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

Fracasso PM, Blum KA, Ma MK, Tan BR, Wright LP, Goodner SA, Fears CL, Hou W, Arquette MA, Picus J, Denes A, Mortimer JE, Ratner L, Ivy SP, McLeod HL - Br. J. Cancer (2005)

Bottom Line: Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction.The mean (range) total doxorubicin clearance decreased from 27 (10-73) ml h(-1) m(-2) in cycle 1 to 18 (3-37) ml h(-1) m(-2) with the addition of valspodar in cycle 2 (P=0.009).Treatment with PEG-LD 25 mg m(-2) 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.

View Article: PubMed Central - PubMed

Affiliation: Alvin J Siteman Cancer Center and the Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA. fracasso@wustl.edu

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(-2) 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(-2) and escalated in an accelerated titration design to 25 mg m(-2). 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(-2). 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(-1) m(-2) in cycle 1 to 18 (3-37) ml h(-1) m(-2) with the addition of valspodar in cycle 2 (P=0.009). Treatment with PEG-LD 25 mg m(-2) 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.

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Plasma doxorubicin concentration vs time plot in patient 1 after receiving intravenous doxorubicin at 20 mg m−2 over 60 min in cycle 1. A second intravenous doxorubicin dose at 8 mg m−2 was started 14 days (336 h) after the first dose in combination with valspodar at a dosing rate of 1.42 mg kg−1 h−1 over 2 h, followed by 0.42 mg kg−1 h−1 over an additional 70 h. Symbols represent measured plasma doxorubicin concentrations, and the solid line represents the best fit from the maximum likelihood estimation using ADAPT II software.
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fig1: Plasma doxorubicin concentration vs time plot in patient 1 after receiving intravenous doxorubicin at 20 mg m−2 over 60 min in cycle 1. A second intravenous doxorubicin dose at 8 mg m−2 was started 14 days (336 h) after the first dose in combination with valspodar at a dosing rate of 1.42 mg kg−1 h−1 over 2 h, followed by 0.42 mg kg−1 h−1 over an additional 70 h. Symbols represent measured plasma doxorubicin concentrations, and the solid line represents the best fit from the maximum likelihood estimation using ADAPT II software.

Mentions: All patients had total doxorubicin pharmacokinetics performed either alone and in combination with valspodar. Initial evaluation with a one-compartment model was used based on a previous study of PEG-LD disposition in children (Marina et al, 2002) and was able to describe total doxorubicin pharmacokinetics in the current study. However, both the AIC score and the goodness of fit were inferior to the two-compartment model (data not shown). Figure 1 depicts a best-fit line for total doxorubicin concentration–time data in patient #1 (PEG-LD 8 mg m−2) during cycles 1 and 2. Maximum-likelihood analysis was updated and two iterations were required to achieve stable estimates of the median parameters. The mean parameters (CV%) observed in the study include K10=0.02 h−1 (61%), V=1.48 l m−2 (29%), K12=0.21 (140%) h−1, and K21=0.64 h−1 (69%). Total doxorubicin pharmacokinetic parameters by patient are listed in Table 5. The interindividual variability in total doxorubicin clearance was seven-fold (10–73 mL h m−2) in cycle 1 and over 12-fold (3–37 ml h−1 m−2) in cycle 2. The correlation between dose and total doxorubicin clearance was weak (Rs=0.06). The mean (range) total doxorubicin clearance decreased from 27 (10–73) ml h−1 m−2 in cycle 1 to 18 (3–37) ml h−1 m−2 with the addition of valspodar in cycle 2 (P=0.009). A three-fold range in V was observed in cycle 1 and there was no significant difference in V between cycles 1 and 2 (P=0.43). The estimated mean (range) terminal elimination half-life was 89 h (40–336 h) in cycle 2, much longer than estimated in cycle 1 (P=0.001). The AUC was also slightly higher in cycle 2 (mean 1689 μg h ml−1, range 492–6257 μg h ml−1) than in cycle 1 (mean 1087 μg h ml−1, range 343–2408 μg h ml−1; P=0.04). In this small set of patients, neither toxicity nor response was clearly related to total doxorubicin AUC or clearance.


