Lipo-Dox Mechanism of Action

The exact mechanism of the antitumor 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 effect. This is probably the result of intercalation of the doxorubicin between adjacent base pairs of the DNA double helix, thus preventing their unwinding for replication.
Pharmacology: Lipo-Dox is a long-circulating pegylated liposomal formulation of doxorubicin HCl that provides greater concentration of doxorubicin in Karposi's sarcoma tumors than in normal skin.
Hydrophilic polymer methoxy-polyethylene glycol (MPEG) is bound to the surface of pegylated liposomes. These linear MPEG groups extend from the liposome surface forming a protective coating that reduces interactions between the liposomal lipid bilayer membrane and the plasma components, so the circulation time of pegylated liposomal doxorubicin is prolonged in the blood stream.
Pegylated liposomes are small enough (average diameter of approximately 100 nm) to pass intact (extravasate) through defective blood vessels supplying tumors. Evidence of penetration of pegylated liposomes from blood vessels and their entry and accumulation in tumors has been seen in mice with C-26 colon carcinoma tumors and in transgenic mice with Kaposi's sarcoma-like lesions. The doxorubicin HCl could been capsulated during liposome residence time in circulation, because of low permeability lipid matrix and internal liquid buffer system of the pegylated liposomes.
Clinical Efficacy: A phase III randomized study of pegylated liposomal doxorubicin versus doxorubicin HCl in patients with metastatic breast cancer was completed in 509 patients. The protocol-specified objective of demonstrating non-inferiority between pegylated liposomal doxorubicin and doxorubicin was met: the hazard ratio (HR) for progression-free survival (PFS) was 1.00 (95% Cl for HR=0.82-1.22). The treatment HR for PFS when adjusted for prognostic variables was consistent with PFS for the ITT population.
301 patients with advanced breast cancer who had failed a taxane-containing regimen were randomized in a phase III comparative study to pegylated liposomal doxorubicin versus an approved salvage regimen (vinorelbine or mitomycin C + vinblastine). Both PFS were the same.
In a 474 patients, phase III clinical study, compared the protocol-specified primary endpoint of time to progression between pegylated liposomal doxorubicin and topotecan in the evaluated patients with epithelial ovarian cancer, who were failed to first-line, platinum based chemotherapy. The results indicated that pegylated liposomal doxorubicin HCl was better than topotecan (hazard ratio of 1.262, 90% CI 1.062-1.500, p=0.026) Supported by a hazard ratio of 1.121 (90% CI 0.920-1.367, P=0.34), for the entire ITT population, the overall survival of pegylated liposomal doxorubicin HCl was at least equivalent to topotecan.
In the protocol-defined platinum-sensitive subgroup in the ITT population, both time to progression and overall survival were significantly in favor of pegylated liposomal doxorubicin (time to progression: hazard ratio of 1.349, p=0.037, 90% CI 1.065-1.709, median=202 days vs. 163 days; overall survival: hazard ratio 1.720, 90% CI 1.222-2.422, p<0.01, median: 756 days vs. 498 days).
When the quality of life, such as toxicity and progression are considered, pegylated liposomal doxorubicin is always preferred over topotecan as demonstrated in the quality-adjusted survival analysis. Although patients treated with pegylated liposomal doxorubicin experience palmar-plantar erythrodysesthesia (PPE) caused pain more frequently, but rarely resulted in study discontinuation.
No matter the efficacy endpoint or different prognostic population, pegylated liposomal doxorubicin showed consistent advantage in clinical studies.
Pharmacokinetics: The plasma pharmacokinetics in humans are significant different between pegylated liposomal doxorubicin and conventional doxorubicin HCl preparations. At lower doses (10 mg/m²-20 mg/m²), pegylated liposomal doxorubicin displayed linear pharmacokinetics. However, the pharmacokinetics are displayed to be non-linear over the dose range of 10 mg/ m² to 60 mg/m².
In contrast to the pharmacokinetic of conventional doxorubicin HCl, which displays extensive tissue distribution (volume of distribution, 700 to 1100 L/m²) and a rapid elimination clearance (24-73 L/h/m²). The pharmacokinetic profile of Lipo-Dox indicates that Lipo-Dox is confined mostly to the vascular fluid volume and that the clearance of doxorubicin from the blood is dependent upon the liposomal carrier. After the liposomes are extravasated and enter the tissue compartment, doxorubicin becomes available.
