Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the enzyme topoisomerase I which relieves torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent religation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topoisomerase I, DNA, and either irinotecan or SN-38. Mammalian cells cannot efficiently repair these double-strand breaks.
Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38. SN-38 is formed from irinotecan by
carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino
side chain. SN-38 is approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase I purified
from human and rodent tumor cell lines. In vitro cytotoxicity assays show that the potency of SN-38 relative to
irinotecan varies from 2- to 2000-fold. However, the plasma area under the concentration versus time curve (AUC) values
for SN-38 are 2% to 8% of irinotecan and SN-38 is 95% bound to plasma proteins compared to approximately 50% bound
to plasma proteins for irinotecan (see Pharmacokinetics). The precise contribution of SN-38 to the activity of CAMPTOSAR is thus
unknown. Both irinotecan and SN-38 exist in an active lactone form and an inactive hydroxy acid anion form.
A pH-dependent equilibrium exists between the two forms such that an acid pH promotes the formation of the
lactone, while a more basic pH favors the hydroxy acid anion form.
Administration of irinotecan has resulted in antitumor activity in mice bearing
cancers of rodent origin and in human carcinoma xenografts of various histological
types.
Pharmacokinetics
After intravenous infusion of irinotecan in humans, irinotecan plasma concentrations decline in a multiexponential manner, with a mean terminal elimination half-life of about 6 to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 to 20 hours. The half-lives of the lactone (active) forms of irinotecan and SN-38 are similar to those of total irinotecan and SN-38, as the lactone and hydroxy acid forms are in equilibrium.
Over the recommended dose range of 50 to 350 mg/m2, the
AUC of irinotecan increases linearly with dose; the AUC of SN-38 increases less
than proportionally with dose. Maximum concentrations of the active metabolite SN-38
are generally seen within 1 hour following the end of a 90-minute infusion of irinotecan.
Pharmacokinetic parameters for irinotecan and SN-38 following a 90-minute infusion
of irinotecan at dose levels of 125 and 340 mg/m2 determined
in two clinical studies in patients with solid tumors are summarized in Table 1:
Table 1.Summary of Mean (±Standard Deviation) Irinotecan and SN-38 Pharmacokinetic
Parameters in Patients with Solid Tumors
Irinotecan exhibits moderate plasma protein binding (30% to 68% bound). SN-38 is
highly bound to human plasma proteins (approximately 95% bound). The plasma protein
to which irinotecan and SN-38 predominantly binds is albumin.
Metabolism and Excretion: The metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzymes and primarily occurs in the liver. SN-38 is subsequently conjugated predominantly by the enzyme UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite. UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A1*28 polymorphism. Approximately 10% of the North American population is homozygous for the UGT1A1*28 allele. In a prospective study, in which irinotecan was administered as a single-agent on a once-every-3-week schedule, patients who were homozygous for UGT1A1*28 had a higher exposure to SN-38 than patients with the wild-type UGT1A1 allele (See WARNINGS and DOSAGE AND ADMINISTRATION). SN-38 glucuronide had 1/50 to 1/100 the activity of SN-38 in cytotoxicity assays using two cell lines in vitro. The disposition of irinotecan has not been fully elucidated in humans. The urinary excretion of irinotecan is 11% to 20%; SN-38, <1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours following administration of irinotecan in two patients ranged from approximately 25% (100 mg/m2) to 50% (300 mg/m2).
Pharmacokinetics in Special Populations
Geriatric: In studies using the weekly schedule, the terminal half-life of irinotecan was 6.0 hours in patients who were 65
years or older and 5.5 hours in patients younger than 65 years. Dose-normalized AUC0-24 for SN-38 in patients who were at least 65
years of age was 11% higher than in patients younger than 65 years. No change in the starting dose is recommended for geriatric
patients receiving the weekly dosage schedule of irinotecan. The pharmacokinetics of irinotecan given once every 3 weeks has not
been studied in the geriatric population; a lower starting dose is recommended in patients 70 years or older based on clinical
toxicity experience with this schedule (see DOSAGE AND ADMINISTRATION).
Pediatric: See Pediatric Use under PRECAUTIONS.
Gender: The pharmacokinetics of irinotecan do not appear to be influenced
by gender.
Race: The influence of race on the pharmacokinetics of irinotecan has not
been evaluated.
Hepatic Insufficiency: Irinotecan clearance is diminished in patients with
hepatic dysfunction while exposure to the active metabolite SN-38 is increased relative
to that in patients with normal hepatic function. The magnitude of these effects
is proportional to the degree of liver impairment as measured by elevations in total
bilirubin and transaminase concentrations. However, the tolerability of irinotecan
in patients with hepatic dysfunction (bilirubin greater than 2 mg/dl) has not been
assessed sufficiently, and no recommendations for dosing can be made (see DOSAGE
AND ADMINISTRATION and PRECAUTIONS: Patients at Particular Risk Sections).
Renal Insufficiency: The influence of renal insufficiency on the pharmacokinetics
of irinotecan has not been evaluated. Therefore, caution should be undertaken in
patients with impaired renal function. Irinotecan is not recommended for use in
patients on dialysis.
Drug-Drug Interactions
5-fluorouracil (5-FU) and leucovorin (LV): In a phase 1 clinical study involving
irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) in 26 patients with solid
tumors, the disposition of irinotecan was not substantially altered when the drugs
were co-administered. Although the Cmax and AUC0-24
of SN-38, the active metabolite, were reduced (by 14% and 8%, respectively) when
irinotecan was followed by 5-FU and LV administration compared with when irinotecan
was given alone, this sequence of administration was used in the combination trials
and is recommended (see DOSAGE AND ADMINISTRATION). Formal in vivo or in vitro drug
interaction studies to evaluate the influence of irinotecan on the disposition of
5-FU and LV have not been conducted.
Anticonvulsants: Exposure to irinotecan and its active metabolite SN-38 is
substantially reduced in adult and pediatric patients concomitantly receiving the
CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital or carbamazepine.
The appropriate starting dose for patients taking these anticonvulsants has not
been formally defined. The following drugs are also CYP3A4 inducers: rifampin, rifabutin.
For patients requiring anticonvulsant treatment, consideration should be given to
substituting non-enzyme inducing anticonvulsants at least 2 weeks prior to initiation
of irinotecan therapy. Dexamethasone does not appear to alter the pharmacokinetics
of irinotecan.
St. John's Wort: St. John's Wort is an inducer of CYP3A4 enzymes.
Exposure to the active metabolite SN-38 is reduced in patients receiving concomitant
St. John's Wort. St. John's Wort should be discontinued at least 2 weeks
prior to the first cycle of irinotecan, and St. John's Wort is contraindicated
during irinotecan therapy.
Ketoconazole: Ketoconazole is a strong inhibitor of CYP3A4 enzymes. Patients
receiving concomitant ketoconazole have increased exposure to irinotecan and its
active metabolite SN-38. Patients should discontinue ketoconazole at least 1 week
prior to starting irinotecan therapy and ketoconazole is contraindicated during
irinotecan therapy.
Neuromuscular blocking agents: Interaction between irinotecan and neuromuscular
blocking agents cannot be ruled out. Irinotecan has anticholinesterase activity,
which may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular
blockade of non-depolarizing drugs may be antagonized.
Atazanavir sulfate: Coadministration of atazanavir sulfate, a CYP3A4 and
UGT1A1 inhibitor has the potential to increase systemic exposure to SN-38, the active
metabolite of irinotecan. Physicians should take this into consideration when co-administering
these drugs.