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Pharmacology: Pharmacodynamics: Mechanism of action: The active substance in ONIVYDE pegylated liposomal is irinotecan (topoisomerase I inhibitor) encapsulated in a lipid bilayer vesicle or liposome.
Irinotecan is a derivative of camptothecin. Camptothecins act as specific inhibitors of the enzyme DNA topoisomerase I. Irinotecan and its active metabolite SN-38 bind reversibly to the topoisomerase I-DNA complex and induce single-strand DNA lesions which block the DNA replication fork and are responsible for the cytotoxicity. Irinotecan is metabolised by carboxylesterase to SN-38. SN-38 is approximately 1,000 times as potent as irinotecan as an inhibitor of topoisomerase I purified from human and rodent tumour cell lines.
Pharmacodynamic effects: In animal models, ONIVYDE pegylated liposomal has been shown to extend plasma levels of irinotecan and prolong the exposure to the active metabolite SN-38 at the site of the tumour.
Clinical efficacy and safety: The safety and efficacy of ONIVYDE pegylated liposomal were investigated in a multinational, randomised, open label, controlled clinical study (NAPOLI-1) that tested two treatment regimens for patients with metastatic pancreatic adenocarcinoma who had documented disease progression after gemcitabine or gemcitabine-containing therapy. The study was designed to assess the clinical efficacy and safety of ONIVYDE pegylated liposomal monotherapy or ONIVYDE pegylated liposomal +5-FU/LV compared to an active control arm of 5-FU/LV.
Patients randomised to ONIVYDE pegylated liposomal +5-FU/LV received ONIVYDE pegylated liposomal at 70 mg/m2 as an intravenous infusion over 90 minutes, followed by LV 400 mg/m2 intravenously over 30 minutes, followed by 5-FU 2,400 mg/m2 intravenously over 46 hours, administered every 2 weeks. Patients homozygous for the UGT1A1*28 allele were given a lower initial dose of ONIVYDE pegylated liposomal (see Dosage & Administration). Patients randomised to 5-FU/LV received leucovorin 200 mg/m2 intravenously over 30 minutes, followed by 5-FU 2,000 mg/m2 intravenously over 24 hours, administered on Days 1, 8, 15 and 22 of a 6 week cycle. Patients randomised to ONIVYDE pegylated liposomal monotherapy received 100 mg/m2 as an intravenous infusion over 90 minutes every 3 weeks.
Key eligibility criteria for patients with metastatic adenocarcinoma of the pancreas in the NAPOLI-1 clinical study were Karnofsky Performance Status (KPS) ≥ 70, normal bilirubin level, transaminase levels ≤ 2.5 times the ULN or ≤ 5 times the ULN for patients with liver metastases and albumin ≥ 3.0 g/dl.
A total of 417 patients were randomised to the ONIVYDE pegylated liposomal +5-FU/LV arm (N=117), ONIVYDE pegylated liposomal monotherapy arm (N=151) and 5-FU/LV arm (N=149). Patient demographic and entry disease characteristics were well balanced study trial arms.
In the intent to treat (all randomised) population, the median age was 63 years (range 31-87 years), 57% were males, and 61% were Caucasian and 33% were Asian. Mean baseline albumin level was 3.6 g/dl, and baseline KPS was 90-100 in 55% of patients. Disease characteristics included 68% of patients with liver metastases and 31% with lung metastases; 12% of patients had no prior lines of metastatic therapy, 56% of patients had 1 prior line of metastatic therapy, 32% of patients had 2 or more prior lines of metastatic therapy.
Patients received treatment until disease progression or unacceptable toxicity. The primary outcome measure was Overall survival (OS). Additional outcome measures included Progression free survival (PFS) and Objective response rate (ORR). Results are shown in Table 1. Overall survival is illustrated in figure. (See Table 1 and figure.)
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Click on icon to see table/diagram/imageIn the limited number of patients with prior exposure to non-liposomal irinotecan, no benefit of ONIVYDE pegylated liposomal has been demonstrated.
Pharmacokinetics: Absorption: Liposome encapsulation of irinotecan extends circulation and limits distribution relative to those of the non-liposomal irinotecan.
