Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: other antineoplastic agents, combinations of antineoplastic agents, cytarabine and daunorubicin, ATCcode: L01XY01.

Mechanism of action
Vyxeos liposomal is a liposomal formulation of a fixed combination of daunorubicin and cytarabine in a 1:5 molar ratio. The 1:5 molar ratio has been shown in vitro and in vivo to maximise synergistic antitumour activity in AML.

Daunorubicin has antimitotic and cytotoxic activity, which is achieved by forming complexes with DNA, inhibiting topoisomerase II activity, inhibiting DNA polymerase activity, affecting regulation of gene expression, and producing DNA-damaging free radicals.

Cytarabine is a cell cycle phase-specific antineoplastic agent, affecting cells only during the S-phase of cell division. Intracellularly, cytarabine is converted into cytarabine-5-triphosphate (ara-CTP), which is the active metabolite. The mechanism of action is not completely understood, but it appears that ara-CTP acts primarily through inhibition of DNA synthesis. Incorporation into DNA and RNA may also contribute to cytarabine cytotoxicity. Cytarabine is cytotoxic to proliferating mammalian cells in culture.

Vyxeos liposomal liposomes exhibit a prolonged plasma half-life following intravenous infusion, with greater than 99% of the daunorubicin and cytarabine in the plasma remaining encapsulated within the liposomes. Vyxeos liposomal delivers a synergistic combination of daunorubicin and cytarabine to leukaemia cells for a prolonged period of time. Based on data in animals, Vyxeos liposomal liposomes accumulate and persist in high concentration in the bone marrow, where they are preferentially taken up intact by leukaemia cells in an active engulfment process. In leukaemia-bearing mice, the liposomes are taken up by leukaemia cells to a greater extent than by normal bone marrow cells. After internalisation, Vyxeos liposomal liposomes undergo degradation, releasing daunorubicin and cytarabine within the intracellular environment, enabling the medicinal products to exert their synergistic antineoplastic activity.

Clinical efficacy and safety
The efficacy of Vyxeos liposomal in adults for the treatment of newly diagnosed AML was evaluated in a single controlled clinical study (Study 301) and the efficacy of Vyxeos liposomal in paediatric patients for the treatment of relapsed AML was evaluated in a single clinical study AAML 1421.

Study 301 in patients with untreated high risk AML
Study 301 was a Phase 3 randomised, multicentre, open-label, parallel-arm, superiority study which evaluated Vyxeos liposomal vs. a standard combination of cytarabine and daunorubicin (7+3) in 309 patients between 60 to 75 years of age with untreated high-risk AML. Patients with the following AML sub-types were included in the study: therapy-related AML (t-AML), myelodysplastic syndrome AML (MDS AML) and chronic myelomonocytic leukaemia AML (CMMoL AML) with documented history of MDS or CMMoL prior to transformation to AML, and de novo AML with karyotype changes characteristic of myelodysplasia, (per 2008 WHO criteria).

The study included 2 phases, 1) Treatment Phase during which patients received up to 2 induction and 2 consolidation courses, and 2) a Follow-up Phase, which began 30 days after the last induction or consolidation course and continued for up to 5 years from randomisation. The number of inductions and consolidations a patient received depended upon Complete Response (CR) or Complete Response with incomplete recovery (CRi), which was confirmed by bone marrow assessment. In clinical studies only, Vyxeos liposomal 100 units/m2/day (equivalent to 44 mg/100 mg/m2) was administered intravenously over 90 minutes on days 1, 3, and 5 for the first induction and on days 1 and 3 for patients requiring a second induction. A second induction was highly recommended for patients who did not achieve a CR or CRi in the first induction course and was mandatory for patients achieving greater than 50% reduction in percent blasts. Post-remission therapy with haematopoietic stem cell transplantation (HSCT) was permitted either in place of or after consolidation chemotherapy. For consolidation courses, in clinical studies only, the Vyxeos liposomal dose was reduced to 65 units/m2/day (equivalent to 29mg/65 mg/m2) on days 1 and 3. In the 7+3 arm, first induction consisted of cytarabine 100 mg/m2/day on days 1 to 7 by continuous infusion, and daunorubicin 60 mg/m2/day on days 1, 2, and 3 whereas second induction and consolidation cytarabine was dosed on days 1 to 5 and daunorubicin on days 1 and 2.

