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Biodrugs 2005; 19 (3): 179-187
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DRUG DELIVERY
 2005 Adis Data Information BV. All rights reserved.
The Science of Megestrol Acetate Delivery
Potential to Improve Outcomes in Cachexia
Robert A. Femia1 and Richert E. Goyette2
1
2
Scientific and Regulatory Affairs, Par Pharmaceutical, Inc., Spring Valley, New York, USA
Consultant, Hematology/Oncology, Knoxville, Tennessee, USA
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
1. Progesterone Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
1.1 Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
1.2 Modulation of Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
1.3 Metabolic Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
2. Pharmacodynamics of Megestrol Acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
2.1 General Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
2.2 Anticytokine Properties of Megestrol Acetate in Cachexia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
2.3 Orexigenic Effects of Megestrol Acetate in Cachexia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
3. Tolerability of Megestrol Acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
4. Pharmacokinetics of Megestrol Acetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
4.1 General Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
4.2 Megestrol Acetate Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
4.3 Megestrol Acetate Oral Suspension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
5. Megestrol Acetate Nanocrystal Oral Suspension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
5.1 Preclinical Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
Abstract
Cachexia, usually defined as the loss of >5% of an individual’s baseline bodyweight over 2–6 months, occurs
with a number of diseases that includes not only AIDS and advanced cancer but also chronic heart failure,
rheumatoid arthritis, chronic obstructive pulmonary disease, Crohn disease, and renal failure. Anorexia is
considered a key component of the anorexia-cachexia syndrome. Progestogens, particularly megestrol acetate,
are commonly used to treat anorexia-cachexia. The mechanism of action of megestrol is believed to involve
stimulation of appetite by both direct and indirect pathways and antagonism of the metabolic effects of the
principal catabolic cytokines. Because the bioavailability of megestrol acetate directly affects its efficacy and
safety, the formulation was refined to enhance its pharmacokinetics.
Such efforts yielded megestrol acetate in a tablet form, followed by a concentrated oral suspension form, and
an oral suspension form developed using nanocrystal technology. Nanocrystal technology was designed
specifically to optimize drug delivery and enhance the bioavailability of drugs that have poor solubility in water.
Megestrol acetate nanocrystal oral suspension is currently under review by the US FDA for the treatment of
cachexia in patients with AIDS. Preclinical pharmacokinetic data suggest that the new megestrol acetate
formulation has the potential to significantly shorten the time to clinical response and thus may improve
outcomes in patients with anorexia-cachexia.
180
Femia & Goyette
Progestational agents are used to treat the anorexia-cachexia
syndrome and sometimes as salvage agents to treat hormonesensitive breast cancer and cancers of the endometrium, ovary,
prostate, and other organs. Because oral progesterone is poorly
absorbed, the agent is usually delivered intramuscularly in an oil
carrier. Megestrol acetate (Megace 1, Par Pharmaceutical, Inc.,
Spring Valley, NY, USA), a synthetic progestogen currently available in tablet and suspension form, has physiologic activity similar
to the natural hormone. First used in humans in 1968, megestrol
acetate tablets became commercially available in the US in 1971
for the treatment of endometrial carcinoma. Since that time,
megestrol acetate has been used as a component of oral contraceptive pills and in the treatment of malignant and nonmalignant
conditions such as melanoma; cancers of the ovary, breast, kidney,
and prostate; benign prostatic hypertrophy; and endometrial hyperplasia.[1]
Cachexia is a condition of starvation characterized by depletion
of muscle mass and, to a lesser extent, adipose tissue. Etymologically, cachexia is derived from ‘kakos’ and ‘hexis’—Greek words
meaning ‘bad condition’.[2] Although there are various definitions
of cachexia in the medical literature, it commonly refers to an
involuntary loss of approximately ≥5% of an individual’s baseline
bodyweight over a defined period, usually 2–6 months. Cachexia
develops in approximately one half of patients with cancer, and
when it does, it can substantially shorten survival time.[2] It is often
associated with other debilitating symptoms such as chronic nausea, asthenia and weakness, autonomic failure, cognitive impairment, psychologic distress, and poor/unsatisfactory quality of
life.[3] Tissue changes associated with cachexia predispose patients
to other comorbidities; for example, insufficient nutrition and loss
of fatty hip pads in patients with cachexia increase the risk of hip
CNS
ct
re nic
ige
ex
Di
Or
CH3
TNF
IL-6
IL-1
C=O
CH3
Anti-TNF
Anti-IL-6
Anti-IL-1
CH3
OCOCH3
H
H
H
O=
CH3
Muscle tissue
Megestrol acetate
Patient with
cachexia
Fatty tissue
Fig. 1. The mechanism of action of megestrol acetate in anorexia/cachexia. IL = interleukin; TNF = tumor necrosis factor.
1
The use of trade names is for product identification purposes only and does not imply endorsement.