The plasma pharmacokinetics of total irinotecan and total SN-38 were evaluated in patients with cancer who received ONIVYDE pegylated liposomal, as a single agent or as part of combination chemotherapy, at doses between 50 and 155 mg/m2. The pharmacokinetic parameters of total irinotecan and SN-38 analytes, following the administration of ONIVYDE pegylated liposomal 70 mg/m2 are presented in Table 2. (See Table 2.)
Click on icon to see table/diagram/imageDistribution: 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 pegylated liposomal 70 mg/m2 was 2.6 l/m2, which suggests that ONIVYDE pegylated liposomal is largely confined to vascular fluid.
The plasma protein binding of ONIVYDE pegylated liposomal is negligible (< 0.44% of total irinotecan in ONIVYDE pegylated liposomal). 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 pegylated liposomal 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 pegylated liposomal 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 non-liposomal 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 body surface area (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 Dosage & Administration and Precautions).
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: Age and gender: The population pharmacokinetic analysis in patients aged 28 to 87 years, of whom 11% were ≥ 75 years suggests that age had no clinically meaningful effect on the exposure to irinotecan and SN-38.
The population pharmacokinetic analysis in 196 male and 157 female patients suggests that gender had no clinically meaningful effect on the exposure to irinotecan and SN-38 after adjusting for BSA.
Ethnicity: The population pharmacokinetic analysis suggest that Asians have 56% lower total irinotecan average steady state concentration (3.93 [95% CI: 3.68-4.2] and 1.74 [95% CI: 1.58-1.93] mg/l, respectively) and 8% higher total SN-38 average steady state concentration (0.97 [95% CI: 0.92-1.03] and 1.05 [95% CI: 0.98-1.11] ng/ml, respectively) than Caucasians.
Pharmacokinetic/pharmacodynamic relationship: In a pooled analysis from 353 patients, higher plasma SN-38 Cmax was associated with increased likelihood of experiencing neutropenia, and higher plasma total irinotecan Cmax was associated with increased likelihood of experiencing diarrhoea.
In the clinical study demonstrating effectiveness of ONIVYDE pegylated liposomal, higher plasma exposures of total irinotecan and SN-38 for patients in the ONIVYDE pegylated liposomal +5-FU/LV treatment arm were associated with longer OS and PFS as well as with higher ORR (objective response rate).
Toxicology: Preclinical safety data: In single and repeated dose toxicity studies in mice, rats and dogs, the target organs of toxicity were the gastrointestinal tract and the hematologic system. The severity of effects was dose-related and reversible. The no-observed-adverse-effect level (NOAEL) in rats and dogs following 90 min intravenous infusion of ONIVYDE pegylated liposomal once every 3 weeks for 18 weeks was 155 mg/m2.
In safety pharmacology studies in dogs, ONIVYDE pegylated liposomal had no effect on cardiovascular, hemodynamic, electrocardiographic, or respiratory parameters at doses up to 18 mg/kg or 360 mg/m2. No findings indicative of CNS related toxicity were observed in the repeated dose toxicity studies in rats.
Genotoxic and carcinogenic potential: No genotoxicity studies have been performed with ONIVYDE pegylated liposomal. Non-liposomal irinotecan and SN-38 were genotoxic in vitro in the chromosomal aberration test on CHO-cells as well as in the in vivo micronucleus test in mice. However, in other studies with irinotecan they have been shown to be devoid of any mutagenic potential in the Ames test.
No carcinogenicity studies have been performed with ONIVYDE pegylated liposomal. For non-liposomal irinotecan, in rats treated once a week during 13 weeks at the maximum dose of 150 mg/m2, no treatment related tumours were reported 91 weeks after the end of treatment. Under these conditions, there was a significant linear trend with dose for the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas. Due to its mechanism of action, irinotecan is considered a potential carcinogen.
Reproduction toxicity: No reproductive and developmental toxicity studies have been performed with ONIVYDE pegylated liposomal.
Non-liposomal irinotecan was teratogenic in rats and rabbits at doses below the human therapeutic dose. In rats, pups born from treated animals and having external abnormalities showed a decrease in fertility. This was not seen in morphologically normal pups. In pregnant rats there was a decrease in placental weight and in the offspring a decrease in foetal viability and increase in behavioural abnormalities.
Non-liposomal irinotecan caused atrophy of male reproductive organs both in rats and dogs after multiple daily doses of 20 mg/kg and 0.4 mg/kg, respectively. These effects were reversible upon cessation of treatment.
