Pharmacokinetic and safety study of weekly irinotecan and oral capecitabine in patients with advanced solid cancers

Sanjay Goel, Kavita Desai, Sirisha Karri, Radharani Gollamudi, Imran Chaudhary, Anca Bulgaru, Andreas Kaubisch, Gary Goldberg, Mark Einstein, Fernando Camacho, Sharyn Baker, Sridhar Mani

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Abstract

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 Tmax 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.

Original languageEnglish (US)
Pages (from-to)237-245
Number of pages9
JournalInvestigational New Drugs
Volume25
Issue number3
DOIs
StatePublished - Jun 2007

Fingerprint

irinotecan
Pharmacokinetics
Safety
Neoplasms
Esterases
Drug Interactions
Ovarian Neoplasms
Area Under Curve
Diarrhea
Capecitabine
Drug Combinations
Neutropenia

Keywords

  • Capecitabine
  • Irinotecan
  • Pharmacokinetics
  • Phase I
  • Solid tumors

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Pharmacokinetic and safety study of weekly irinotecan and oral capecitabine in patients with advanced solid cancers. / Goel, Sanjay; Desai, Kavita; Karri, Sirisha; Gollamudi, Radharani; Chaudhary, Imran; Bulgaru, Anca; Kaubisch, Andreas; Goldberg, Gary; Einstein, Mark; Camacho, Fernando; Baker, Sharyn; Mani, Sridhar.

In: Investigational New Drugs, Vol. 25, No. 3, 06.2007, p. 237-245.

Research output: Contribution to journalArticle

Goel, S, Desai, K, Karri, S, Gollamudi, R, Chaudhary, I, Bulgaru, A, Kaubisch, A, Goldberg, G, Einstein, M, Camacho, F, Baker, S & Mani, S 2007, 'Pharmacokinetic and safety study of weekly irinotecan and oral capecitabine in patients with advanced solid cancers', Investigational New Drugs, vol. 25, no. 3, pp. 237-245. https://doi.org/10.1007/s10637-006-9028-1
Goel, Sanjay ; Desai, Kavita ; Karri, Sirisha ; Gollamudi, Radharani ; Chaudhary, Imran ; Bulgaru, Anca ; Kaubisch, Andreas ; Goldberg, Gary ; Einstein, Mark ; Camacho, Fernando ; Baker, Sharyn ; Mani, Sridhar. / Pharmacokinetic and safety study of weekly irinotecan and oral capecitabine in patients with advanced solid cancers. In: Investigational New Drugs. 2007 ; Vol. 25, No. 3. pp. 237-245.
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AU - Goel, Sanjay

AU - Desai, Kavita

AU - Karri, Sirisha

AU - Gollamudi, Radharani

AU - Chaudhary, Imran

AU - Bulgaru, Anca

AU - Kaubisch, Andreas

AU - Goldberg, Gary

AU - Einstein, Mark

AU - Camacho, Fernando

AU - Baker, Sharyn

AU - Mani, Sridhar

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AB - 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 Tmax 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.

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