 2005 Adis Data Information BV. All rights reserved.
Biodrugs 2005; 19 (3)
Enhancing Megestrol Acetate Delivery for Cachexia
181
CH3
fractures due to falls, and compromise patients’ ability to retain
body heat.[4]
The word cachexia often evokes the image of a patient with
advanced cancer or a disadvantaged individual with extensive
protein-calorie malnutrition in a Third World nation; however,
cachexia is common in devloped countries and in patients with
diseases other than cancer. Cachexia is a manifestation of AIDS,
chronic heart failure, rheumatoid arthritis, chronic obstructive
pulmonary disease, Crohn disease, chronic renal disease, and other
chronic disorders.[2,5-10]
Anorexia is a key component of cachexia, and accumulating
data suggest that the anorexia-cachexia syndrome is a cytokinederived process manifested by loss of appetite and cytokine-driven
hypercatabolism.[11] Megestrol acetate is commonly used to treat
anorexia-cachexia and is the only FDA-approved treatment of
cancer- and AIDS-related anorexia-cachexia syndrome. Other less
common interventions include dronabinol, glucocorticoids, anabolic steroids, antiserotonergic drugs, and prokinetic medications.[12] Until recently, the mechanism of action of megestrol
acetate in anorexia-cachexia was poorly understood, but it is now
believed that megestrol acetate acts by stimulating appetite, by
both direct and indirect mechanisms, and by antagonizing the
metabolic effects of the main or most relevant catabolic cytokines
(figure 1). Since the efficacy and safety of megestrol acetate is
directly linked to the drug’s bioavailability,[13] this article reviews
the science of megestrol acetate delivery and describes recent
advances in the therapeutic area, focusing on the numerous metabolic effects of physiologic levels of progesterone and the specific
effects of pharmacologic amounts of the hormone on processes
associated with cachexia.
1. Progesterone Physiology
1.1 Secretion
Progesterone is a naturally occurring steroid hormone secreted
by the ovary, testes, placenta, and adrenal gland.[14] In menstruating women, endogenous progesterone is secreted from the ovarian follicle just before ovulation and thereafter from the corpus
luteum, with concentrations peaking approximately 7 days after
ovulation. If a fertilized ovum does not implant, progesterone
concentrations fall to basal levels immediately prior to menstruation.[14] Progesterone has a variety of physiologic activities in the
reproductive tract, mammary gland, and central nervous system
that are beyond the scope of this article.
 2005 Adis Data Information BV. All rights reserved.
C=O
CH3
CH3
OCOCH3
H
H
H
O=
CH3
Fig. 2. Chemical structure of megestrol acetate.
1.2 Modulation of Activity
Progesterone enters the cell by passively diffusing through the
plasma membrane.[14] The actions of the hormone are mediated by
binding to progesterone receptor (PR)-A and -B, which are
isoforms of the progesterone nuclear factor (NF) receptor coded
by a single PR gene. Unligated, the PR isoforms exist as monomers bound to heat shock proteins. These proteins dissociate after
binding, and the receptors are phosphorylated and dimerize as
either homodimers or heterodimers. These dimers subsequently
bind to progesterone response elements on various target genes
and, through steps involving transcriptional activators and coactivators and proteins with histone deacetylase activity, chromatin
is remodeled and general transcription factors become accessible
to transcription proteins such as RNA polymerase II. The biologic
activities of PR-A and -B are a function of the target genes.
However, PR-A generally acts as a transcriptional inhibitor and
PR-B as a stimulator of other steroid response elements. Although
the major activities of progesterone are mediated genomically,
some nongenomic mechanisms are also operative.[14]
1.3 Metabolic Activity
Progesterone exerts myriad metabolic effects on carbohydrate
and lipid metabolism.[14] Although the hormone does not alter
glucose tolerance, it increases basal insulin levels and the insulin
response to carbohydrate load. It also stimulates the activity of
lipoprotein lipase and may enhance fat deposition and alter plasma
lipids and lipoprotein levels, but the physiologic consequences of
the latter effect are unknown. Progesterone also modulates body
temperature. Elevated levels of progesterone raise core temperatures after ovulation, presumably through the temperature regulatory activity of the hypothalamus.[14]
2. Pharmacodynamics of Megestrol Acetate
2.1 General Characteristics
Megestrol acetate is a synthetic derivative of naturally occurring progesterone, chemically designated 17α-(acetoxy)-6-methylpregna-4,6-diene-3,20-dione (figure 2).[15] A white,
Biodrugs 2005; 19 (3)
182
Femia & Goyette
crystalline solid, megestrol acetate is delivered in both tablet and
suspension form. The suspension is generally preferred over the
tablet because it has significantly greater bioavailability as well as
a lower cost, which tends to improve adherence.[12]
Considerable evidence demonstrates the efficacy of megestrol
acetate in the treatment of cachexia, the key characteristics of
which are decreased appetite and low bodyweight.[16,17] Megestrol
acetate significantly increases both appetite and bodyweight. In
doses ranging from 160 to 1600 mg/day, megestrol acetate has
been shown to stimulate appetite, increase caloric intake, induce a
sense of wellbeing, and produce weight gain (for details see
review in Drugs[18]). Weight gain occurs predominantly in the
form of fat, which is potentially beneficial because the caloric
stores in fatty tissue provide more kilocalories per gram than
similar amounts of either protein or carbohydrate (i.e. 9.0 kcal vs
4.0 kcal and 4.0 kcal, respectively). Fat also helps stabilize core
body temperatures and protects bony tissue; for example, the fat
pads in the hips can help protect debilitated patients from hip
fractures secondary to falls.
