ROCHESTER, MinnesotaAccording to Richard M. Goldberg, MD,
the potential advantages of oral irinotecan include prolonged blood levels,
less toxicity, greater convenience, and reduced cost. Interestingly, more
complete responses and sustained remissions were associated with oral
irinotecan vs IV administration in mice with CX-1 colon cancer xenografts. Dr.
Goldberg is chair of gastrointestinal oncology research at the Mayo Clinic in
Pharmacology studies in mice showed that oral irinotecan was
rapidly absorbed, with SN-38 detected within 5 minutes of dosing.
"Absolute oral bioavailability was 21%, and the molar ratio of the SN-38
metabolite to irinotecan was three times higher after oral than after
intravenous doses. This may be a consequence of the activity of gut
carboxylesterases," Dr. Goldberg said.
Irinotecan has also been studied as a prolonged infusion given
daily for 5 days for 2 consecutive weeks. Dose-limiting toxicities were
diarrhea and neutropenia, and the maximum tolerated dose (MTD) on this schedule
was 22 mg/m2/d.
"Dr. Mace Rothenberg also tried intravenous irinotecan
given orally," Dr. Goldberg said. "The taste was a problem, and he
finally settled on IV solution mixed with CranGrape juice given on days 1 to 5
every 3 weeks." Twenty-eight patients were treated with this regimen, and
the MTD was 50 mg/m2/d. Dose-limiting toxicities were diarrhea and neutropenia.
Irinotecan peaked in 1 to 2 hours, and SN-38 peaked in 2 to 4 hours.
Powder Filled Capsules
More easily used oral formulations were subsequently developed
including powder-filled capsules and a semi-solid matrix. "These have less
variable bioavailability than the IV form taken orally, and the capsule has a
better shelf life," Dr. Goldberg said.
Powder-filled capsules were tested in a phase I trial in 19
patients. Data submitted for presentation at the 2001 annual meeting of the
American Society of Clinical Oncology (ASCO), describe a series of patients
treated with the capsules daily for 14 days every 3 weeks. Dose-limiting
toxicities were nausea, vomiting, and diarrhea. There was no neutropenia. Dr.
Goldberg said that half-life calculations were precluded by the fact that
plasma irinotecan and metabolites were measurable for only 6 to 10 hours.
"We think that the phase II dose is likely to be 30 mg/m2/d," he
Twenty-three patients have been treated in a phase I trial of
irinotecan powder-filled capsules given daily for 5 days every 3 weeks. Dr.
Goldberg said that the MTD was 50 mg/m2 and that dose-limiting toxicities at 60
mg/m2 were nausea, vomiting, diarrhea, and febrile neutropenia. There were no
objective tumor responses.
Data from a European phase I study that used a daily ´ 5
schedule are also expected to be presented at ASCO. Results included partial
responses in 2 of 47 patients, both in melanomas.
Dr. Goldberg said that data from a recent US phase I trial of
capsules given for 14 days, repeating every 3 weeks, showed no responses in 24
treated patients. The MTD was 30 mg/m2, and dose-limiting toxicity was grade 3
"This points up certain differences in mice vs men,"
Dr. Goldberg said. "In mice the lactone form predominates, there is a high
tumor/blood ratio with oral irinotecan, and irinotecan exists as the
carboxylate or open salt. Salts cause toxicity, while lactones have antitumor
In man, high concentrations of carboxylesterases in the GI tract promote
presystemic conversion to SN-38. Low pH in the GI tract favors the lactone
During the discussion period, Langdon Miller, MD, of Pharmacia
Oncology in Peapack, New Jersey, said the company has moved from the
powder-filled capsules used in most of these studies to the semi-solid matrix
formulation to limit the risk that workers will be exposed to aerosolized
irinotecan powder, which is potentially mutagenic.