Limits...
Pharmacokinetic study of aldoxorubicin in patients with solid tumors.

Mita MM, Natale RB, Wolin EM, Laabs B, Dinh H, Wieland S, Levitt DJ, Mita AC - Invest New Drugs (2014)

Bottom Line: Limited blood sampling was done in cycle 3, before aldoxorubicin infusion, and at 60 min and at 2, 4, and 8 h after infusion.Results The long mean half-life (20.1-21.1 h), narrow mean volume of distribution (3.96-4.08 L/m(2)), and slow mean clearance rate (0.136-0.152 L/h/m(2)) suggest that aldoxorubicin is stable in circulation and does not accumulate readily in body compartments outside of the bloodstream.Conclusions Our findings support dosing and administration schemas used in an ongoing phase 3 clinical study of aldoxorubicin in soft tissue sarcoma, and phase 2 clinical studies in small cell lung cancer, glioblastoma, and Kaposi's sarcoma.

View Article: PubMed Central - PubMed

Affiliation: Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite MS31, Los Angeles, CA, 90048, USA, monica.mita@cshs.org.

ABSTRACT
Introduction Aldoxorubicin, a prodrug of doxorubicin, binds covalently to serum albumin in the bloodstream and accumulates in tumors. Aldoxorubicin can be administered at doses several-fold higher than doxorubicin can, without associated acute cardiotoxicity. Purpose This study fully evaluated the pharmacokinetic profile of aldoxorubicin (serum and urine). Methods Eighteen patients with advanced solid tumors received aldoxorubicin 230 or 350 mg/m(2) (equivalent in drug load to doxorubicin at doses of 170 or 260 mg/m(2), respectively) once every 21 days. Blood samples were taken in cycle 1 before aldoxorubicin infusion, and at 5, 15, 30, and 60 min, and at 2, 4, 8, 12, 16, 24, 48, and 72 h after infusion. Urine samples were taken in cycle 1 at 24, 48, and 72 h after infusion. Limited blood sampling was done in cycle 3, before aldoxorubicin infusion, and at 60 min and at 2, 4, and 8 h after infusion. Results The long mean half-life (20.1-21.1 h), narrow mean volume of distribution (3.96-4.08 L/m(2)), and slow mean clearance rate (0.136-0.152 L/h/m(2)) suggest that aldoxorubicin is stable in circulation and does not accumulate readily in body compartments outside of the bloodstream. Very little doxorubicin and its major metabolite doxorubicinol, which has been implicated in doxorubicin-associated cardiotoxicity, are excreted in urine. This might explain the lack of cardiotoxicity observed thus far with aldoxorubicin. Conclusions Our findings support dosing and administration schemas used in an ongoing phase 3 clinical study of aldoxorubicin in soft tissue sarcoma, and phase 2 clinical studies in small cell lung cancer, glioblastoma, and Kaposi's sarcoma.

Show MeSH

Related in: MedlinePlus

Mean plasma concentration-time profiles of albumin-bound doxorubicin (closed circles), free doxorubicin (open circles), and doxorubicinol (closed triangles) after aldoxorubicin infusion on day 1 of cycle 1 (N = 18)
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4387275&req=5

Fig1: Mean plasma concentration-time profiles of albumin-bound doxorubicin (closed circles), free doxorubicin (open circles), and doxorubicinol (closed triangles) after aldoxorubicin infusion on day 1 of cycle 1 (N = 18)

Mentions: Results of the cycle 1 pharmacokinetic analyses are summarized in Table 2. Mean plasma concentrations over time after aldoxorubicin infusion for each dose group are shown in Fig. 1. Following a single dose of aldoxorubicin on day 1 of cycle 1, peak plasma concentrations (Cmax) of aldoxorubicin were reached at a median of 0.75 h (230 mg/m2) and 1.00 h (350 mg/m2) after the start of aldoxorubicin infusion (tmax). The tmax of doxorubicin was 0.58 h (230 mg/m2) and 0.68 h (350 mg/m2). The tmax for doxorubicinol was much longer, a median of 36.5 h (230 mg/m2) and 48.5 h (350 mg/m2). The plasma concentration of aldoxorubicin was greater than that of doxorubicin by about 40–to 300-fold, depending on the individual. The plasma concentration of doxorubicinol, the main metabolite of doxorubicin, was very near the limit of detection.Table 2


Pharmacokinetic study of aldoxorubicin in patients with solid tumors.