The benefits of megestrol acetate are dose related. Although
dosages up to 1600 mg/day of megestrol acetate have been used,
the drug’s effects on anorexia-cachexia tend to plateau at 800 mg/
day.[18] Thus, current recommendations are that treatment be titrated from 160 mg/day (40mg four times daily) up to 800 mg/day
according to clinical response.[18-20]
2.2 Anticytokine Properties of Megestrol Acetate
in Cachexia
The principal cytokines involved in cachexia include tumor
necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, and interferon
(IFN)-γ.[2] TNF-α is believed to work through numerous mechanisms to produce much of the severe cachexia that occurs in
patients with chronic infections and cancer.[21] At low concentrations (≤1 U/mL) in C2C12 myotubes in cell culture, TNF-α has
been shown to exert a clearly catabolic effect, decreasing both
total and myofibrillar protein content.[22] Additional data suggest
TNF-α and other inflammatory cytokines contribute to muscle
wasting through inhibition of myogenic differentiation via an NFκB-dependent pathway.[23] TNF-α also increases levels of mitochondrial uncoupling proteins, thus providing an energy sink,[24,25]
and it inhibits lipoprotein lipase activity and directly stimulates
lipolysis.[26]
Both IL-6 and IL-1 interact with other cytokines in the development of cachexia. In nude mice transplanted with human cachexiainducing tumors, administration of a monoclonal antibody to IL-6
either essentially abrogated weight loss or resulted in a net weight
gain.[27] Binding of IL-1 to its receptors induces a variety of effects
 2005 Adis Data Information BV. All rights reserved.
within the central nervous system and liver, including anorexia,
acute-phase protein synthesis, and downregulation of hepatic production of albumin and other ‘housekeeping’ proteins. Some of the
anorexigenic effects of IL-1 are due to the ability of the cytokine to
stimulate leptin release, an effect that is blocked by administration
of soluble IL-1 receptor.[28]
Megestrol acetate appears to have direct anticytokine properties. The drug significantly antagonizes the effects of cytokines
such as TNFα, IL-6, and IL-1. In patients with cancer, megestrol
acetate has been shown to significantly reduce serum levels of
IL-1α and β and reduce IL-6 production in peripheral blood
mononuclear cells.[29,30] In humans, anti-IL-6 monoclonal antibody therapy has been shown to decrease the incidence of
cancer-related anorexia/cachexia.[31] Experimentally, in Naval
Medical Research Institute (NMRI) mice, megestrol acetate has
been shown to prevent the weight loss induced by TNF-α and a
cachexia-inducing tumor (MAC-16).[32] In patients with advanced
metastatic cancer, the drug has been shown to reverse anorexia and
weight loss associated with IFNα- and IL-2-based therapies.[33]
2.3 Orexigenic Effects of Megestrol Acetate in Cachexia
The mechanisms of anorexia-cachexia are complex. The disorder appears to be associated with disruption in a number of
neurohumoral orexigenic signaling pathways including hypothalamic neuropeptides and possibly melanocortin signaling. Physiologically, low plasma levels of leptin, a hormone of adipocyte
origin associated with loss of body fat, increase orexigenic signals
within the hypothalamus, decrease neurohormonal anorexigenic
signals, and suppress energy expenditures.[11,12,34-36] Cytokines
may contribute to the anorexia component of the anorexia-cachexia syndrome by stimulating the expression and release of leptin or
mimicking the hypothalamic effects of excess leptin on orexigenic
neuropeptides such as neuropeptide Y, galanin, opioids, melaninconcentrating hormone, orexin, and agouti-related peptide.[12] In
addition, a disruption in energetics leads to an imbalance in energy
intake and expenditure.
Megestrol acetate has significant orexigenic properties. Although the precise mechanism of action of megestrol acetate has
not been fully elucidated, the drug is believed to alter levels of
central neurotransmitters involved in appetite regulation (e.g.
neuropeptide Y). This effect may be mediated by modulation of
calcium channels in the satiety center of the ventromedial hypothalamus or directly through increased levels of neuropeptide Y.
Neuropeptide Y is a 36-amino-acid peptide present in significant
amounts in the hypothalamus and other areas of the brain.[36]
Acting directly, through a variety of interconnected pathways,
Biodrugs 2005; 19 (3)
Enhancing Megestrol Acetate Delivery for Cachexia
neuropeptide Y stimulates release of other orexigenic neuropeptides and may itself be intrinsically orexigenic.[12]
Alterations in endogenous opioid-mediated receptors and response mechanisms have also been implicated in the pathogenesis
of anorexia-cachexia.[37] Megestrol acetate has been reported to
stabilize declining cerebrospinal fluid levels of β-endorphin in the
elderly, as well as to increase plasma and cerebrospinal fluid levels
of the appetite-stimulatory neuropeptide Y.[38,39] A direct sex
hormone effect may also be operative in megestrol acetate-induced appetite stimulation. Whereas estrogen has been shown to
decrease food intake in animal models, progestational agents such
as megestrol acetate antagonize this effect.[40]
183
associated with high-dose megestrol acetate therapy and speculate
a causative relationship.
