Mechanism Of Action
Irinotecan liposome injection is a topoisomerase 1
inhibitor encapsulated in a lipid bilayer vesicle or liposome. Topoisomerase 1
relieves torsional strain in DNA by inducing single-strand breaks. Irinotecan
and its active metabolite SN-38 bind reversibly to the topoisomerase 1-DNA
complex and prevent re-ligation of the single-strand breaks, leading to
exposure time-dependent double-strand DNA damage and cell death. In mice
bearing human tumor xenografts, irinotecan liposome administered at irinotecan
HCl-equivalent doses 5-fold lower than irinotecan HCl achieved similar
intratumoral exposure of SN-38.
The plasma pharmacokinetics of total irinotecan and total
SN-38 were evaluated in patients with cancer who received ONIVYDE, as a single
agent or as part of combination chemotherapy, at doses between 50 and 155 mg/m²
and 353 patients with cancer using population pharmacokinetic analysis.
The pharmacokinetic parameters of total irinotecan and
total SN-38 following the administration of ONIVYDE 70 mg/m² as a single agent
or part of combination chemotherapy are presented in Table 4.
Table 4: Summary of Mean (±Standard Deviation) Total
Irinotecan and Total SN-38
|Cmax: Maximum plasma concentration
AUC0-∞: Area under the plasma concentration curve extrapolated to time
t½: Terminal elimination half-life
Vd: Volume of distribution
Over the dose range of 50 to 155 mg/m², the Cmax and AUC of total irinotecan
increases with dose. Additionally, the Cmax of total SN-38 increases
proportionally with dose; however, the AUC of total SN-38 increases less than
proportionally with dose.
Direct measurement of irinotecan liposome showed that 95%
of irinotecan remains liposome-encapsulated, and the ratios between total and
encapsulated forms did not change with time from 0 to 169.5 hours post-dose.
The mean volume of distribution is summarized in Table 4.
Plasma protein binding is < 0.44% of the total
irinotecan in ONIVYDE.
The metabolism of irinotecan liposome has not been
evaluated. Irinotecan is subject to extensive metabolic conversion by various
enzyme systems, including esterases to form the active metabolite SN-38, and
UGT1A1 mediating glucuronidation of SN-38 to form the inactive glucuronide
metabolite SN-38G. Irinotecan can also undergo CYP3A4-mediated oxidative
metabolism to several inactive oxidation products, one of which can be
hydrolyzed by carboxylesterase to release SN-38. In the population
pharmacokinetic analysis 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.
The disposition of ONIVYDE has not been elucidated in
humans. Following administration of irinotecan HCl , 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 HCl in two patients, ranged from approximately 25% (100 mg/m²) to
50% (300 mg/m²).
Age, Gender, and Renal Impairment
The population pharmacokinetic analysis suggests that age
(28 to 87 years) had no clinically meaningful effect on the exposure of
irinotecan and SN-38.
The population pharmacokinetic analysis suggests that
gender (196 males and 157 females) had no clinically meaningful effect on the
exposure of irinotecan and SN-38 after adjusting for body surface area (BSA).
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) renal impairment, 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.
Ethnicity: The population pharmacokinetic analysis
suggests that Asians (East Asians, N=150) have 56% lower total irinotecan
average steady state concentration and 8% higher total SN-38 average steady
state concentration than Whites (N=182).
Hepatic Impairment: The pharmacokinetics of
irinotecan liposome have not been studied in patients with hepatic impairment.
In a population pharmacokinetic analysis, patients with baseline bilirubin
concentrations of 1-2 mg/dL (N=19) had average steady state concentrations for
total SN-38 that were increased by 37% 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 bilirubin > 2 mg/dL.
In a population pharmacokinetic analysis, the
pharmacokinetics of total irinotecan and total SN-38 were not altered by the
co-administration of fluorouracil/leucovorin.
Following administration of irinotecan HCl, dexamethasone,
a moderate CYP3A4 inducer, does not alter the pharmacokinetics of irinotecan.
In vitro studies indicate that irinotecan, SN-38 and
another metabolite, aminopentane carboxylic acid (APC), do not inhibit
cytochrome P-450 isozymes.
Individuals who are homozygous for the UGT1A1*28 allele
are at increased risk for neutropenia from irinotecan HCl. In Study 1, patients
homozygous for the UGT1A1*28 allele (N=7) initiated ONIVYDE at a reduced dose
of 50 mg/m² in combination with 5-FU/LV. The frequency of Grade 3 or 4
neutropenia in these patients [2 of 7 (28.6% )] was similar to the frequency in
patients not homozygous for the UGT1A1*28 allele who received a starting dose
of ONIVYDE of 70 mg/m² [30 of 110 (27.3%)].