Mita MM, Natale RB, Wolin EM, Laabs B, Dinh H, Wieland S, Levitt DJ, Mita AC - Invest New Drugs (2014)

Mean plasma concentration-time profiles of albumin-bound doxorubicin (closed circles), free doxorubicin (open circles), and doxorubicinol (closed triangles) after aldoxorubicin infusion on day 1 of cycle 1 (N = 18)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4387275&req=5

Fig1: Mean plasma concentration-time profiles of albumin-bound doxorubicin (closed circles), free doxorubicin (open circles), and doxorubicinol (closed triangles) after aldoxorubicin infusion on day 1 of cycle 1 (N = 18)
Mentions: Results of the cycle 1 pharmacokinetic analyses are summarized in Table 2. Mean plasma concentrations over time after aldoxorubicin infusion for each dose group are shown in Fig. 1. Following a single dose of aldoxorubicin on day 1 of cycle 1, peak plasma concentrations (Cmax) of aldoxorubicin were reached at a median of 0.75 h (230 mg/m2) and 1.00 h (350 mg/m2) after the start of aldoxorubicin infusion (tmax). The tmax of doxorubicin was 0.58 h (230 mg/m2) and 0.68 h (350 mg/m2). The tmax for doxorubicinol was much longer, a median of 36.5 h (230 mg/m2) and 48.5 h (350 mg/m2). The plasma concentration of aldoxorubicin was greater than that of doxorubicin by about 40–to 300-fold, depending on the individual. The plasma concentration of doxorubicinol, the main metabolite of doxorubicin, was very near the limit of detection.Table 2

Bottom Line: Limited blood sampling was done in cycle 3, before aldoxorubicin infusion, and at 60 min and at 2, 4, and 8 h after infusion.Results The long mean half-life (20.1-21.1 h), narrow mean volume of distribution (3.96-4.08 L/m(2)), and slow mean clearance rate (0.136-0.152 L/h/m(2)) suggest that aldoxorubicin is stable in circulation and does not accumulate readily in body compartments outside of the bloodstream.Conclusions Our findings support dosing and administration schemas used in an ongoing phase 3 clinical study of aldoxorubicin in soft tissue sarcoma, and phase 2 clinical studies in small cell lung cancer, glioblastoma, and Kaposi's sarcoma.

View Article: PubMed Central - PubMed

Affiliation: Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite MS31, Los Angeles, CA, 90048, USA, monica.mita@cshs.org.

ABSTRACT
Introduction Aldoxorubicin, a prodrug of doxorubicin, binds covalently to serum albumin in the bloodstream and accumulates in tumors. Aldoxorubicin can be administered at doses several-fold higher than doxorubicin can, without associated acute cardiotoxicity. Purpose This study fully evaluated the pharmacokinetic profile of aldoxorubicin (serum and urine). Methods Eighteen patients with advanced solid tumors received aldoxorubicin 230 or 350 mg/m(2) (equivalent in drug load to doxorubicin at doses of 170 or 260 mg/m(2), respectively) once every 21 days. Blood samples were taken in cycle 1 before aldoxorubicin infusion, and at 5, 15, 30, and 60 min, and at 2, 4, 8, 12, 16, 24, 48, and 72 h after infusion. Urine samples were taken in cycle 1 at 24, 48, and 72 h after infusion. Limited blood sampling was done in cycle 3, before aldoxorubicin infusion, and at 60 min and at 2, 4, and 8 h after infusion. Results The long mean half-life (20.1-21.1 h), narrow mean volume of distribution (3.96-4.08 L/m(2)), and slow mean clearance rate (0.136-0.152 L/h/m(2)) suggest that aldoxorubicin is stable in circulation and does not accumulate readily in body compartments outside of the bloodstream. Very little doxorubicin and its major metabolite doxorubicinol, which has been implicated in doxorubicin-associated cardiotoxicity, are excreted in urine. This might explain the lack of cardiotoxicity observed thus far with aldoxorubicin. Conclusions Our findings support dosing and administration schemas used in an ongoing phase 3 clinical study of aldoxorubicin in soft tissue sarcoma, and phase 2 clinical studies in small cell lung cancer, glioblastoma, and Kaposi's sarcoma.

Show MeSH
Related in: MedlinePlus