As previously noted, discontinuation of megestrol acetate is
seldom required; however, a few precautions are indicated. For
example, in patients with a history of thromboembolic disease or
heart disease or a serious risk of fluid retention, megestrol acetate
should be administered only after a thoughtful risk-benefit assessment.[46]
4. Pharmacokinetics of Megestrol Acetate
4.1 General Characteristics
3. Tolerability of Megestrol Acetate
Megestrol acetate is generally well tolerated, with mild adverse
effects that rarely lead to drug discontinuation.[12] However,
megestrol acetate can induce thromboembolic phenomena in patients with risk factors for venous thromboembolic disease.[12] This
appears to be partly a result of the drug’s ability to increase
availability of thrombin receptors on smooth muscle cell membrane and thus markedly potentiate the procoagulant effects of
thrombin.[41] A hormone-induced decrease in tissue factor pathway inhibitor may also play a role in the development of venous
thromboembolic disease.[42] In addition, progestogens may increase venous distensibility and capacitance, resulting in reduced
blood flow and stasis,[43] and are likely to induce breakthrough
endometrial bleeding.[12]
Nonprogestational effects of megestrol acetate may account for
sporadic case reports of Addison disease and exacerbation of
glucose intolerance, which appear to be manifestations of the
steroid’s intrinsic activity at corticosteroid and glucocorticoid
hormone receptors. In this setting, Addison disease results from
receptor ligation with either stimulation or blockade, and exacerbations of glucose intolerance is a function of the ability of
megestrol acetate to stimulate gluconeogenesis or insulin secretion, or both. In a study of patients treated with megestrol acetate
160–800 mg/day, Loprinzi et al.[44] found that the drug reversibly
inhibited the hypothalamic-pituitary-adrenal axis and decreased
serum cortisol concentrations. This effect is generally asymptomatic and patients do not acquire Cushingoid symptoms while
receiving megestrol acetate. Furthermore, Addisonian crisis requiring abrupt discontinuation of therapy has not been reported
despite the widespread use of megestrol acetate for decades. In
addition to its glucocorticoid effect, megestrol acetate significantly suppresses plasma levels of estradiol. Wermers et al.[45] have
reported two cases of osteoporosis and multiple vertebral fractures
 2005 Adis Data Information BV. All rights reserved.
Megestrol acetate is absorbed rapidly from the gastrointestinal
tract. However, studies in patients given the oral suspension
demonstrate considerable variability in the rate and degree of
absorption;[47] a factor that may be more significant in patients
receiving the tablet formulation. In some patients, absorption is
slower, with the more sustained plasma drug levels seen in a
1-compartment model. In others, absorption is rapid, with a
2-compartment-like elimination curve.[47] Megestrol acetate is
completely metabolized in the liver to free steroids and the metabolites are conjugated with glucuronic acid. Metabolites account for
only 5–8% of the administered dose, which is considered negligible.[15] The major route of drug elimination in humans is renal.[15]
The effects of megestrol acetate on weight gain appear to be a
function of at least four factors: (i) duration of administration; (ii)
patient morbidities; (iii) concomitant medications; and (iv)
pharmacokinetic effects, particularly those related to bioavailability. Studies in patients with cancer have shown that weight gain
continues with longer duration of therapy.[48,49] In patients with
AIDS, absorption of megestrol acetate shows significant interpatient variability,[47] possibly owing to comorbidities such as enteropathy, achlorhydria, and other disorders that alter gastrointestinal
tract physiology. Concomitant medications affect megestrol acetate pharmacodynamics; for example, drugs such as azoles affect
the rate or extent of megestrol acetate metabolism and thus alter
efficacy. According to Graham et al.,[47] the area under the plasma
concentration-time curve (AUC) of megestrol acetate was not
directly correlated with weight gain; instead, a significant relationship was observed between weight gain and the percentage of the
24-hour administration interval that plasma megestrol acetate
levels exceeded 300 ng/mL. That is, at least during the early stages
of megestrol acetate therapy, weight gain requires plasma megestrol acetate concentrations >300 ng/mL for ≥40% of a 24-hour
administration interval. Alterations in the formulation of megestrol acetate have produced three formulations of drug, a progresBiodrugs 2005; 19 (3)
184
Femia & Goyette
sion associated with increased bioavailability and thus improved
efficacy in the treatment of anorexia-cachexia.
4.2 Megestrol Acetate Tablets
Megestrol acetate was formulated as a tablet requiring administration four times daily.[15] In humans, the rate of excretion of
radiolabeled megestrol acetate 4–90mg given in tablet form was
56.5–78.4% (mean 66.4%) in urine and 7.7–30.3% (mean 19.8%)
in feces within 10 days of administration. The total recovered
radioactivity varied between 83.1% and 94.7% (mean 86.2%). At
least part of the radioactivity not found in the urine and feces may
have been excreted by respiration as labeled carbon dioxide or
held in fat storage.[15]
Absorption of megestrol acetate 160 mg/day (40mg tablets
given four times daily) varied among 23 healthy male volunteers.[15] Peak plasma drug concentrations (Cmax) after the first
40mg dose ranged from 10 to 56 ng/mL (mean 27.6 ng/mL), and
the times to Cmax (tmax) ranged from 1 to 3 hours (mean 2.2 hours).
