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

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/m(2). 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/m(2)), inter-compartment clearance (6.70 L/h/m(2)) and clearance (16.0 L/h/m(2)) 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.

journal_name

Eur J Clin Pharmacol

journal_title

European journal of clinical pharmacology

authors

Ahn BJ,Choi MK,Park YS,Lee J,Park SH,Park JO,Lim HY,Kang WK,Ko JW,Yim DS

doi

10.1007/s00228-010-0885-3

subject

Has Abstract

pub_date

2010-12-01 00:00:00

pages

1235-45

issue

eissn

0031-6970

issn

1432-1041

journal_volume

pub_type

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