Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Cytotoxic agents (anthracyclines and related substances), ATC code: L01DB01.

Mechanism of action
The active ingredient of Lipodox Liposomal is doxorubicin hydrochloride, a cytotoxic anthracycline antibiotic obtained from Streptomyces peucetius var. caesius. The exact mechanism of the antitumour activity of doxorubicin is not known. It is generally believed that inhibition of DNA, RNA and protein synthesis is responsible for the majority of the cytotoxic effects. This is probably the result of intercalation 
of the anthracycline between adjacent base pairs of the DNA double helix thus preventing their unwinding for replication.

Clinical efficacy and safety
A phase III randomized study of Lipodox Liposomal versus doxorubicin in patients with metastatic breast cancer was completed in 509 patients. The protocol-specified objective of demonstrating non-inferiority between Lipodox Liposomal and doxorubicin was met, the hazard ratio (HR) for progression-free survival (PFS) was 1.00 (95% CI for HR=0.82 - 1.22). The treatment HR for PFS when adjusted for prognostic variables was consistent with PFS for the ITT population.
The primary analysis of cardiac toxicity showed the risk of developing a cardiac event as a function of cumulative anthracycline dose was significantly lower with Lipodox Liposomal than with doxorubicin (HR=3.16, p < 0.001). At cumulative doses greater than 450 mg/m 2 there were no cardiac events with Lipodox Liposomal.
A phase III comparative study of Lipodox Liposomal versus topotecan in patients with epithelial ovarian cancer following the failure of first-line, platinium based chemotherapy was completed in 474 patients.
There was a benefit in overall survival (OS) for Lipodox Liposomal -treated patients over topotecan-treated patients as indicated by a hazard ratio (HR) of 1.216 (95 % CI; 1.000, 1.478), p=0.050. The survival rates at 1, 2 and 3 years were 56.3%, 34.7% and 20.2% respectively on Lipodox Liposomal, compared to 54.0%, 23.6% and 13.2% on topotecan.
For the sub-group of patients with platinium-sensitive disease the difference was greater: HR of 1.432 (95% CI; 1.066, 1.923), p=0.017. The survival rates at 1, 2 and 3 years were 74.1 %, 51.2 % and 28.4 % respectively on Lipodox Liposomal, compared to 66.2 %, 31.0 % and 17.5 % on topotecan.
The treatments were similar in the sub-group of patients with platinium refractory disease: HR of 1.069 (95% CI; 0.823, 1.387), p=0.618. The survival rates at 1, 2 and 3 years were 41.5 %, 21.1% and 13.8 % respectively on Lipodox Liposomal, compared to 43.2 %, 17.2 % and 9.5 % on topotecan.
A phase III randomized, parallel-group, open-label, multicentre study comparing the safety and efficacy of Lipodox Liposomal plus bortezomib combination therapy with bortezomib monotherapy in patients with multiple myeloma who have received at least 1 prior therapy and who did not progress while receiving anthracycline-based therapy, was conducted in 646 patients. There was a significant improvement in the primary endpoint of time to progression (TTP) for patients treated with combination therapy of Lipodox Liposomal plus bortezomib compared to patients treated with bortezomib monotherapy as indicated by a risk reduction (RR) of 35% (95% CI; 21-47%), p < 0.0001, based on 407 TTP events. The median TTP was 6.9 months for the bortezomib monotherapy patients compared with 8.9 months for the Lipodox Liposomal plus bortezomib combination therapy patients. A protocol-defined interim analysis (based on 249 TTP events) triggered early study termination for efficacy. This interim analysis showed a TTP risk reduction of 45 % (95% CI; 29-57%), p < 0.0001. The median TTP was 6.5 months for the bortezomib monotherapy patients compared with 9.3 months for the Lipodox Liposomal plus bortezomib combination therapy patients. These results, though not mature, constituted the protocol defined final analysis. The final analysis for overall survival (OS) performed after a median follow-up of 8.6 years showed no significant difference in OS between the two treatment arms. The median OS was 30.8 months (95% CI; 25.2-36.5 months) for the bortezomib monotherapy patients and 33.0 months (95% CI; 28.9-37.1 months) for the Lipodox Liposomal plus bortezomib combination therapy patients.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Lipodox Liposomal is a long-circulating pegylated liposomal formulation of doxorubicin hydrochloride.
Pegylated liposomes contain surface-grafted segments of the hydrophilic polymer methoxypolyethylene glycol (MPEG). These linear MPEG groups extend from the liposome surface creating a protective coating that reduces interactions between the lipid bilayer membrane and the plasma components. This allows the Lipodox Liposomal liposomes to circulate for prolonged periods in the blood stream. Pegylated liposomes are small enough (average diameter of approximately 100 nm) to pass intact (extravasate) through defective blood vessels supplying tumours. Evidence of penetration of pegylated liposomes from blood vessels and their entry and accumulation in tumours has been seen in mice with C-26 colon carcinoma tumours and in transgenic mice with KS-like lesions. The pegylated liposomes also have a low permeability lipid matrix and internal aqueous buffer system that combine to keep doxorubicin hydrochloride encapsulated during liposome residence time in circulation.
The plasma pharmacokinetics of Lipodox Liposomal in humans differ significantly from those reported in the literature for standard doxorubicin hydrochloride preparations. At lower doses (10 mg/m 2 – 20 mg/m2) Lipodox Liposomal displayed linear pharmacokinetics. Over the dose range of 10 mg/m 2 – 60 mg/m2 Lipodox Liposomal displayed non-linear pharmacokinetics. Standard doxorubicin hydrochloride displays extensive tissue distribution (volume of distribution: 700 to 1,100 l/m 2) and a rapid elimination clearance (24 to 73 l/h/m2). In contrast, the pharmacokinetic profile of Lipodox Liposomal indicates that Lipodox Liposomal is confined mostly to the vascular fluid volume and that the clearance of doxorubicin from the blood is dependent upon the liposomal carrier. Doxorubicin becomes available after the liposomes are extravasated and enter the tissue compartment.
At equivalent doses, the plasma concentration and AUC values of Lipodox Liposomal which represent mostly pegylated liposomal doxorubicin hydrochloride (containing 90 % to 95 % of the measured doxorubicin) are significantly higher than those achieved with standard doxorubicin hydrochloride preparations.
Lipodox Liposomal should not be used interchangeably with other non-liposomal formulations of doxorubicin hydrochloride.