There were 153 patients randomised to Vyxeos liposomal and 156 patients randomised to the 7+3 control arm. The randomised patients had a median age of 68 (range 60-75 years), 61% were male, and 88% had an ECOG performance status of 0-1. At baseline 20% had t-AML, 54% had AML with an antecedent haematological disorder and 25% had de novo AML with myelodysplasia-related cytogenetic abnormalities; 34% had been treated previously with a hypomethylating agent for MDS;54% had an adverse karyotype.

The demographic and baseline disease characteristics were generally balanced between the study arms. FLT3 mutation was identified in 15% (43/279) of patients tested and NPM1 mutation was identified in 9% (25/283) patients tested.

The primary endpoint was overall survival measured from the date of randomisation to death from any cause. Vyxeos liposomal demonstrated superiority in overall survival in the ITT population compared with the comparator 7+3 treatment regimen (Figure 1). The median survival for the Vyxeos liposomal treatment group was 9.56 months compared with 5.95 months for the 7+3 treatment group (Hazard Ratio = 0.69, 95% CI = 0.52, 0.90, two-sided log-rank test p = 0.005).

The overall rate of HSCT was 34% (52/153) in the Vyxeos liposomal arm and 25% (39/156) on the control arm.



Figure 1:        Kaplan-Meier curve for overall survival, ITT population 


Table 4:         Efficacy results for study 301

Vyxeos liposomal             7+3
N=153                   N=156
Overall survival
Median survival, months (95% CI)                    9.56 (6.60, 11.86)     5.95 (4.99, 7.75) Hazard ratio (95% CI)                                           0.69 (0.52, 0.90) p-value (2-sided) a                                                   0.005 Event free survival

Median survival, months (95% CI)                     2.53 (2.07, 4.99)     1.31 (1.08, 1.64) 
Hazard ratio (95% CI)                                           0.74 (0.58, 0.96)  p-value (2-sided) a                                                   0.021 
Complete response rate
CR, n (%)                                                57 (37)                40 (26) Odds ratio (95% CI)                                             1.69 (1.03, 2.78) p-value (2-sided) b                                                   0.040 CR + CRi, n (%)                                           73 (48)               52 (33) Odds ratio (95% CI)                                             1.77 (1.11, 2.81) p-value (2-sided) b                                                   0.016 Abbreviations: CI = Confidence interval; CR= Complete response; CRi= Complete response with incomplete recovery a p-value from stratified log rank test stratifying by age and AML sub-type b p-value from stratified Cochran-Mantel-Haenszel test stratified by age and AML sub-type 


60 Month Follow-up
The 60 month overall survival rate was higher for the Vyxeos liposomal treatment arm (18%) versus the 7+3 treatment arm (8%); the hazard ratio was 0.70, 95% CI= 0.55, 0.91.

Paediatric population

Relapsed AML
The efficacy of Vyxeos liposomal as a single agent was evaluated in a phase 1/2, single-arm study (AAML 1421) conducted to evaluate safety and efficacy of Vyxeos liposomal in 38 paediatric and young adult patients aged 1-21 years with AML in first relapse. Study treatment consisted of one induction cycle of Vyxeos liposomal 59 mg/135 mg/m2 administered intravenously over 90 minutes on Days 1, 3, and 5 followed by Fludarabine, Cytarabine, and G-CSF (FLAG) for cycle 2. The median age of patients was 11 years (range, 1-21 years). Eight (21%) of the patients were between 18 and 21 years; patients who received > 450 mg/m2 daunorubicin equivalents were excluded from the study.

The primary endpoint was overall response rate (defined as CR or CRp) after Vyxeos liposomal (Cycle 1) followed by FLAG (Cycle 2). The overall response rate was 68 (90% Clopper-Pearson CI 53% to 80%). After cycle 1, 16 (43%) patients had a treatment response of CR + CRp, including 14 (38%) patients who achieved CR, and based on the 7 subjects with relapse data available the median duration of CR was 284 days

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
The pharmacokinetics of daunorubicin and cytarabine administered as Vyxeos liposomal were investigated in adult patients who received a dose of daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 administered as a 90-minute intravenous infusion on days 1, 3, and 5. The pharmacokinetics of each medicinal product was based on total plasma concentrations (i.e., encapsulated plus unencapsulated medicinal product). Following the dose administered on day 5, the mean (% coefficient of variation [CV]) maximum plasma concentrations (Cmax) for daunorubicin was 26.0 (32.7%) mcg/mL and cytarabine was 62.2 (33.7%) mcg/mL. The mean (%CV) area under the curve (AUC) during one dosing interval for daunorubicin was 637 (38.4%) mcg.h/mL and cytarabine was 1900 (44.3%) mcg.h/mL.

