Population pharmacokinetics of CPT-11 (irinotecan) in gastric cancer patients with peritoneal seeding after its intraperitoneal administration.
OBJECTIVE
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.
Ahn
Byung-Jin
BJ
Medical Science Research Center, Dongguk University, Seoul, Korea.
Choi
Moon Ki
MK
Park
Young Suk
YS
Lee
Jeeyun
J
Park
Se Hoon
SH
Park
Joon Oh
JO
Lim
Ho Yeong
HY
Kang
Won Ki
WK
Ko
Jae-Wook
JW
Yim
Dong-Seok
DS
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D000077146:Irinotecan; D008297:Male; D008962:Models, Theoretical; D009366:Neoplasm Seeding; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin
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