Population pharmacokinetics
The pharmacokinetics of Lipodox Liposomal was evaluated in 120 patients from 10 different clinical trials using the population pharmacokinetic approach. The pharmacokinetics of Lipodox Liposomal over the dose range of 10 mg/m 2 to 60 mg/m2 was best described by a two compartment non-linear model with zero order input and Michaelis-Menten elimination. The mean intrinsic clearance of Lipodox Liposomal was 0.030 l/h/m2 (range 0.008 to 0.152 l/h/m 2) and the mean central volume of distribution was 1.93 l/m2 (range 0.96– 3.85 l/m2) approximating the plasma volume. The apparent half-life ranged from 24 – 231 hours, with a mean of 73.9 hours.

Breast cancer patients
The pharmacokinetics of Lipodox Liposomal determined in 18 patients with breast carcinoma were similar to the pharmacokinetics determined in the larger population of 120 patients with various cancers. The mean intrinsic clearance was 0.016 l/h/m 2 (range 0.008-0.027 l/h/m2), the mean central volume of distribution was 1.46 l/m 2 (range 1.10-1.64 l/m2). The mean apparent half-life was 71.5 hours (range 45.2 - 98.5 hours).

Ovarian cancer patients


The pharmacokinetics of Lipodox Liposomal determined in 11 patients with ovarian carcinoma were similar to the pharmacokinetics determined in the larger population of 120 patients with various cancers. The mean intrinsic clearance was 0.021 l/h/m 2 (range 0.009–0.041 l/h/m2), the mean central volume of distribution was 1.95 l/m 2 (range 1.67–2.40 l/m2). The mean apparent half-life was 75.0 hours (range 36.1–125 hours).

AIDS-related KS patients
The plasma pharmacokinetics of Lipodox Liposomal were evaluated in 23 patients with KS who received single doses of 20 mg/m 2 administered by a 30-minute infusion. The pharmacokinetic parameters of Lipodox Liposomal (primarily representing pegylated liposomal doxorubicin hydrochloride and low levels of unencapsulated doxorubicin hydrochloride) observed after the 20 mg/m2 doses are presented in Table 6.

Table 6. Pharmacokinetic Parameters in Lipodox Liposomal-Treated AIDS-KS Patients 
Mean ± Standard Error
Parameter                                       20 mg/m2 (n=23)
Maximum Plasma Concentration* (µg/ml)                                   8.34 ± 0.49 Plasma Clearance (l/h/m2)                                             0.041 ± 0.004 Volume of Distribution (l/m2)                                          2.72 ± 0.120 AUC (µg/ml·h)                                                         590.00 ± 58.7 λ1 half-life (hours)                                                      5.2 ± 1.4 λ2 half-life (hours)                                                     55.0 ± 4.8 *Measured at the end of a 30-minute infusion