The efficacy of ONIVYDE was evaluated in Study 1, a
three-arm, randomized, open-label trial in patients with metastatic pancreatic
adenocarcinoma with documented disease progression, after gemcitabine or
gemcitabine-based therapy. Key eligibility criteria included Karnofsky
Performance Status (KPS) ≥ 70, serum bilirubin within institution limits
of normal, and albumin ≥ 3.0 g/dL. Patients were randomized to receive
ONIVYDE plus fluorouracil/leucovorin (ONIVYDE/5-FU/LV), ONIVYDE, or
fluorouracil/leucovorin (5-FU/LV). Randomization was stratified by ethnicity
(White vs. East Asian vs. other), KPS (70-80 vs. 90-100), and baseline albumin
level ( ≥ 4 g/dL vs. 3.0-3.9 g/dL). Patients randomized to ONIVYDE/5-FU/LV
received ONIVYDE 70 mg/m² as an intravenous infusion over 90 minutes, followed
by leucovorin 400 mg/m² intravenously over 30 minutes, followed by fluorouracil
2400 mg/m² intravenously over 46 hours, every 2 weeks. The ONIVYDE dose of 70
mg/m² is based on irinotecan free base (equivalent to 80 mg/m² of irinotecan as
the hydrochloride trihydrate). Patients randomized to ONIVYDE as a single agent
received ONIVYDE 100 mg/m² as an intravenous infusion over 90 minutes every 3
weeks. Patients randomized to 5-FU/LV received leucovorin 200 mg/m² intravenously
over 30 minutes, followed by fluorouracil 2000 mg/m² intravenously over 24
hours, administered on Days 1, 8, 15 and 22 of a 6-week cycle. Patients
homozygous for the UGT1A1*28 allele initiated ONIVYDE at a reduced dose (50
mg/m² ONIVYDE, if given with 5-FU/LV or 70 mg/m² ONIVYDE as a single agent).
When ONIVYDE was withheld or discontinued for adverse reactions, 5-FU was also
withheld or discontinued. When the dose of 15
ONIVYDE was reduced for adverse reactions, the dose of
5-FU was reduced by 25%. Treatment continued until disease progression or
The major efficacy outcome measure was overall survival
(OS) with two pair-wise comparisons: ONIVYDE versus 5-FU/LV and ONIVYDE/5-FU/LV
versus 5-FU/LV. Additional efficacy outcome measures were progression-free
survival (PFS) and objective response rate (ORR). Tumor status assessments were
conducted at baseline and every 6 weeks thereafter. The trial was initiated as
a two-arm study and amended after initiation to include a third arm
(ONIVYDE/5-FU/LV). The comparisons between the ONIVYDE/5-FU/LV and the 5-FU/LV
arms are limited to patients enrolled in the 5-FU/LV arm after this protocol
Four hundred seventeen patients were randomized to:
ONIVYDE/5-FU/LV (N=117), ONIVYDE (N=151), or 5-FU/LV (N=149). Baseline
demographics and tumor characteristics for the 236 patients randomized to
ONIVYDE/5-FU/LV or 5-FU/LV (N=119) after the addition of the third arm to the
study were a median age of 63 years (range 34-81 years) and with 41% ≥ 65
years of age; 58% were men; 63% were White, 30% were Asian, 3% were Black or
African American, and 5% were other. Mean baseline albumin level was 3.97 g/dL,
and baseline KPS was 90-100 in 53% of patients. Disease characteristics
included liver metastasis (67%) and lung metastasis (31%). A total of 13% of
patients received gemcitabine in the neoadjuvant/adjuvant setting only, 55% of
patients had 1 prior line of therapy for metastatic disease, and 33% of
patients had 2 or more prior lines of therapy for metastatic disease. All
patients received prior gemcitabine (alone or in combination with another
agent), 54% received prior gemcitabine in combination with another agent, and
13% received prior gemcitabine in combination with nab-paclitaxel.
Study 1 demonstrated a statistically significant
improvement in overall survival for the ONIVYDE/5-FU/LV arm over the 5-FU/LV
arm as summarized in Table 5 and Figure 1.
There was no improvement in overall survival for the
ONIVYDE arm over the 5-FU/LV arm (hazard ratio=1.00, p-value=0.97 (two-sided
Table 5: Efficacy Results from Study 1†
| Number of Deaths, n (%)
| Median Overall Survival (months)
| (95% CI)
| Hazard Ratio (95% CI)
||0.68 (0.50, 0.93)
| p-value (log-rank test)
| Death or Progression, n (%)
| Median Progression-Free Survival (months)
| (95% CI)
| Hazard Ratio (95% CI)
||0.55 (0.41, 0.75)
|Objective Response Rate
| Confirmed Complete or Partial Response n (%)
|† 5-FU/LV=5-fluorouracil/leucovorin; CI=confidence
Figure 1: Overall Survival
1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html