Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar

Abstract

Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction. In animal models, valspodar has minimal interaction with pegylated liposomal doxorubicin (PEG-LD). To determine any pharmacokinetic interaction in humans, we designed a study to determine maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of total doxorubicin, in PEG-LD and valspodar combination therapy in patients with advanced malignancies. Patients received PEG-LD 20 -25 mg m À2 intravenously over 1 h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72 h continuous intravenous infusion with PEG-LD beginning at 8 mg m À2 and escalated in an accelerated titration design to 25 mg m À2 . Pharmacokinetic data were collected with and without valspodar. A total of 14 patients completed at least two cycles of therapy. No DLTs were observed in six patients treated at the highest level of PEG-LD 25 mg m À2 . The most common toxicities were fatigue, nausea, vomiting, mucositis, palmar plantar erythrodysesthesia, diarrhoea, and ataxia. Partial responses were observed in patients with breast and ovarian carcinoma. The mean (range) total doxorubicin clearance decreased from 27 (10 -73) ml h À1 m À2 in cycle 1 to 18 (3 -37) ml h À1 m À2 with the addition of valspodar in cycle 2 (P ¼ 0.009). Treatment with PEG-LD 25 mg m À2 in combination with valspodar results in a moderate prolongation of total doxorubicin clearance and half-life but did not increase the toxicity of this agent.

Chemotherapeutic agents doxorubicin and epirubicin induce a procoagulant phenotype on endothelial cells and blood monocytes

“…Plasma concentrations of chemotherapeutic drugs in our in vitro experiments approximate the maximal initial plasma concentrations ( C max ) observed in chemotherapy patients. Doxorubicin has a detected C max between 2 and 6 μg mL −1 [9,10], while liposome‐encapulated doxorubicin (Doxil) displays higher plasma concentrations ( C max of 10 μg mL −1 ) and lower clearance (8 μg mL −1 after 24 h) [11]. Pharmacokinetic studies have indicated that the C max of epirubicin is approximately 2–3.7 μg mL −1 [9,12], methotrexate is 11–24 μg mL −1 [13], and 5‐fluorouracil is 0.4 μg mL −1 [14].…”

Effects of the chemotherapeutic agent doxorubicin on the protein C anticoagulant pathway

“…We acknowledge that one limitation of our in vitro study is that the concentrations of doxorubicin used (0.1 -10 Ag/mL) are more similar to the maximal initial plasma concentrations than to the plasma concentrations at t = 24 h. However, the concentrations that we used may still have clinical relevance because liposome-encapsulated formulations of doxorubicin (e.g., Myocet, Doxil) have been shown to be as effective as conventional doxorubicin and have much less toxicity (e.g., cardiotoxicity) in phase II and phase III studies (49). The plasma levels of doxorubicin after infusion of liposomal forms of doxorubicin are substantially higher than those after the administration of the same dose of conventional doxorubicin (23,50). For example, the initial plasma concentration of doxorubicin and the plasma doxorubicin concentration at t = 24 h in patients receiving Doxil are 10 and 8 Ag/mL, respectively (50).…”

“…The plasma levels of doxorubicin after infusion of liposomal forms of doxorubicin are substantially higher than those after the administration of the same dose of conventional doxorubicin (23,50). For example, the initial plasma concentration of doxorubicin and the plasma doxorubicin concentration at t = 24 h in patients receiving Doxil are 10 and 8 Ag/mL, respectively (50). In a phase II study, deep vein thrombosis was one of the side effects experienced by patients treated with liposomal doxorubicin (Doxil) in combination with vincristine, dexamethasone, and thalidomide (51,52).…”

In vitro and in vivo reversal of resistance to 5-fluorouracil in colorectal cancer cells with a novel stealth double-liposomal formulation

“…Similarly, the strategy of combining encapsulated anticancer drugs with a modulator has been established, for example, in the case of doxorubicin combined with valspodar. However, these two drugs were not encapsulated in a single liposome (Fracasso et al, 2005). The specific, well-tolerated modulator, d-Ino, has been identified as a promising agent that can improve the antitumour action of 5-FU (Ciccolini et al, 2000b(Ciccolini et al, , 2001.…”