SAN ANTONIO, TexasIrinotecan is metabolized via CYP3A4 to
the less active oxidative metabolites APC and NPC and is bioactivated in the
liver and intestine by human carboxylesterases (hCE) to the topoisomerase I
inhibitor SN-38 (Figure 1). The pharmacology of irinotecan (Camptosar, CPT-11),
a water-soluble, semisynthetic derivative of camptothecin, was reviewed at the
Vanderbilt University Symposium by John G. Kuhn, PharmD, of the Departments of
Medicine and Pharmacology, University of Texas Health Science Center, San
Antonio, and College of Pharmacy, University of Texas.
"The carbamate prodrug irinotecan and its metabolites are
in reversible pH/protein-dependent equilibrium with their active lactone and
inactive hydroxy acid forms, with an average irinotecan lactone area under the
concentration-time curve (AUC)/total AUC IV of 37%," Dr. Kuhn said. The
average SN-38 lactone/total AUC IV is 55%. The similar ratio for topotecan
(Hycamtin) is 33%.
Converting to Active Form
"Carboxylesterase 2 in the liver is important for the
conversion of irinotecan to the active SN-38 form, which is 94% bound to
albumin," Dr. Kuhn said. SN-38 (and bilirubin) are conjugated by UGT1A1.
Dr. Kuhn said that polymorphisms of UGT1A1 are common and that severe toxicity
has been observed in patients with deficient UGT1A1 (Gilbert’s syndrome).
"Patients with the 7/7 polymorphism in glucuronidation of
SN-38 can expect to have a 50% increase in SN-38 levels. Those with the 6/7
polymorphism can expect a 25% increase in SN-38. In such patients I would think
about using a lower starting dose of irinotecan, then dose escalating,"
Dr. Kuhn said.
MRP2 is one of the liver export pumps responsible for biliary
transport and removal of open forms of irinotecan/SN-38 and of closed and open
forms of SN-38G. Inhibitors of MRP2 include cyclosporin and probenecid.
Dr. Kuhn emphasized the importance of hepatic elimination of
irinotecan. "In patients with elevation of bilirubin, there is a lower
clearance of CPT-11, compared to normal subjects. Elevated transaminases appear
to have no effect on clearance of irinotecan. The driver in irinotecan
clearance appears to be bilirubin," he said.
Oral Administration Tested
Oral irinotecan had significant activity in human tumor
xenografts, so Dr. Kuhn and colleagues tested oral administration of the
intravenous formulation. (Oral formulations are not available in the United
States, although investigational formulations have been tested in clinical
"Because the first patient complained of bitterness, we
were worried about development of anticipatory nausea and vomiting. To prevent
that, we mixed the IV irinotecan with various beverages. We found that
stability was excellent in CranGrape juice but not with CocaCola or other
drinks, so a CranGrape mixture (IV dose diluted in 50 mL D5W) was used in the
study," he said.
The maximum tolerated dose was 66 mg/m2/d. Dose-limiting
toxicity was diarrhea, similar to that seen with IV administration. The lactone
to total AUC ratio for irinotecan was similar with the oral and IV forms (36%
vs 37%), and the ratio for SN-38 was 73% with the oral dose vs 55% with the IV
dose. The SN-38 AUC dose exposure at the MTD was 330 mg • hr/mL with the oral
formulation. Dr. Kuhn reported that oral irinotecan was rapidly absorbed, with
a Tmax of 1 hour.
Dr. Kuhn also reviewed pharmacokinetics and pharmacodynamic
data from trials of irinotecan used in combination regimens. There were no
sequence-dependent side effects or kinetic alterations between irinotecan and
No pharmacokinetics effects were reported for docetaxel
followed by irinotecan or for paclitaxel (Taxol). Mitomycin-C (Mutamycin)
followed 24 hours later by irinotecan had no pharmacokinetics effects, but
mitomycin-C increased topoisomerase I gene expression," he said.
"A recent provocative study showed that 1 µg/mL of SN-38,
which is not a clinically achievable level, used in colorectal cancer cell
lines induced an increase in NFkB," Dr. Kuhn said.
He suggested that this might be a mechanism of chemoresistance and
that future studies should test combinations of irinotecan with
cyclooxygenase-2 (COX-2) inhibitors, which block NFkB.