Pharmacokinetic study of aldoxorubicin in patients with solid tumors

Abstract

SummaryIntroduction 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/m2 (equivalent in drug load to doxorubicin at doses of 170 or 260 mg/m2, 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/m2), and slow mean clearance rate (0.136–0.152 L/h/m2) 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.

Synovial sarcoma diagnosis and management in the era of targeted therapies

“…Another potentially active agent is aldoxorubicin, a prodrug of doxorubicin, which binds covalently to serum albumin and subsequently accumulates in tumors. In a phase 1/2 trial in patients with solid tumors, aldoxorubicin was administered safely at doses several-fold higher than conventional doxorubicin, without associated acute cardiotoxicity [42].…”

Current and advancing systemic treatment options for soft tissue sarcomas

“…Aldoxorubicin is a pro-drug of doxorubicin which is derivatized at its C-13 keto-position with a thiol-binding spacer molecule (6-maleimidocaproic acid hydrazide) [49]. This agent enters blood stream and is rapidly and covalently bound to the most reactive thiol group in human plasma --the cysteine-34 amino acid of endogenous albumin.…”

Development and In Vitro Evaluation of a Novel Drug Delivery System (Albumin Microspheres Containing Liposomes) Applied to Vancomycin

“…9 Many drugs are delivered to their targeted organs/tissues by binding with human serum albumin, which not only protects the bound drugs against oxidation but also alters their pharmacokinetic and pharmacodynamic behavior. 10,11 The relevant role of albumin on drug intracellular uptake has recently been considered and some authors 12 have investigated the impact of albumin concentration on the uptake of drugs in cells. They conclude that for drugs highly bound to albumin the uptake is primarily driven by the albumin-bound form and that physiologically based pharmacokinetic and pharmacodynamic models considering the albumin-facilitated mechanism predict more accurately the in vivo conditions.…”