Biomedical Engineering Reference
In-Depth Information
12.3.4
Conclusions of Our Clinical Experience with OLV-
DOX as the Basis for the Development of Novel
Liposomal DOX for Treatment of Metastatic
Tumors
Our study that reports on the PK and BD of OLV-DOX and on imaging
of
111
In-OLV in humans (Gabizon et al., 1991) is the first study in
which a complete pharmacokinetic and biodistribution analysis of
a drug-liposome dosage form in human patients was described. The
clearance of DOX when delivered as OLV-DOX is a composite of two
processes: (i) clearance of liposomes containing DOX by the RES,
predominantly liver and spleen and (ii) clearance of DOX released
from liposomes in plasma. The analysis that includes PK of total drug
(DOX), liposome-associated DOX, and liposome markers (PG and
111
In-OLV) suggests that both processes operate in human patients
and that factors such as the patient's liver function may aff ect their
relative contribution.
Delivery of DOX in liposome-entrapped form (OLV-DOX) has
been proposed as a means to reduce the toxicity of DOX and improve
its therapeutic index based on a number of preclinical studies (rev.
in Gabizon and Barenholz, 1988).
The PK, BD, and imaging data (Gabizon et al., 1991) suggest that
the reduced clinical toxicity of OLV-DOX results from a somewhat
lower peak level of free drug and possibly some changes in the tissue
distribution of the liposomes, with a partial shift toward OLV and
possibly some drug accumulation in the RES at the expense of other
tissues. The main limitations of our therapeutic strategy based on
OLV-DOX, as revealed by this study, are the significant drug leakage
and preferential RES uptake. These shortcomings are probably the
result of the basic formulation physicochemical characteristics, such
as
(i) Drug entrapment in the liposome bilayer as opposed to
encapsulation in liposome aqueous interior. Bilayer-associated
drug may be more accessible to be released to the plasma
upon dilution and to associate with plasma proteins (Goren
et al., 1990; Goren, 1990). This process will be aff ected by the
degree of dilution upon injection, which is also dependent on
the mode of administration (greater dilution eff ect occurs
for slow infusion than for bolus injection). The association of
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