Anthracyclines—liposomal formulations

Pharmacokinetics

The differences between liposomal doxorubicin and liposomal daunorubicin are due to the differences in their liposomal packaging.

Pegylated liposomal doxorubicin (Caelyx/Doxil) and liposomal daunorubicin (DaunoXome) produce lower peak plasma concentrations and longer circulation times than free drug [ ].

Liposomal doxorubicin in Myocet has systemic availability, metabolism, and excretion similar to that of conventional doxorubicin, but at a slower rate [ ]. In dogs, the plasma concentrations of doxorubicin from Myocet were 1000-fold greater than conventional doxorubicin at 6 hours, but the difference diminished at 24 hours [ ]. This distinguishes Myocet from Doxil, which persists in the circulation for significantly longer.

Caelyx has linear pharmacokinetics and its disposition occurs in two phases, the first relatively short (5 hours) and the second prolonged (55 hours). Unlike free doxorubicin, most of the pegylated liposomal doxorubicin is confined to the vascular fluid volume, and its blood clearance depends on the liposomal carrier. Liposomal daunorubicin acts similarly to Caelyx, but produces a lower AUC and has a higher clearance and a shorter terminal half-life [ ].

Pegylated liposomes (diameter about 70–100 nm) and liposomal daunorubicin (diameter 45 nm) are small enough to pass intact through defective blood vessels that supply tumors. This, rather than any particular affinity for tumor cells, is the reason for their accumulation in tumor tissue [ ]. Caelyx provides a greater concentration of doxorubicin in Kaposi’s sarcoma tumors than in normal skin.

Cardiovascular

The incidence of cardiotoxicity in anthracycline-treated patients has been related to the peak plasma drug concentration [ , ]. One of the aims in developing pegylated liposomal doxorubicin was to reduce plasma concentrations of free doxorubicin and restrict myocardial penetration, to minimize cardiotoxicity. Preclinical data suggested that the liposomal formulation was indeed less cardiotoxic than the free drug: about 50% more pegylated liposomal doxorubicin than free doxorubicin can be given to rabbits without producing the same frequency of cardiotoxicity [ ].

Cardiac adverse events that have been considered probably or possibly related to pegylated liposomal doxorubicin have been reported in 3–9% of patients [ ]. These include hypotension, pericardial effusion, thrombophlebitis, heart failure, and tachycardia [ , ].

Left ventricular failure has been reported in a few patients, particularly those who received high cumulative lifetime doses of pegylated liposomal doxorubicin (over 550 mg/m ² ) [ , ]. However, cumulative doses of 450 mg/m ² or more and 550 mg/m ² have been administered without significant reduction in ejection fraction or the development of cardiac failure [ , ]. To date, no or minimal cardiotoxicity has been observed in patients with AIDS-related Kaposi’s sarcoma who received pegylated liposomal doxorubicin in high cumulative doses [ ].

Both peak and overall concentrations of doxorubicin in myocardial tissue are reduced by 30–40% after Myocet relative to conventional doxorubicin [ ]. This reduced myocardial exposure resulted in a significant reduction in cardiotoxicity, assessed both functionally and histologically [ , ]. Compared with free doxorubicin 75 mg/m ² given 3-weekly, Myocet 75 mg/m ² caused significantly less congestive cardiac failure (1% versus 6%) [ ]. However, a high dose of Myocet (135 mg/m ² , median cumulative dose 405 mg/m ² ) caused a significant increase in cardiac toxicity: 38% of patients had a protocol-defined cardiac event, including 13% who developed congestive heart failure [ ].

In one study there was a significant (over 20%) reduction in the shortening fraction with liposomal daunorubicin measured by echocardiography [ ]. In contrast, in another study there was no significant fall in cardiac function, even after cumulative doses of liposomal daunorubicin over 1000 mg/m ² [ ].

Women with metastatic breast cancer were randomized to receive either liposomal doxorubicin (Myocet) 75 mg/m ² (n = 108) or conventional doxorubicin 75 mg/m ² (n = 116) [ ]. The liposomal formulation was less cardiotoxic than the conventional one, and the cumulative doses before the onset of cardiotoxicity were 780 versus 570 mg/m ² respectively; the liposomal formulation provided comparable antitumor activity. In another study the authors tried to define the cumulative toxic intravenous dose of daunorubicin (DaunoXome) and concluded that it may be 750–900 mg/m ² or even higher (exceeding 1000 mg/m ² ) [ ].

Respiratory

Acute dyspnea, low back pain, and/or pain at the site of tumor have been described, beginning within 1–5 minutes of the start of infusion of pegylated liposomal doxorubicin [ ]. Three of 35 patients were described as suffering acute dyspnea, two with back pain and two with abdominal pain. In each case the symptoms resolved within 5–15 minutes of stopping the infusion, which was restarted without adverse effects. The mechanism of these symptoms was unclear. However, because the dyspnea was reminiscent of that seen in hemodialysis neutropenia, complete blood counts were obtained from four patients about 2 minutes after the onset of symptoms. All four had relative neutropenia (neutrophil counts of 3–46% of pre-treatment), which resolved by the end of the infusion. In vitro, pegylated liposomal doxorubicin, in concentrations predicted to be present in the plasma during the start of treatment, stimulates neutrophil adhesion to human umbilical vein endothelial cells [ ]. Thus, pegylated liposomal doxorubicin may cause transient sequestration of neutrophils in the pulmonary circulation, resulting in reduced lung compliance and associated dyspnea.

