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1173-8804/05/0003-0179/$34.95/0
DRUG DELIVERY
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 individuals baseline bodyweight over 26 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
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
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.
The use of trade names is for product identification purposes only and does not imply endorsement.
181
CH3
1.1 Secretion
C=O
CH3
CH3
OCOCH3
H
O=
CH3
Megestrol acetate is a synthetic derivative of naturally occurring progesterone, chemically designated 17-(acetoxy)-6-methylpregna-4,6-diene-3,20-dione (figure 2).[15] A white,
Biodrugs 2005; 19 (3)
182
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)
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 -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
184
Megestrol acetate was formulated as a tablet requiring administration four times daily.[15] In humans, the rate of excretion of
radiolabeled megestrol acetate 490mg given in tablet form was
56.578.4% (mean 66.4%) in urine and 7.730.3% (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
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
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
AUC0t (nghr/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
AUC0inf (nghr/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.
185
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
186
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