Plasma elimination half-life ranged from 13 to 104.9 hours (mean
34.2 hours). Steady-state plasma drug concentrations with a
megestrol acetate 40mg four times daily regimen have not been
established.[15]
4.3 Megestrol Acetate Oral Suspension
To obviate the need for administration of multiple tablets, a
megestrol acetate preparation was formulated as a concentrated
oral suspension.[15] Plasma steady-state pharmacokinetics of
megestrol acetate oral suspension were evaluated in 10 adult male
patients with AIDS and cachexia manifesting as involuntary
weight loss >10% from baseline.[47] Patients received oral megestrol acetate 800mg once daily for 21 days, and plasma concentrations were measured up to 48 hours after the last dose on day 21.
Data analysis showed that mean ± 1 SD Cmax was 828 ± 513 ng/
mL,[47] and mean AUC0–24h was 11 250 ± 7305 ng•hr/mL, results
similar to those reported in the megestrol acetate oral suspension
(40 mg/mL) package insert (Cmax 753 ± 539 ng/mL and AUC
10 476 ± 7788 ng•hr/mL).[15] The median tmax was 5 hours. All
patients reported an increase in appetite, and 8 of 10 patients
gained weight by the end of 3 weeks of treatment.[47] These data
underscore the clinical significance of the pharmacokinetic profile
of megestrol acetate. The two patients who did not gain weight had
the lowest Cmax, trough plasma concentration (Cmin), and AUC in
the study. A statistically significant relationship was observed
between weight gain and the percentage of the 24-hour administration interval that plasma concentrations of megestrol acetate exceeded 300 ng/mL. No correlation could be made between weight
gain and AUC, and investigators suggested that early weight gain
can be anticipated when plasma megestrol acetate concentrations
exceed 300 ng/mL for at least 40% (10 hours) of a 24-hour
administration interval.[47]
In another study, megestrol acetate oral suspension 750mg was
administered once daily for 14 days in 24 asymptomatic HIVseropositive men. On pharmacokinetic evaluation, the mean Cmax
was found to be 490 ± 238 ng/mL and the mean AUC was
6779 ± 3048 ng•hr/mL. The mean Cmin was 202 ± 101 ng/mL,
with a median tmax of 3 hours. The mean percentage of fluctuation
was 107% ± 40%.[15]
The relative bioavailability of megestrol acetate 40mg tablets
or oral suspension and the effect of food on the bioavailability of
the oral megestrol acetate suspension have not been evaluated.[15]
5. Megestrol Acetate Nanocrystal Oral Suspension
Megestrol acetate nanocrystal oral suspension was designed to
optimize drug delivery and enhance the performance of drugs with
poor water solubility. This megestrol acetate formulation is currently under review by the US FDA for the treatment of cachexia
in patients with AIDS.[50] Compared with micronized drug particles, nanocrystalline particles produced with nanocrystal technology have significantly increased surface area per unit mass. The
manufacturing process uses a conventional high-energy medial
milling technique to process a mixture of megestrol acetate, water,
and stabilizers, creating a colloidal dispersion of megestrol acetate
Table I. Pharmacokinetic parameters of megestrol acetate in beagle dogs.[51] Four megestrol acetate formulations were given by gavage tube to male
beagle dogs (n = 3 per formulation) in fed or fasted state. All data are presented as mean (CV%)
Parameter
Cmax (ng/mL)
tmax (h)
Nanocrystal formulation #1
Nanocrystal formulation #2
Oral suspension (BMS)
Oral suspension (Par)
fed
fed
fed
fed
fasted
3777.3
1.67
2209.7
fasted
2875.8
1563.0
fasted
2577.8
339.9
fasted
2180.7
485.0
0.8
3.0
0.5
0.8
2.7
1.0
18.7
AUC0–t (ng•hr/mL)
48 543.6
37 774.2
36 687.9
21 857.7
31 397.2
10 094.3
27 332.1
17 394.9
AUC0–inf (ng•hr/mL)
61 734.9
49 408.9
42 787.7
27 863.6
40 218.7
12 007.11
31 721.0
6948.5
AUC = area under the plasma concentration-time curve; BMS = Bristol-Myers Squibb; Cmax = peak plasma concentration; CV = coefficient of variation;
Par = Par Pharmaceutical, Inc.; tmax = median time to Cmax.