Hematologic

In a phase I dose-finding study of pegylated liposomal doxorubicin, myelosuppression was not a major problem with the doses tested (20–80 mg/m ² , re-dosing every 3–4 weeks). Median nadir white cell and platelet counts were well above 2 × 10 ⁹ /l and 100 × 10 ⁹ /l respectively. In the occasional patient in whom profound granulocytopenia developed there was quick recovery of the cell counts within less than 7 days. Neutropenic fever was documented in only one patient at the top dose of 80 mg/m ² [ ]. There was no significant indication of cumulative myelosuppression. Treatment-related anemia was generally mild and blood transfusions were not required. However, two patients with head and neck malignancies and extensive pretreatment were given erythropoietin to maintain hemoglobin concentrations above 9.0 g/dl [ ].

Pooled data from 12 phase I or II studies, in 308 patients with solid tumors who received pegylated liposomal doxorubicin in doses of 10–80 mg/m ² , showed that there was neutropenia (neutrophil count below 1 × 10 ⁹ /l) in 50%, anemia in 19%, and thrombocytopenia in 9.2% [ ].

Of 71 patients with metastatic breast cancer treated with pegylated liposomal doxorubicin in doses of 45–60 mg/m ² given 3- or 4-weekly, grade 3/4 neutropenia occurred in 10% and thrombocytopenia in 1% [ ].

If pegylated liposomal doxorubicin and liposomal daunorubicin are used to treat AIDS-related Kaposi’s sarcoma, one has to consider additional factors that affect the white cell count. In patients with HIV/AIDS, myelosuppression was the most frequent dose-limiting adverse effect of liposomal anthracyclines [ , ]. In one study of 30 patients with Kaposi’s sarcoma given liposomal daunorubicin 40 mg/m ² , 53% developed granulocytopenia (white cell count below 1 × 10 ⁹ /l); 17% had a hemoglobin concentration below 8.0 g/dl, but none had thrombocytopenia [ ].

In another study in 53 patients with AIDS-related Kaposi’s sarcoma given pegylated liposomal doxorubicin 20 mg/m ² every 3 weeks, 21 had leukopenia and three had thrombocytopenia [ ].

At doses of 20 mg/m ² liposomal doxorubicin, combined tolerability data from 705 patients with AIDS-related Kaposi’s sarcoma showed that neutropenia (below 1 × 10 ⁹ /l) and anemia were the most common adverse events, affecting 50% and 19% of patients respectively [ ].

In summary, myelosuppression after treatment with pegylated liposomal doxorubicin does not appear to be a major problem in patients with solid tumors and relatively intact immunological systems, but is the dose-limiting adverse effect in immunocompromised patients with HIV/AIDS.

High-dose Myocet (135 mg/m ² ) caused significant hematological toxicity, namely grade 4 neutropenia in 98% and thrombocytopenia in 46 of 52 patients [ ]. However, Myocet 75 mg/m ² 3-weekly caused less hematological toxicity than conventional doxorubicin [ ].

Gastrointestinal

Stomatitis and pharyngitis have been confirmed, along with hand–foot syndrome, as dose-limiting adverse effects of pegylated liposomal anthracyclines [ ]. Stomatitis was dose-limiting at high single doses over 70 mg/m ² . Similarly, 12 of 35 patients who received pegylated liposomal doxorubicin 50 mg/m ² every 3 weeks for advanced ovarian carcinoma required dose reduction (to 40 mg/m ² ) or treatment delay (to 4 weeks) because of mucositis [ ]. Stomatitis and mucositis are dose-dependent [ ]. In the treatment of Kaposi’s sarcoma in patients with HIV/AIDS, mucositis and stomatitis are rarely problematic and are not dose-limiting. Presumably this is because significantly lower doses of pegylated liposomal doxorubicin are used in these patients.

Nausea and vomiting have been reported but appear to be mild and infrequent adverse effects of pegylated liposomal anthracyclines and liposomal daunorubicin [ , ]. In most patients pegylated liposomal doxorubicin can be given without prophylactic antiemetics. In one study there was only mild nausea and vomiting in eight of 53 patients who had not received prophylactic antiemetics [ ]. Further reviews in patients with AIDS-related Kaposi’s sarcoma have reported nausea and vomiting in 17% and 8% of patients respectively [ ]. Pooled data from 12 phase I and II studies in patients with solid tumors showed that 3.6% of patients had had grade 3/4 nausea or vomiting [ ]. Diarrhea has similarly been recognized as a mild and infrequent adverse effect of pegylated liposomal doxorubicin (three of 53 patients) [ ].

Myocet (75 mg/m ² ) causes significantly less vomiting (11% versus 23%) than conventional free doxorubicin (75 mg/m ² ) [ ]. It also leads to lower peak-free doxorubicin concentrations in the gastrointestinal mucosa compared with conventional doxorubicin, and less gastrointestinal toxicity [ ]. However, high-dose Myocet (135 mg/m ² ) caused grade 4 mucositis in 10 of 52 patients [ ].