When daunorubicin and cytarabine are administered as components of Vyxeos liposomal, the liposomes appear to govern their tissue distribution and rates of elimination; therefore, while the non- liposomal medicinal products have markedly different clearance (CL), volume of distribution (V), and terminal half-life (t1/2) Vyxeos liposomal causes these pharmacokinetic parameters to converge.

The accumulation ratio was 1.3 for daunorubicin and 1.4 for cytarabine. There was no evidence of time-dependent kinetics or major departures from dose proportionality over the range of 1.3 mg/3 mg per m2 to 59 mg/134 mg per m2 (0.03 to 1.3 times the approved recommended dosage).

Distribution
The volume of distribution (%CV) for daunorubicin is 6.6 L (36.8%) and cytarabine is 7.1 L (49.2%).
Plasma protein binding was not evaluated.

Metabolism and biotransformation
Similar to non-liposomal daunorubicin and cytarabine, subsequent to release from Vyxeos liposomal liposomes, both daunorubicin and cytarabine are extensively metabolised in the body. Daunorubicin is mostly catalysed by hepatic and non-hepatic aldo-keto reductase and carbonyl reductase to the active metabolite daunorubicinol. Cytarabine is metabolised by cytidine deaminase to the inactive metabolite 1-β (beta)-D-arabinofuranosyluracil (AraU). Unlike non-liposomal daunorubicin and cytarabine, which are quickly metabolised to the respective metabolites, daunorubicin and cytarabine after Vyxeos liposomal administration are free bases encapsulated in liposomes. Plasma concentration-time profiles obtained from 13 to 26 patients who received Vyxeos liposomal 100 units/m2 (equivalent to 44 mg/ m² of daunorubicin and 100 mg/m² of cytarabine).on days 1, 3, and 5 show the mean AUClast metabolite:parent ratio for daunorubicinol and AraU were 1.79% and 3.22% to that for daunorubicin and cytarabine, respectively; which are lower than those typically reported for non-liposomal products, ~40-60% for daunorubicinol:daunorubicin and ~80% for AraU:cytarabine. The lower percentages of metabolite:parent ratios after Vyxeos liposomal administration indicate that most of the total daunorubicin and cytarabine in the circulation is trapped inside the Vyxeos liposomal liposomes, where they are inaccessible to medicinal product-metabolising enzymes.

Elimination
Vyxeos liposomal exhibits a prolonged half-life (%CV) of 31.5 h (28.5%) for daunorubicin and 40.4 h (24.2%) for cytarabine with greater than 99% of the daunorubicin and cytarabine in the plasma remaining encapsulated within the liposomes. The clearance (%CV) is 0.16 L/h (53.3%) for daunorubicin and 0.13 L/h (60.2%) for cytarabine.

Urinary excretion of daunorubicin and daunorubicinol accounts for 9% of the administered dose of daunorubicin, and urinary excretion of cytarabine and AraU accounts for 71% of the administered dose of cytarabine.

Special populations
In a population pharmacokinetic analysis, no clinically meaningful effects on clearance and volume parameters of daunorubicin and cytarabine by age (1 to 81 years),, sex, race, body weight, body mass index, and white blood cell count were observed.

Paediatric population
The dose-normalized mean exposures of total daunorubicin and cytarabine observed in paediatric patients after 59 mg/135 mg/m2 were comparable to those of daunorubicin and cytarabine after 44 mg/100 mg/m2 in adults
Elderly population
The pharmacokinetics of Vyxeos liposomal in patients aged > 85 years has not yet been evaluated. No data are available.

Renal impairment
Based on a dedicated study to evaluate the impact of moderate to severe renal impairment on the pharmacokinetics of Vyxeos liposomal and a population pharmacokinetic analysis using data from clinical studies in patients with mild to moderate renal impairment, no significant difference in clearance of daunorubicin or cytarabine was observed in patients with pre-existing mild, moderate or severe renal impairment compared to patients with baseline normal renal function. The potential effects of end-stage renal disease managed with dialysis on the pharmacokinetics of daunorubicin and cytarabine administered as Vyxeos liposomal are unknown(see section 4.2).

Hepatic impairment
The pharmacokinetics of total daunorubicin and cytarabine were not altered in patients with bilirubin ≤ 50 µmol/L. The pharmacokinetics in patients with bilirubin greater than 50 µmol/L is unknown.