cer Res. 2006 Jun 15;12:3782-91]
Distribution
Direct measurement of liposomal irinotecan shows that 95% of irinotecan remains liposome-encapsulated during circulation. Non-liposomal irinotecan displays a large volume of distribution (138 l/m2). The volume of distribution of ONIVYDE 80 mg/m2 was 2.6 l/m2, which suggests that ONIVYDE is largely confined to vascular fluid.
The plasma protein binding of ONIVYDE is negligible (< 0.44% of total irinotecan in ONIVYDE). The plasma protein binding of non-liposomal irinotecan is moderate (30% to 68%), and SN-38 is highly bound to human plasma proteins (approximately 95%).
Biotransformation
Irinotecan released from liposome encapsulation follows a similar metabolic pathway reported with non-liposomal irinotecan.
The metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzymes. In vitro studies indicate that irinotecan, SN-38 and another metabolite aminopentane carboxylic acid (APC) do not inhibit cytochrome P-450 isozymes. 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. In the population pharmacokinetic analysis in patients with ONIVYDE using the results of a subset with UGT1A1*28 genotypic testing, in which the analysis adjusted for the lower dose administered to patients homozygous for the UGT1A1*28 allele, patients homozygous (N=14) and non-homozygous (N=244) for this allele had total SN-38 average steady-state concentrations of 1.06 and 0.95 ng/ml, respectively.
Elimination
The disposition of ONIVYDE and non-liposomal irinotecan has not been fully elucidated in humans.
The urinary excretion of non-liposomal irinotecan is 11% to 20%; SN-38 <1%; and SN-38 glucuronide is 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).
Renal impairment
No dedicated pharmacokinetic study has been conducted in patients with renal impairment. In a population pharmacokinetic analysis, mild-to-moderate renal impairment had no effect on the exposure of total SN-38 after adjusting for BSA. The analysis included 68 patients with moderate (CLcr 30-59 ml/min), 147 patients with mild (CLcr 60-89 ml/min) renal impairment, and 135 patients with normal renal function (CLcr > 90 ml/min). There was insufficient data in patients with severe renal impairment (CLcr < 30 ml/min) to assess its effect on pharmacokinetics (see sections 4.2 and 4.4).
Hepatic impairment
No dedicated pharmacokinetic study has been conducted in patients with hepatic impairment. In a population pharmacokinetic analysis, patients with baseline total bilirubin concentrations of 1-2 mg/dl (n=19) had average steady state concentrations for total SN-38 that were increased by 37% (0.98 [95%CI: 0.94-1.02] and 1.29 [95%CI: 1.11-1.5] ng/ml, respectively) compared to patients with baseline bilirubin concentrations of < 1 mg/dl (n=329); however, there was no effect of elevated ALT/AST concentrations on total SN-38 concentrations. No data are available in patients with total bilirubin more than 2 times the ULN.
Other special populations
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