Druc DELIVERY rattan oes
The Science of Megestrol Acetate Delivery
Potential to Improve Outcomes in Cachexia
Robert A. Femia! and Richert E. Goyette
1. Scientific and Regulatory Affairs, Par Pharmaceutical, Inc, Spring Valley, New York, USA
2. Consultant, Hematology /Oncology, Knoxville, Tennessee, USA
Contents
Aberact v9
1. Progetierone Physiology 18
1 secretion 181
2. Moduation of Actly 181
13. Metabote Actity 181
2 Pharmacodynamics of Megesrol Acetate 181
2.1 General Characters 181
22 Anicyloline Properiss of Magestol Acelcie n Cochexca 182
23 Croxigonic Effects of Megestol Acetate hn Cachexia eo
3, Toleabity of Megestol Acetate 133
4 Phaimacoknetics of Megestol Acetate. 183,
41 General Characters ie
Tabels 184
Oral Suspension ea
5, Megestol Acetate Nanecrystal Oral Suspension ea
5.1, Mecined Phormacolinetics rs
6 Conctione 185
Abstract CCachexia, 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, Crobn disease, and renal failure, Anorexia is
considered a key component of the anorexia-cachexia syndrome. Progestogens, particularly megestrolacctat,
are commonly used to treat anorexia-cachexia. The mechanism of action of megestrol is believed to involve
simulation of appetite by both ditect and indirect pathways and antagonism of the metabolic effects of the
principal catabolic cytokines. Because the bioavailability of megesttol acetate ditectly affects its efficacy and
safety, the formulation was refined to enhance its pharmacokinetics.
Such efforts yielded megestrol acctate in tablet form, followed by a concentrated ol 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 tweatment 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 pa
le with anorexia-cachexia.180
Femia & Goyette
Progestational agents are used to treat the anorexia-cachexia
syndrome and sometimes as salvage agents to treat hormone-
sensitive 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® #, Par Pharmaceutical, Inc,
Spring Valley, NY, USA), a synthetic progestogen currently avail-
able 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 heen used as a component of oral contracep-
tive pills and in the weatment of malignant and nonmalignant
conditions such as melanoma; cancers ofthe ovary, breast, kidney,
‘and prostate; benign prostatic hypertrophy: and endometsial hy-
perplasia."!
Cachexia isa condition of starvation characterized by depletion
of muscle mass and, to a lesser extent, adipose tissue, Btymologi-
cally, cachexia is derived from ‘kakos’ and ‘hexis'—Greek words
‘meaning “bad condition’! Although there are various definitions
of cachexia in the medical literature, it commonly refers to an
involuntary loss of approximately 25% 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, itean substantially shorten survival time." Tis often
associated with other debilitating symptoms such as chronic nau-
sea, asthenia and weakness, autonomic failure, cognitive impair-
ment, psychologic distress, and poorfunsatisfactory quality of
life"! 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
ks ———>
any tecue
Fig. 1. The mechanism of action of megestol acetate in ancrex'a/cachena. Ul
+ nats 7 “oc00H,
H
ou,
“The use of trade names is for product identification purposes only and di
db Gove Hornaten BY. Alo eee
joes not imply endorsement,Enhancing Megestrol Acetate Delivery for Cacheia
181
fractures due to falls, and compromise patients ability to retain
body heat.
‘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,
ehonic heart failure, rheumatoid arthritis, chronie obstructive
pulmonary disease, Croln disease, chronic renal disease, and other
chronic disorders >=!
Anorexia is a key component of cachexia, and accumulating
data suggest that the anorexia-cachexia syndrome is a cytokine
derived process manifested by loss of appetite and cytokine-300 ng/ml. for 240% of a 24-hour
administration interval. Alterations in the formulation of meges-
twol avetate have produced thee formulations of drug, a progres-Femia & Goyette
sion associated with increased bioavailability and thus improved
efficacy in the weatment of anorexia-cachexia.
4.2 Megestiol Acetate Tablets
Megestrol acetate was formulated as a tablet requiring adminis-
tration four times daily."5! In humans, the rate of excretion of
radiolabeled megestrol acetate 490mg 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
hhave been excreted by respiration as labeled carbon dioxide or
held in fat storage."
