Doxil — The First FDA-Approved Nano-Drug: From an Idea to a Product - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 378

i.v. administration is liposome associated. Pharmacokinetics was
determined for 25 and 50 mg/m 2 . The plasma elimination time of
Doxil followed a biexponential curve with half-lives of 2 and 45 h
(median values), most of the dose being cleared from plasma under the
longer half-life. A large diff erence in volume of distribution was also
found (4 L for Doxil versus 254 L for free DOX. Similarly, doxorubicin
derived from Doxil showed a much slower rate of clearance (compare
0.1 L/h for Doxil with 45 L/h for free DOX).
The types of Doxil-derived doxorubicin metabolites in patients'
urine were identical to those of patients injected with free DOX;
however, the overall urinary excretion in the Doxil group was
significantly reduced. Most encouraging are the results on the levels
of drug in the malignant eff usions, which were 4 to 16 times higher
than after free DOX administration. In addition, doxorubicin level
there peaked after Doxil administration between 3 to 7 days, which
means the exposure of the tumor cells to the drug is much longer
than after free DOX administration. HPLC analysis of the drug at the
tumor site demonstrated that a large fraction of the doxorubicin was
metabolized to the conventional metabolites of doxorubicin. The
fact that doxorubicin is metabolized only intracellularly and not in
the plasma indicates internalization of the doxorubicin derived from
Doxil. Two diff erent mechanisms may explain this: doxorubicin can
be released outside the tumor cell and be taken up by it, or Doxil
can be taken up by the tumor cell, and then doxorubicin is released.
These data are in excellent agreement with our preclinical studies
and indicate that stable remote loading of doxorubicin into long-
circulating nano-liposomes serve well the objectives of passive
targeting of doxorubicin to tumors. Our 1994 Cancer Research paper
is the first demonstration of the of EPR relevance in cancer patients
to antitumor therapy by nano-drugs.
The localization of Doxil in humans' tumors was further supported
by direct fluorescence microscopy of patient biopsies (Symon et al.,
1999).
For extended information on the superiority of the pharmaco-
kinetic (PK) performance of Doxil, see Gabizon et al. (2003). That
review summarizes the PK profile in humans at doses between 10
and 80 mg/m 2 . The PK has one or two distribution phases: an initial
phase, with a half-life of 1-3 h, and a second phase responsible for
most of the clearance, with a half-life of 30-90 h. The AUC after a dose