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

Fracasso PM, Blum KA, Ma MK, Tan BR, Wright LP, Goodner SA, Fears CL, Hou W, Arquette MA, Picus J, Denes A, Mortimer JE, Ratner L, Ivy SP, McLeod HL - Br. J. Cancer (2005)

Plasma doxorubicin concentration vs time plot in patient 1 after receiving intravenous doxorubicin at 20 mg m−2 over 60 min in cycle 1. A second intravenous doxorubicin dose at 8 mg m−2 was started 14 days (336 h) after the first dose in combination with valspodar at a dosing rate of 1.42 mg kg−1 h−1 over 2 h, followed by 0.42 mg kg−1 h−1 over an additional 70 h. Symbols represent measured plasma doxorubicin concentrations, and the solid line represents the best fit from the maximum likelihood estimation using ADAPT II software.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2361488&req=5

fig1: Plasma doxorubicin concentration vs time plot in patient 1 after receiving intravenous doxorubicin at 20 mg m−2 over 60 min in cycle 1. A second intravenous doxorubicin dose at 8 mg m−2 was started 14 days (336 h) after the first dose in combination with valspodar at a dosing rate of 1.42 mg kg−1 h−1 over 2 h, followed by 0.42 mg kg−1 h−1 over an additional 70 h. Symbols represent measured plasma doxorubicin concentrations, and the solid line represents the best fit from the maximum likelihood estimation using ADAPT II software.
Mentions: All patients had total doxorubicin pharmacokinetics performed either alone and in combination with valspodar. Initial evaluation with a one-compartment model was used based on a previous study of PEG-LD disposition in children (Marina et al, 2002) and was able to describe total doxorubicin pharmacokinetics in the current study. However, both the AIC score and the goodness of fit were inferior to the two-compartment model (data not shown). Figure 1 depicts a best-fit line for total doxorubicin concentration–time data in patient #1 (PEG-LD 8 mg m−2) during cycles 1 and 2. Maximum-likelihood analysis was updated and two iterations were required to achieve stable estimates of the median parameters. The mean parameters (CV%) observed in the study include K10=0.02 h−1 (61%), V=1.48 l m−2 (29%), K12=0.21 (140%) h−1, and K21=0.64 h−1 (69%). Total doxorubicin pharmacokinetic parameters by patient are listed in Table 5. The interindividual variability in total doxorubicin clearance was seven-fold (10–73 mL h m−2) in cycle 1 and over 12-fold (3–37 ml h−1 m−2) in cycle 2. The correlation between dose and total doxorubicin clearance was weak (Rs=0.06). The mean (range) total doxorubicin clearance decreased from 27 (10–73) ml h−1 m−2 in cycle 1 to 18 (3–37) ml h−1 m−2 with the addition of valspodar in cycle 2 (P=0.009). A three-fold range in V was observed in cycle 1 and there was no significant difference in V between cycles 1 and 2 (P=0.43). The estimated mean (range) terminal elimination half-life was 89 h (40–336 h) in cycle 2, much longer than estimated in cycle 1 (P=0.001). The AUC was also slightly higher in cycle 2 (mean 1689 μg h ml−1, range 492–6257 μg h ml−1) than in cycle 1 (mean 1087 μg h ml−1, range 343–2408 μg h ml−1; P=0.04). In this small set of patients, neither toxicity nor response was clearly related to total doxorubicin AUC or clearance.

Bottom Line: Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction.The mean (range) total doxorubicin clearance decreased from 27 (10-73) ml h(-1) m(-2) in cycle 1 to 18 (3-37) ml h(-1) m(-2) with the addition of valspodar in cycle 2 (P=0.009).Treatment with PEG-LD 25 mg m(-2) 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.

View Article: PubMed Central - PubMed

Affiliation: Alvin J Siteman Cancer Center and the Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA. fracasso@wustl.edu

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(-2) 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(-2) and escalated in an accelerated titration design to 25 mg m(-2). 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(-2). 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(-1) m(-2) in cycle 1 to 18 (3-37) ml h(-1) m(-2) with the addition of valspodar in cycle 2 (P=0.009). Treatment with PEG-LD 25 mg m(-2) 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.

Show MeSH
Related in: MedlinePlus