 2005 Adis Data Information BV. All rights reserved.
Biodrugs 2005; 19 (3)
Enhancing Megestrol Acetate Delivery for Cachexia
185
Megestrol acetate nanocrystal oral suspension #1, 10 mg/kg
Megestrol acetate nanocrystal oral suspension #2, 10 mg/kg
Megestrol acetate oral suspension, 10 mg/kg (BMS)
Megestrol acetate oral suspension, 10 mg/kg (Par)
2200
2000
1800
Plasma levels (ng/mL)
1600
1400
1200
1000
800
600
400
200
0
0
10
20
30
40
50
60
70
80
Time (h)
Fig. 3. Mean plasma megestrol acetate levels in male beagle dogs given megestrol acetate nanocrystal oral suspension formulation #1 (n = 3), megestrol
acetate nanocrystal oral suspension formulation #2 (n = 3), megestrol acetate oral suspension by Bristol-Myers Squibb (BMS; n = 3), or megestrol acetate
oral suspension by Par Pharmaceutical, Inc. (PAR; n = 3) by oral gavage tube, 1 hour after a high-fat meal.
to obtain a mean particle size of <200nm. During milling, aggregation of the nanocrystalline particles is prevented by stabilizing the
mixture with hydroxypropyl methylcellulose and docusate sodium. Since the absorption of megestrol acetate is dissolution-rate
limited, the nanocrystalline particles increase the rate of absorption and decrease absorption variability when the drug is taken
with food.
5.1 Preclinical Pharmacokinetics
A study was conducted in 12 male beagle dogs to determine the
pharmacokinetic characteristics of megestrol acetate when administered as a 10 mg/kg suspension or colloidal dispersion by oral
gavage.[51] The assay was calibrated over the range of 1–512 ng/
mL. The following four formulations were evaluated at a dose of
10 mg/kg: (i) nanocrystal formulation #1; (ii) nanocrystal formulation #2; (iii) megestrol acetate oral suspension manufactured by
Bristol-Myers Squibb; and (iv) megestrol acetate nanocrystal oral
suspension manufactured by Par Pharmaceutical, Inc. Each product was available in a concentration of 40 mg/mL, so all study
treatments were administered in equal volumes by oral gavage to a
group of three dogs, first under fasted conditions and then under
fed conditions, after a 14-day washout. Before administration on
day 1, all dogs were fasted 12–16 hours. On day 14, the dogs were
fed a high-fat meal approximately 1 hour before administration,
and on days 1 and 14, blood samples were collected pre-administration and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 24, 48, and 72 hours after
administration to determine plasma megestrol acetate concentrations and calculate pharmacokinetic parameters.
 2005 Adis Data Information BV. All rights reserved.
In the fasted state, the nanocrystal formulations of megestrol
acetate produced 4- to 6-fold higher Cmax values >2 hours earlier
than the two currently available suspensions (table I). As reflected
in the AUC, exposure to the drug was 2- to 4-fold higher with the
nanocrystal formulations than with the suspensions, and variability was lower, particularly with nanocrystal formulation #2. Administration after a high-fat meal markedly increased bioavailability; peak concentrations were 5- to 7-fold higher and occurred
earlier, and AUC values were 2- to 3-fold higher (figure 3).
Although a high-fat meal increased the bioavailability of all formulations, the increase was of a lower magnitude for the nanocrystal formulations, with only 1- to 2-fold higher Cmax and AUC
values; however, the resultant concentrations were still higher than
those seen with the suspensions. A high-fat meal also raised
average tmax values by 1–2 hours.
6. Conclusions
Progestational agents have long been used in the treatment of
the anorexia-cachexia syndrome, a component of numerous diseases including AIDS, cancer, chronic heart failure, rheumatoid
arthritis, chronic obstructive pulmonary disease, Crohn disease,
and chronic renal disease. Megestrol acetate, the preferred progestational agent for the treatment of anorexia-cachexia, has been
shown to be effective in stabilizing weight loss or even producing
weight gain. However, the tablet and oral suspension formulations
of the drug are accompanied by pharmacokinetic characteristics
that may have limited optimal use.
Biodrugs 2005; 19 (3)
186
Femia & Goyette
The improved bioavailability of megestrol acetate nanocrystal
oral suspension has the potential to address unmet needs in the
treatment of anorexia-cachexia. By rapidly increasing plasma
megestrol acetate concentrations, this formulation may have the
potential to produce a more rapid clinical response and significantly improve outcomes in patients with this common and potentially
deadly disorder.
Acknowledgments
Robert A. Femia is the Executive Vice President, Scientific and Regulatory Affairs for Par Pharmaceutical, Inc.
Dr Goyette is not an employee, shareholder, or retained consultant of Par
Pharmaceutical, Inc. There is no conflict of interest.
