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Population pharmacokinetics of CPT-11 (irinotecan) in gastric cancer patients with peritoneal seeding after its intraperitoneal administration

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

It is well known that CPT-11 (irinotecan) is biotransformed to its active metabolite, SN-38, by carboxylesterase in the liver and other tissues. However, little is known about its pharmacokinetics (PK) when administered intraperitoneally. The aim of our study was to develop a population pharmacokinetic model for CPT-11 and SN-38 following the intraperitoneal (IP) administration of CPT-11.

Methods

Pharmacokinetic data obtained from 16 gastric adenocarcinoma patients with peritoneal seeding were used. Administered doses ranged from 50 to 250 mg/m2. To measure CPT-11 and SN-38 levels, we collected samples of peritoneal fluid, plasma and urine 0, 0.5, 1.5, 2, 3.5, 8, 12, 25.5, 49 and 56 h after IP infusion. Several multicompartmental pharmacokinetic models were tested for CPT-11 and SN-38 in the sampled peritoneal fluid, plasma and urine. NONMEM ver. 6 was used throughout the model-building process.

Results

Peak concentrations were achieved earlier for peritoneal SN-38 than for plasma SN-38. The apparent metabolic clearance of peritoneal and plasma CPT-11 to peritoneal and plasma SN-38 accounted for 0.2 and 7.3% of the total clearance of peritoneal and plasma CPT-11, respectively. The typical values of steady-state volume of distribution (Vss) (46.6 L/m2), inter-compartment clearance (6.70 L/h/m2) and clearance (16.0 L/h/m2) for plasma CPT-11 were estimated in a two-compartment PK model.

Conclusions

Our results demonstrate that a small fraction of intraperitoneally administered CPT-11 was metabolized in situ to active SN-38 and that the Vss of plasma CPT-11 following IP administration in our patient cohort was lower than that estimated in previous reports following the intravenous administration of CPT-11.

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Transparency declarations

A part of this manuscript was presented at the American Society for Clinical Pharmacology and Therapeutics 2010 annual meeting held in Atlanta, GA, USA. With regard to the conflict of interest, the authors have nothing to declare.

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Authors and Affiliations

  1. Medical Science Research Center, Dongguk University, Seoul, Korea

    Byung-Jin Ahn

  2. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Moon Ki Choi, Young Suk Park, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Ho Yeong Lim & Won Ki Kang

  3. Department of Clinical Pharmacology & Therapeutics, Samsung Medical Center, Seoul, Korea

    Jae-Wook Ko

  4. Department of Pharmacology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-701, South Korea

    Dong-Seok Yim

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  1. Byung-Jin Ahn
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  2. Moon Ki Choi
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Correspondence to Dong-Seok Yim.

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Ahn, BJ., Choi, M.K., Park, Y.S. et al. Population pharmacokinetics of CPT-11 (irinotecan) in gastric cancer patients with peritoneal seeding after its intraperitoneal administration. Eur J Clin Pharmacol 66, 1235–1245 (2010). https://doi.org/10.1007/s00228-010-0885-3

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  • DOI: https://doi.org/10.1007/s00228-010-0885-3

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