark Morrison; Subramanian Hariharan; Benjamin Wang; Alan Sandler Journal: J Clin Oncol Date: 2006-05-01 Impact factor: 44.544
Authors: Thomas G Roberts; Bernardo H Goulart; Lee Squitieri; Sarah C Stallings; Elkan F Halpern; Bruce A Chabner; G Scott Gazelle; Stan N Finkelstein; Jeffrey W Clark Journal: JAMA Date: 2004-11-03 Impact factor: 56.272
Authors: J P Delord; J Y Pierga; V Dieras; F Bertheault-Cvitkovic; F L Turpin; F Lokiec; I Lochon; E Chatelut; P Canal; R Guimbaud; D Mery-Mignard; X Cornen; Z Mouri; R Bugat Journal: Br J Cancer Date: 2005-03-14 Impact factor: 7.640
Authors: Femke M de Man; Andrew K L Goey; Ron H N van Schaik; Ron H J Mathijssen; Sander Bins Journal: Clin Pharmacokinet Date: 2018-10 Impact factor: 6.447