An open-label study to evaluate dose and cycle dependence of the pharmacokinetics of pegylated liposomal doxorubicin

Abstract BACKGROUND: Pegylated liposomal doxorubicin (CAELYX®) is a liposomal formulation of doxorubicin sterically stabilized by the grafting of segments of polyethylene glycol (PEG) onto the liposomal surface. Given the demonstrated efficacy of VAD (vincristine and doxorubicin and oral dexamethasone) in Multiple Myeloma (MM) patients and the potential for CAELYX® to extend the duration of bone marrow exposure to therapeutic levels of doxorubicin, a combination regimen of CAELYX®, vincristine, and reduced-dose dexamethasone (DVD) has been actively investigated in MM patients. Studies showed that substituting CAELYX® for doxorubicin in the VAD regimen and reducing the dose of dexamethasone in MM patients improves the safety profile and convenience of the treatment regimen without compromising efficacy. Due to potential differences in metabolism of these patients, safety and efficacy results may vary. Thus, we carried out this study in 82 newly diagnosed MM patients in China, in order to demonstrate the efficacy and safety profiles of DVD. METHODS: Patients (n=82) from 15 sites were recruited in this study. CAELYX® (40mg/m2) was infused intravenously over 60-minutes, administered every 28 days. Vincristine (2.0mg) was administered intravenously on Day 1 of each cycle. Dexamethasone (40 mg) was administered from Day 1- Day 4 of each cycle orally or intravenously. The treatment was repeated every 28 days for 4 cycles. RESULTS: Upon ITT analysis, the overall response rate was approximately 68% (56/82); 11% of the patients achieved complete remission (CR), 40% achieved partial response (PR), 17% achieved minimal response; 15% had stable disease (SD), and 12% o had progressive disease (PD) after the treatment. The cumulative 4-month progression-free survival (PFS) was 88%. The incidence of all the adverse events was 46%. The most common non-hematological toxicities were palmar-plantar erythrodysesthesia (13.4%) and stomatitis (6.1%), respectively. CONCLUSION: Pegylated liposomal doxorubicin, vincristine and reduced dose dexamethasone combination (DVD) regimen is an effective and safe regimen in newly diagnosed multiple myeloma patients in Chinese population.

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An open-label study to evaluate dose and cycle dependence of the pharmacokinetics (PK) of pegylated liposomal doxorubicin (PLD)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.2012 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 2012-2012 ◽

Cited By ~ 2

Author(s):

A. Gabizon ◽

R. Isacson ◽

O. Rosengarten ◽

D. Tzemach ◽

H. Shmeeda ◽

...

Keyword(s):

Dose Range ◽

Pegylated Liposomal Doxorubicin ◽

Skin Toxicity ◽

Significant Inhibition ◽

Open Label ◽

Cycle Number ◽

Open Label Study ◽

Label Study ◽

Mean Values ◽

Significant Difference

2012 Background: There are no definitive data in humans on the dose dependency and/or cycle dependency of the pharmacokinetics of PLD. The skin toxicity of PLD tends to worsen after several treatment cycles. Therefore, it is important to characterize the PK of PLD after 2 or more cycles. Methods: Fifteen patients with various solid tumors were randomized to two arms of treatment in an open-label study. Arm A received PLD at doses of 60, 30, and 45 mg/m2 in 3 successive cycles every 4 weeks (q4w). Arm B received PLD at doses of 30, 60, and 45 mg/m2 in 3 successive cycles q4w. Twelve patients, 6 on each arm, completed all three cycles and were fully evaluable. Plasma levels of doxorubicin were analyzed by HPLC and fluorimetry following a previously published method (J Chromatogr B, 779:259–69, 2002) with minor modifications. PK analysis was done by non-compartmental method. The following parameters were obtained: Cmax, AUC∞, terminal half-life (T1/2), and Clearance (CL). The paired t test was used for statistical analysis. Results: There was no significant difference in the parameters examined when the dose was increased from 30 to 60 mg/m2. However, when we analyzed the effect of cycle number on the PK, we found a gradual and significant inhibition of CL when patients advance from the 1st through the 3rd cycle of PLD (p=0.0003), with a mean increase of 44% in AUC/mg dose (p=0.0011). Cmax and T1/2 mean values increased by 17% and 18% respectively between the 1st and 3rd cycles, but only the increase in T1/2 was statistically significant (p=0.0127). Conclusion: While the PK of PLD is not dose-dependent within the dose range of 30 to 60mg/m2, there is evidence of a cycle-dependent effect that results in inhibition of CL when patients receive successive cycles of PLD. This effect may account for the delayed skin toxicity of PLD. These results suggest the need for dose adjustments of PLD to minimize the risk of toxicity, such as an initial high loading dose followed by reduced maintenance doses from the 2nd or 3rd cycle onwards. [Table: see text] [Table: see text]

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