Pharmacokinetic and allometric scaling studies of nanoparticle formulations of anthracyclines
Creators: name: Herity, Leah
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2017

description: INTRODUCTION
Nanoparticle drug formulations have many unique properties that differentiate them from small
molecule drugs. The pharmacokinetics of nanoparticle agents often vary substantially from their small
molecule counterparts. This change in pharmacokinetics occurs because small molecule drugs that are
encapsulated into nanoparticles follow the pharmacokinetic behavior of the carrier.1 Nanoparticle
agents, such as liposomes and especially PEGylated liposomes, typically have the benefit of prolonged
duration of drug exposure as well as increased delivery of the drug to the site of action.2 The clearance
mechanisms affecting liposomes are theorized to differ from those of small molecule drugs, which partly
explains the prolonged duration of exposure noted with liposomal agents. Conventional liposomes are
thought to be cleared mainly by uptake into cells of the mononuclear phagocyte system (MPS). As a
result, liposomal agents accumulate in MPS-associated tissues such as the spleen and liver.2 This differs
from the typical renal elimination or hepatic metabolism clearance pathways followed by small molecule
drugs. The addition of polyethylene glycol (PEG) onto the surface of the liposome to create a PEGylated
formulation helps further stabilize the liposome and reduce the rate of clearance by cells of the MPS.1
Liposomal formulations have also been noted to have smaller volumes of distribution than the
small molecule drugs they contain. A reduced volume of distribution helps prevent accumulation of the
drug into off-target tissues.1 This is especially important with anticancer agents, where off-target
distribution of drugs can have cytotoxic effects on healthy tissues. One class of drug that has been used
clinically in multiple nanoparticle formulations is anthracyclines, a type of anticancer antibiotic.
Anthracyclines, such as doxorubicin and daunorubicin, exert their anticancer activity through
intercalation of DNA base-pairs and subsequent inhibition of DNA topoisomerase II.3 Anthracyclines
have been an area of interest for nanoparticle development partly because of serious adverse effects,
namely cardiotoxicity, associated with non-specific tissue distribution. Cardiotoxicity can manifest as
either acute cardiovascular complications, which tend to resolve with removal of the drug, or chronic
cardiotoxicity. Chronic myocardial damage as a result of anthracycline use is typically irreversible and
can eventually lead to heart failure and death. Liposomal formulations of doxorubicin have been shown
to drastically reduce the incidence of anthracycline-induced cardiotoxicity. This occurs because
liposomal formulations distribute preferentially into tumors as a result of leaky tumor microvasculature,
leaving normal heart tissue with intact vasculature relatively safe from accumulating high
concentrations of the drug.3
Development of nanoparticle formulations of anticancer drugs, such as anthracyclines, is an
active area of research because of the potential for tumor selectivity and favorable safety profiles.3 An
essential feature of the drug development process is selecting an appropriate starting dose for phase 1
clinical trials. Starting doses are derived from the results of pharmacokinetic and toxicological studies in
preclinical animal models, such as mice, rats, and dogs.4 One commonly used method for predicting
pharmacokinetic behavior in humans is allometric scaling. Allometric scaling, which has historically been
used as a way to predict physiological characteristics based on total body weight, can also be used to
predict pharmacokinetic parameters based on other physiological variables. One application of
allometric scaling in pharmacokinetics has been to predict drug clearance based on blood flow or weight
of the eliminating organ, such as the kidneys or liver. By assessing the relationship between clearance
and these physiological variables in multiple different mammalian species, a prediction of human
clearance can be made using interspecies scaling.4
As mentioned above, nanoparticle formulations of drugs take on the pharmacokinetic profile of
their carriers and thus have different clearance mechanisms than are typical of small molecule drugs.1
The purpose of this study was to evaluate if traditional interspecies allometric scaling can be applied to
different types of nanoparticle formulations of small molecule drugs. More specifically, the study aimed
to identify which physiological variables, if any, most accurately predict the clearance of these agents in
humans. Based on the proposed involvement of the MPS in clearance of nanoparticles, MPS-related
physiological variables were assessed in addition to more typical physiological variables, such as body
weight and liver blood flow. Anthracyclines were selected as the agents of interest because of the
availability of four different formulations: non-liposomal (NL) doxorubicin (NL-doxorubicin;
Adriamycin®), PEGylated liposomal doxorubicin (PLD; Doxil®), non-PEGylated liposomal daunorubicin
(DaunoXome®), and polymeric micellar doxorubicin (SP1049C). Based on our prior allometric studies of
PEG-liposomal agents alone, it was hypothesized that interspecies scaling using MPS-associated
parameters would better predict clearance for all types of nanoparticle formulations while liverassociated
factors would produce the most accurate predictions for small molecule doxorubicin.5