Absorption of megestrol acetate 160 mg/day (40mg tablets
given four times daily) varied among 23 healthy male volun-
teers."5| 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 Cina (Imex) Fanged from I to 3 hours (mean 2,2 hours)
Plasma elimination half-life ranged from 13 to 104.9 hours (mean
342 hours). Steady-state plasma drug concentrations with a
rmegestrol acetate 40mg four times daily regimen have not been,
established !%)
43 Megestol Acetate Oral Suspension
To obviate the need for administration of multiple tablets, a
megestrol acetate preparation was formulated as a concentrated
coral suspension.) 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." Patients received oral meges-
trol acetate 800mg once daily for 21 days, and plasma concentra-
tions were measured up to 48 hours after the last dose on day 21
Data analysis showed that mean +1 SD Cinax was 828 + 513 ng/
mL, and mean AUCo-2sh was 1] 250+ 7305 ngehr/mL, results
similar to those reported in the megestrol acetate oral suspension,
(40 mg/mL) package insert (Cox 753 +539 ng/ml. and AUC
Table
beagle dogs (n = 3 por formulation) in fed or fasted stato. Al data a
10.476 +7788 ngehu/mL).!"9 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. 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 (Chin), and AUC in
the study. A statistically significant relationship was observed
between weight gain and the percentage of the 24-hour administea-
tion interval that plasma concentrations of megestrol acctate ex-
ceeded 300 ng/ml. No correlation could be made between weight
gain and AUC, and investigators suggested that carly weight gain
can be anticipated when plasma megestrol acetate concentrations
exceed 300 ngimL for at least 40% (10 hours) of @ 24-hour
administration interval)
In another study, megestrol acetate oral suspension 750mg was
administered once daily for 14 days in 24 asymptomatic HIV-
seropositive men. On pharmacokinetic evaluation, the mean Cmax
was found to be 4904238 ng/ml. and the mean AUC was
6779 + 3048 ngshr/mL. The mean Cmin Was 202+ 101 ng/ml,
With a median tax of 3 hours. The mean percentage of fluctuation
was 107% + 40%.51
‘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 1
5, Megestrol Acetate Nanocrystal Oral Suspension
“Mgestrol 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 cur-
rently under review by the US FDA for the treatment of cachexia
in patients with AIDS"! Compared with micronized drug parti-
eles, nanocrystalline particles produced with nanocrystal technolo-
ay have significantly increased surface area per unit mass. The
manufacturing process uses a conventional high-energy medial
zilling technique to process a mixture of megestrol acetate, water,
and stabilizers, creating a colloidal dispersion of megestrol acetate
Pharmacokinetic parameters of megestol acetate In beagle dogs." Four megesiol acetate formulations were given by gavage tube fo male
sented as mean (CV)
Parameter ‘Nanosrystal formulation #1 _ Nanosrytal formulation #2 Oral suspension (GMS) Oral suspension (Par
‘ea fasted ied tasted ‘ea fasted tea tasted
nae (agit) S773 —«22087-~=~*«TSBSCS*«*SWO.*~*«STTB 33982807 4850
ime th) 187 os 30 os. os Ea 10 187
AUCo-s (ngs) 495636 877742 M66879 «218577 «1897.2 TONKS 78H. «IT BBA.
AUCo- (nash) G17349 494089 2 7e77 278636 402187 __—*12007.11_s17210 64.5
[AUG = area under the plasma concentration time curve; BMS = Bristol Myers Squibb, Cmax = peak plasma concentalion; GV = cosfcient of vara
Par = Par Pharmaceulal, Inc. tax
edian tie to Cr
(2005 hl ota Heaton B.A gs reve2 enacetoon supra onave o)
Z soo
200 ———
tot
acetate nanocrystal oral suspension formulation #2 (a
coral suspension by Par Pharmaceutical, nc. (PAR; n
to obtain a mean particle size of <200nm. During milling, aggrega-
tion of the nanocrystalline particles is prevented by stabilizing the
mixture with hydroxypropyl methylcellulose and docusate sodi-
‘um, Since the absorption of megestrol acetate is dissolution-rate
limited, the nanocrystalline particles increase the rate of absorp-
tion 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 admin-
istered as a 10 mg/kg suspension or colloidal dispersion by oral
gavage. 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; (i) nanocrystal formula-
tion #2; (ii) megestrol acetate oral suspension manufactured by
Bristol-Myers Squibb; and (iv) megestrol acctate nanocrystal oral
suspension manufactured by Par Pharmaceutical, Inc. Each prod-
uct was available in a concentration of 40 mg/mL, so all study
‘weatments were administered in equal volumes by oral gavage to a
‘group of three dogs, first under fasted conditions and then under
{ed conditions, ater a 14-day washout, Before administration on
day 1, all dogs were fasted 12-16 hours. On day 14, the dogs were
{ed a high-fat meal approximately 1 hour before administration,
and on days 1 and 14, blood samples were collected pre-adminis-
tration and at 0.25, 05, 1, 2,3, 4,6, 8, 24, 48, and 72 hours after
‘administration to determine plasma megestrol acetate concentra
tions and calculate pharmacokinetic parameters,
db Gove Hornaten BY. Alo eee
3), mgestol acetate oral suspension by Brsto-Myers Squibb (BMS;
3} by oral gavage tube, 1 hour alter a high-at meal
3), or megesiral acetate
In the fasted state, the nanocrystal formulations of megestrol
acetate produced 4- to 6-fold higher Ciusx values >2 hours earlier
‘than the two currently available suspensions (table 1. As reflected
in the AUC, exposute to the drug was 2- to 4-fold higher with the
nanocrystal formulations than with the suspensions, and variabili-
ty was lower, particularly with nanocrystal formulation #2. Ad-
‘ministration after a high-fat meal matkedly increased bicavai-
lability; peak concenttations were S-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 for-
‘ulations, the increase was of a lower magnitude for the nanocrys-
tal formulations, with only 1- to 2-fold higher Cinax 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
mndrome, a component of numerous dis-
eases including AIDS, cancer, chronic heart failure, rheumatoid
the anorexia-cachexi
arthritis, chronic obstructive pulmonary disease, Crohn disease,
and chronie renal disease, Megestrol acetate, the preferred proges-
lational 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.186
emia Goyette
‘The improved bioavailability of megestrol acetate nanocrystal
‘oral suspension has the potential to address unmet needs in the
leatment of anorexia-cachexia. By rapidly increasing plasma
megestrol acetate concentrations, this formulation may have the
potential to produce a mote rapid clinical response and significant-
ly improve outcomes in patients with this common and potentially
deadly disorder.
Acknowledgments
Robert A. Femia it the Executive Viee President, Seieniic and Regulato-
ty Afi for Par Pharaceutial, ne
Dr Goyette is not an employee, shareholder, or retained consultant of Par
Parmacestical, le. There i no coast of interes.
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‘Corespondence and offprints: Dr Robert A. Femi, Scientific and Regulatory
Alois, Par Pharmaceutical Ine, One Ram Ridge Rosé, Spring Valley, NY
10977, USA,
E-mail: remia@parpharm.com