References
1. Schacter L, Rozencweig M, Canetta R, et al. Megestrol acetate: clinical experience.
Cancer Treat Rev 1989; 16 (1): 49-63
2. Tisdale MJ. Biology of cachexia. J Natl Cancer Inst 1997; 89 (23): 1763-73
3. Strasser F, Bruera ED. Update on anorexia and cachexia. Hematol Oncol Clin
North Am 2002; 16 (3): 589-617
4. Akner G, Cederholm T. Treatment of protein-energy malnutrition in chronic
nonmalignant disorders. Am J Clin Nutr 2001; 74 (1): 6-24
5. Milani RV, Mehra MR, Endres S, et al. The clinical relevance of circulating tumor
necrosis factor-alpha in acute decompensated chronic heart failure without
cachexia. Chest 1996; 110 (4): 992-5
6. Ferrari R. The importance of cachexia in the syndrome of heart failure. Eur Heart J
1997; 18 (2): 187-9
7. Roubenoff R, Roubenoff RA, Cannon JG, et al. Rheumatoid cachexia: cytokinedriven hypermetabolism accompanying reduced body cell mass in chronic
inflammation. J Clin Invest 1994; 93 (6): 2379-86
8. Lewis MI. Apoptosis as a potential mechanism of muscle cachexia in chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 166 (4):
434-6
9. Rigaud D, Angel LA, Cerf M, et al. Mechanisms of decreased food intake during
weight loss in adult Crohn’s disease patients without obvious malabsorption.
Am J Clin Nutr 1994; 60 (5): 775-81
10. Mitch WE. Robert H Herman Memorial Award in Clinical Nutrition Lecture, 1997:
mechanisms causing loss of lean body mass in kidney disease. Am J Clin Nutr
1998; 67 (3): 359-66
11. Inui A. Cancer anorexia-cachexia syndrome: are neuropeptides the key? Cancer
Res 1999; 59 (18): 4493-501
12. Inui A. Cancer anorexia-cachexia syndrome: current issues in research and management. CA Cancer J Clin 2002; 52 (2): 72-91
13. Farinha A, Bica A, Tavares P. Improved bioavailability of a micronized megestrol
acetate tablet formulation in humans. Drug Dev Ind Pharm 2000; 26 (5): 567-70
14. Loose-Mitchell DS, Stancel GM. Estrogens and progestins. In: Hardman JG,
Limbird LE, Gilman AG, editors. Goodman and Gilman’s the pharmacological
basis of therapeutics. 10th ed. New York: McGraw-Hill, 2001: 1597-634
15. Par Pharmaceutical. Megestrol acetate oral suspension. Spring Valley (NY): Par
Pharmaceutical, Inc., 2004 [online]. Available from URL: http://
www.parpharm.com/downloads/megestroloral_po.pdf [Accessed 2005 Apr 5]
16. Pascual Lopez A, Figuls M, Urrutia Cuchi G, et al. Systematic review of megestrol
acetate in the treatment of anorexia-cachexia syndrome. J Pain Symptom
Manage 2004; 27 (4): 360-9
17. Tomiska M, Tomiskova M, Salajka F, et al. Palliative treatment of cancer anorexia
with oral suspension of megestrol acetate. Neoplasma 2003; 50 (3): 227-33
18. Gagnon B, Bruera E. A review of the drug treatment of cachexia associated with
cancer. Drugs 1998; 55 (5): 675-88
19. Mantovani G, Maccio A, Massa E, et al. Managing cancer-related anorexia/
cachexia. Drugs 2001; 61 (4): 499-514
 2005 Adis Data Information BV. All rights reserved.
20. Loprinzi CL, Michalak JC, Schaid DJ, et al. Phase III evaluation of four doses of
megestrol acetate as therapy for patients with cancer anorexia and/or cachexia. J
Clin Oncol 1993; 11 (4): 762-7
21. Beutler B, Cerami A. The biology of cachectin/TNF: a primary mediator of the host
response. Annu Rev Immunol 1989; 7: 625-55
22. Alvarez B, Quinn LS, Busquets S, et al. Direct effects of tumor necrosis factor
alpha (TNF-alpha) on murine skeletal muscle cell lines: bimodal effects on
protein metabolism. Eur Cytokine Netw 2001; 12 (3): 399-410
23. Langen RC, Schols AM, Kelders MC, et al. Inflammatory cytokines inhibit
myogenic differentiation through activation of nuclear factor-kappaB. FASEB J
2001; 15 (7): 1169-80
24. Jezek P. Possible physiological roles of mitochondrial uncoupling proteins: UCPn.
Int J Biochem Cell Biol 2002; 34 (10): 1190-206
25. Busquets S, Sanchis D, Alvarez B, et al. In the rat, tumor necrosis factor alpha
administration results in an increase in both UCP2 and UCP3 mRNAs in
skeletal muscle: a possible mechanism for cytokine-induced thermogenesis?
