12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
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 Clinical Pharmacology (12.3)]. 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.
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 9:
|Cmax - Maximum plasma concentration|
|AUC0–24 - Area under the plasma concentration-time curve from time|
|0 to 24 hours after the end of the 90-minute infusion|
|t1/2 - Terminal elimination half-life|
|Vz - Volume of distribution of terminal elimination phase|
|CL - Total systemic clearance|
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.
Irinotecan is subject to extensive metabolic conversion by various enzyme systems, including esterases that form an active metabolite SN-38, and UGT1A1 which mediates the glucuronidation of SN-38 to form an inactive metabolite. SN-38 glucuronide had 1/50 to 1/100 the activity of SN-38. Patients who are homozygous for either the UGT1A1*28 or *6 alleles, or who are compound heterozygous for these alleles, have higher SN-38 AUC than patients with the wild-type UGT1A1 alleles [see Dosage and Administration (2.3), Warnings and Precautions (5.3), and Clinical Pharmacology (12.5)].
Irinotecan can also undergo CYP3A4-mediated oxidative metabolism to several inactive metabolites, one of which can be hydrolyzed by carboxylesterase to release the active metabolite SN-38.
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).
The pharmacokinetics of irinotecan administered using the weekly schedule was evaluated in a study of 183 patients that was prospectively designed to investigate the effect of age on irinotecan toxicity. Results from this trial indicate that there are no differences in the pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide in patients <65 years of age compared with patients ≥65 years of age. In a study of 162 patients that was not prospectively designed to investigate the effect of age, small (less than 18%) but statistically significant differences in dose-normalized irinotecan pharmacokinetic parameters in patients <65 years of age compared to patients ≥65 years of age were observed. Although dose-normalized AUC0–24 for SN-38 in patients ≥65 years of age was 11% higher than in patients <65 years of age, this difference was not statistically significant. No change in the starting dose is recommended for geriatric patients receiving the weekly dosage schedule of irinotecan [see Dosage and Administration (2)].
Male and Female Patients
The pharmacokinetics of irinotecan do not appear to be influenced by gender.
Racial and Ethnic Groups
The influence of race on the pharmacokinetics of irinotecan has not been evaluated.
Patients with Renal Impairment
The influence of renal impairment on the pharmacokinetics of irinotecan has not been evaluated.
Patients with Hepatic Impairment
Irinotecan clearance is diminished in patients with hepatic impairment 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.
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Dexamethasone, a moderate CYP3A4 inducer, does not appear to alter the pharmacokinetics of irinotecan.
The active metabolite SN-38 is further metabolized via UGT1A1. Genetic variants of the UGT1A1 gene such as the UGT1A1*28 [(TA)7] and *6 alleles lead to reduced UGT1A1 enzyme expression or activity and decreased function to a similar extent.
Individuals who are homozygous or compound (double) heterozygous for these alleles (e.g., *28/*28, *6/*6, *6/*28) are UGT1A1 poor metabolizers and are at increased risk for severe or life-threatening neutropenia from CAMPTOSAR due to elevated systemic exposure to SN-38. The UGT1A1*6/*6 genotype should not be confused with 6/6 genotype, which is sometimes used to represent the genotype of individuals who are wild type for UGT1A1*28. Individuals who are heterozygous for either the UGT1A1*28 or *6 alleles (*1/*6, *1/*28) are UGT1A1 intermediate metabolizers and may also have an increased risk of severe or life-threatening neutropenia [see Dosage and Administration (2.3), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)].
Published studies have shown that individuals with UGT1A1*28 and *6 alleles may be at an increased risk of severe diarrhea. The risk evidence appears greater in UGT1A1*28 and *6 homozygous patients and in those taking irinotecan doses > 125 mg/m2 [see Warnings and Precautions (5.1)].
UGT1A1*28 and *6 alleles occur at various frequencies in different populations. Approximately 20% of Black or African American, 10% of White, and 2% of East Asian individuals are homozygous for the UGT1A1*28 allele. Approximately 2–6 % of East Asian individuals are homozygous for the UGT1A1*6 allele. The UGT1A1*6 allele is uncommon in Black or African American or in White individuals. Decreased function alleles other than UGT1A1*28 and *6 may be present in certain populations.