At equivalent doses, the plasma concentration and AUC values of pegylated liposomal doxorubicin which mostly exist as encapsulated in liposomes (containing 90% to 95% of the measured doxorubicin) are significant higher than conventional doxorubicin HCl.
Population Pharmacokinetics: The population pharmacokinetics of pegylated liposomal doxorubicin were evaluated in 120 patients from 10 different clinical trials. The pharmacokinetics of pegylated liposomal doxorubicin over the dose range of 10 mg/m² 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 pegylated liposomal doxorubicin was 0.030 L/h/m² (0.008-0.152 L/h/m²) and the central volume of distribution was 1.93 L/m² (0.96-3.85 L/m²), approximating the volume of human plasma, and the half-life ranged from 24 to 231 hours with a mean of 73.9 hours.
Breast Cancer Patients: The pharmacokinetics of Lipo-Dox determined in 18 patients with breast cancer were similar to the pharmacokinetics determined in the large population of 120 patients with various cancers. The mean intrinsic clearance was 0.016 L/h/m² (range 0.009-0.027 L/h/m²), the mean central volume of distribution was 1.46 L/m² (range 1.10-1.64 L/m²). The mean half-life was 71.5 hours (range 45.2-98.5 hours).
Ovarian Cancer Patients: The pharmacokinetics data from 11 ovarian cancer patients were similar with the pharmacokinetics data from the other 120 patients with various cancers. The mean intrinsic clearance was 0.021 L/h/m² (0.009-0.041 L/h/m²), the mean central volume of distribution was 1.95 L/m² (1.67 -2.40 L/m²), and the mean half-life was 75.0 hours (36.1-125 hours).
AIDS-KS Patients: The pharmacokinetics of pegylated liposomal doxorubicin HCl were evaluated in 23 patients with Kaposi's sarcoma who received single doses of 20 mg/m² administered by a 30-minute infusion. The pharmacokinetic parameters of pegylated liposomal doxorubicin (primarily representing liposome-encapsulated doxorubicin HCl and low levels of unencapsulated doxorubicin HCl), are presented in the Table 1. (See Table 1.)

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Toxicology: Pre-clinical Toxicological Study: In repeat dose studies conducted in animals, the toxicity profile of pegylated liposomal doxorubicin appears very similar to that reported in humans who receive long-term infusions of conventional doxorubicin HCl. However, the pegylated liposomal doxorubicin HCl and conventional doxorubicin HCl have different toxicity strength, as follows: Cardiotoxicity: In rabbits studies, the cardiotoxicity of pegylated liposomal doxorubicin was reduced compared with conventional formulation of doxorubicin HCl preparations.
(Skin) Dermal Toxicity: After the repeated administration of pegylated liposomal doxorubicin, which at clinically relevant dosages to rats and dogs, severe dermatitis and ulcer were observed. In the study in dogs, lowering the dose or prolonging the intervals between doses could reduce the incidence and severity of skin lesions. Similar dermal lesions, which are described as palmar-plantar erythrodysesthesia were also observed in patients after long-term intravenous infusion. (See Adverse Reactions).
Anaphylactoid response: During repeated-dose toxicity studies in dogs, the acute response characterized by hypotension, ashen mucosa, salivation, emesis and periods of hyperactivity followed by hypoactivity and lethargy was observed following administration of pegylated liposomes (placebo). Similar but less severe reactions were also noted in dogs treated with pegylated liposomal doxorubicin or conventional doxorubicin. Pretreatment with antihistamines could reduce hypotension magnitude. However, the dogs recovered quickly upon discontinuation of treatment and the responses were not life-threatening.
Local Toxicity: In subcutaneous tolerance studies, the local irritation or damage to the tissue that were caused by extravasations of pegylated liposomal doxorubicin were slighter than conventional doxorubicin HCl.
Mutagenicity and Carcinogenicity: Although no studies have been conducted with pegylated liposomal doxorubicin, doxorubicin HCl, the pharmacologically active ingredient of Lipo-Dox, is mutagenic and carcinogenic. Pegylated placebo liposomes are neither mutagenic nor genotoxic.
Reproductive Toxicity: Pegylated liposomal doxorubicin resulted in mild to moderate ovarian and testicular atrophy in mice after a single dose of 36 mg/kg. Decreased testicular weights and hypospermia were present in rats after repeat doses ≧0.25 mg/kg/day. Diffuse degeneration of the seminiferous tubules and a marked decrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day.