FEBS Lett 1998; 440 (3): 348-50
26. Berg M, Fraker DL, Alexander HR. Characterization of differentiation factor/
leukaemia inhibitory factor effect on lipoprotein lipase activity and mRNA in
3T3-L1 adipocytes. Cytokine 1994; 6 (4): 425-32
27. Zaki MH, Nemeth JA, Trikha M. CNTO 328, a monoclonal antibody to IL-6,
inhibits human tumor-induced cachexia in nude mice. Int J Cancer 2004; 111
(4): 592-5
28. Francis J, MohanKumar PS, MohanKumar SM, et al. Systemic administration of
lipopolysaccharide increases plasma leptin levels: blockade by soluble interleukin-1 receptor. Endocrine 1999; 10 (3): 291-5
29. Mantovani G, Maccio A, Bianchi A, et al. Megestrol acetate in neoplastic anorexia/
cachexia: clinical evaluation and comparison with cytokine levels in patients
with head and neck carcinoma treated with neoadjuvant chemotherapy. Int J
Clin Lab Res 1995; 25 (3): 135-41
30. Mantovani G, Maccio A, Esu S, et al. Medroxyprogesterone acetate reduces the
production of cytokines and serotonin involved in anorexia/cachexia and emesis by peripheral blood mononuclear cells of cancer patients. Biochem Soc
Trans 1997; 25 (2): 296S
31. Trikha M, Corringham R, Klein B, et al. Targeted anti-interleukin-6 monoclonal
antibody therapy for cancer: a review of the rationale and clinical evidence. Clin
Cancer Res 2003; 9 (13): 4653-65
32. Beck SA, Tisdale MJ. Effect of megestrol acetate on weight loss induced by
tumour necrosis factor alpha and a cachexia-inducing tumour (MAC16) in
NMRI mice. Br J Cancer 1990; 62 (3): 420-4
33. Ackermann M, Kirchner H, Atzpodien J. Low dose megestrol acetate can abrogate
cachexia in advanced tumor patients receiving systemic interferon-alpha and/or
interleukin-2 based antineoplastic therapy. Anticancer Drugs 1993; 4 (5): 585-7
34. Flier JS. Clinical review 94: what’s in a name? In search of leptin’s physiologic
role. J Clin Endocrinol Metab 1998; 83 (5): 1407-13
35. Schwartz MW, Dallman MF, Woods SC. Hypothalamic response to starvation:
implications for the study of wasting disorders. Am J Physiol 1995; 269 (5 pt 2):
R949-57
36. Schwartz MW, Seeley RJ. Seminars in medicine of the Beth Israel Deaconess
Medical Center: neuroendocrine responses to starvation and weight loss. N
Engl J Med 1997; 336 (25): 1802-11
37. Morley JE, Silver AJ. Anorexia in the elderly. Neurobiol Aging 1988; 9 (1): 9-16
38. Martinez M, Hernanz A, Gomez-Cerezo J, et al. Alterations in plasma and
cerebrospinal fluid levels of neuropeptides in idiopathic senile anorexia. Regul
Pept 1993; 49 (2): 109-17
39. Karcic E, Philpot C, Morley JE. Treating malnutrition with megestrol acetate:
literature review and review of our experience. J Nutr Health Aging 2002; 6 (3):
191-200
40. Morley JE. Orexigenic and anabolic agents. Clin Geriatr Med 2002; 18 (4): 853-66
41. Herkert O, Kuhl H, Sandow J, et al. Sex steroids used in hormonal treatment
increase vascular procoagulant activity by inducing thrombin receptor (PAR-1)
expression: role of the glucocorticoid receptor. Circulation 2001; 104 (23):
2826-31
42. Bladbjerg EM, Skouby SO, Andersen LF, et al. Effects of different progestin
regimens in hormone replacement therapy on blood coagulation factor VII and
tissue factor pathway inhibitor. Hum Reprod 2002; 17 (12): 3235-41
43. Kuhl H. Effects of progestogens on haemostasis. Maturitas 1996; 24 (1-2): 1-19
Biodrugs 2005; 19 (3)
Enhancing Megestrol Acetate Delivery for Cachexia
44. Loprinzi CL, Jensen MD, Jiang NS, et al. Effect of megestrol acetate on the human
pituitary-adrenal axis. Mayo Clin Proc 1992; 67 (12): 1160-2
45. Wermers RA, Hurley DL, Kearns AE. Osteoporosis associated with megestrol
acetate. Mayo Clin Proc 2004; 79 (12): 1557-61
46. Nelson KA. The cancer anorexia-cachexia syndrome. Semin Oncol 2000; 27 (1):
64-8
47. Graham KK, Mikolich DJ, Fisher AE, et al. Pharmacologic evaluation of megestrol
acetate oral suspension in cachectic AIDS patients. J Acquir Immune Defic
Syndr 1994; 7 (6): 580-6
48. Aisner J, Parnes H, Tait N, et al. Appetite stimulation and weight gain with
megestrol acetate. Semin Oncol 1990; 17 (6 Suppl. 9): 2-7
49. Aisner J, Tchekmedyian NS, Moody M, et al. High-dose megestrol acetate for the
treatment of advanced breast cancer: dose and toxicities. Semin Hematol 1987;
24 (2 Suppl. 1): 48-55
 2005 Adis Data Information BV. All rights reserved.
187
50. Par Pharmaceutical, Inc. FDA accepts for filing Par Pharmaceutical’s NDA for
megestrol acetate oral suspension NCD. Press release 2004 Sep 16 [online].
Available from URL: http://www.parpharm.com/html/nf/PR_ 20040916.html
[Accessed 2005 Apr 5]
51. Data on file, Par Pharmaceutical, Inc., 2004
Correspondence and offprints: Dr Robert A. Femia, Scientific and Regulatory
Affairs, Par Pharmaceutical, Inc., One Ram Ridge Road, Spring Valley, NY
10977, USA.
E-mail: [email protected]
Biodrugs 2005; 19 (3)