CLINICAL PHARMACOLOGY
Several investigators have reported on the appetite enhancing property of megestrol acetate and its possible use in cachexia. The precise mechanism by which megestrol acetate produces effects in anorexia and cachexia is unknown at the present time.
There are several analytical methods used to estimate megestrol acetate plasma
concentrations, including gas chromatography-mass fragmentography (GC-MF), high
pressure liquid chromatography (HPLC) and radioimmunoassay (RIA). The GC-MF
and HPLC methods are specific for megestrol acetate and yield equivalent concentrations.
The RIA method reacts to megestrol acetate metabolites and is, therefore, non-specific
and indicates higher concentrations than the GC-MF and HPLC methods. Plasma
concentrations are dependent, not only on the method used, but also on intestinal
and hepatic inactivation of the drug, which may be affected by factors such
as intestinal tract motility, intestinal bacteria, antibiotics administered,
body weight, diet and liver function.
The major route of drug elimination in humans is urine. When radiolabeled megestrol acetate was administered to humans in doses of 4 to 90 mg, the urinary excretion within 10 days ranged from 56.5 to 78.4% (mean 66.4%) and fecal excretion ranged from 7.7 to 30.3% (mean 19.8%).The total recovered radioactivity varied between 83.1 and 94.7% (mean 86.2%). Megestrol acetate metabolites which were identified in urine constituted 5 to 8% of the dose administered. Respiratory excretion as labeled carbon dioxide and fat storage may have accounted for at least part of the radioactivity not found in urine and feces.
Plasma steady state pharmacokinetics of megestrol acetate were evaluated in 10 adult, cachectic male patients with acquired immunodeficiency syndrome (AIDS) and an involuntary weight loss greater than 10% of baseline. Patients received single oral doses of 800 mg/day of megestrol acetate oral suspension for 21 days. Plasma concentration data obtained on day 21 were evaluated for up to 48 hours past the last dose.
Mean (±1SD) peak plasma concentration (Cmax) of megestrol acetate was 753 (±539) ng/mL. Mean area under the concentration time-curve (AUC) was 10476 (±7788) ng x hr/mL. Median Tmax value was five hours. Seven of 10 patients gained weight in three weeks.
Additionally, 24 adult, asymptomatic HIV seropositive male subjects were dosed once daily with 750 mg of megestrol acetate oral suspension. The treatment was administered for 14 days. Mean Cmax and AUC values were 490 (±238) ng/mL and 6779 (±3048) hr x ng/mL, respectively.The median Tmax value was three hours. The mean Cmin value was 202 (±101) ng/mL. The mean % of fluctuation value was 107 (±40).
The relative bioavailability of megestrol acetate 40 mg tablets and megestrol acetate oral suspension has not been evaluated. The effect of food on the bioavailability of megestrol acetate oral suspension has not been evaluated.
Description Of Clinical Studies
The clinical efficacy of megestrol acetate oral suspension was assessed in
two clinical trials. One was a multicenter, randomized, double-blind, placebo-controlled
study comparing megestrol acetate (MA) at doses of 100 mg, 400 mg, and 800 mg
per day versus placebo in AIDS patients with anorexia/cachexia and significant
weight loss. Of the 270 patients entered on study, 195 met all inclusion/exclusion
criteria, had at least two additional post baseline weight measurements over
a 12 week period or had one post baseline weight measurement but dropped out
for therapeutic failure. The percent of patients gaining five or more pounds
at maximum weight gain in 12 study weeks was statistically significantly greater
for the 800 mg (64%) and 400 mg (57%) MA-treated groups than for the placebo
group (24%).Mean weight increased from baseline to last evaluation in 12 study
weeks in the 800 mg MA-treated group by 7.8 pounds, the 400 mg MA group by 4.2
pounds, the 100 mg MA group by 1.9 pounds and decreased in the placebo group
by 1.6 pounds. Mean weight changes at 4, 8 and 12 weeks for patients evaluable
for efficacy in the two clinical trials are shown graphically. Changes in body
composition during the 12 study weeks as measured by bioelectrical impedance
analysis showed increases in non-water body weight in the MA-treated groups
(see Clinical Studies table). In addition, edema developed or worsened
in only 3 patients.
Greater percentages of MA-treated patients in the 800 mg group (89%), the 400
mg group (68%) and the 100 mg group (72%), than in the placebo group (50%),
showed an improvement in appetite at last evaluation during the 12 study weeks.A
statistically significant difference was observed between the 800 mg MA-treated
group and the placebo group in the change in caloric intake from baseline to
time of maximum weight change. Patients were asked to assess weight change,
appetite, appearance, and overall perception of well-being in a 9 question survey.
At maximum weight change only the 800 mg MA-treated group gave responses that
were statistically significantly more favorable to all questions when compared
to the placebo-treated group. A dose response was noted in the survey with positive
responses correlating with higher dose for all questions.
The second trial was a multicenter, randomized, double-blind, placebo-controlled
study comparing megestrol acetate 800 mg/day versus placebo in AIDS patients
with anorexia/cachexia and significant weight loss. Of the 100 patients entered
on study, 65 met all inclusion/exclusion criteria, had at least two additional
post baseline weight measurements over a 12 week period or had one post baseline
weight measurement but dropped out for therapeutic failure. Patients in the
800 mg MA-treated group had a statistically significantly larger increase in
mean maximum weight change than patients in the placebo group. From baseline
to study week 12, mean weight increased by 11.2 pounds in the MA-treated group
and decreased 2.1 pounds in the placebo group. Changes in body composition as
measured by bioelectrical impedance analysis showed increases in non-water weight
in the MA-treated group (see Clinical Studies table). No edema was reported
in the MA-treated group. A greater percentage of MA-treated patients (67%) than
placebo-treated patients (38%) showed an improvement in appetite at last evaluation
during the 12 study weeks;this difference was statistically significant. There
were no statistically significant differences between treatment groups in mean
caloric change or in daily caloric intake at time to maximum weight change.
In the same 9 question survey referenced in the first trial, patients' assessments
of weight change, appetite, appearance, and overall perception of well-being
showed increases in mean scores in MA-treated patients as compared to the placebo
group.
In both trials, patients tolerated the drug well and no statistically significant
differences were seen between the treatment groups with regard to laboratory
abnormalities, new opportunistic infections, lymphocyte counts, T4
counts, T8 counts, or skin reactivity tests (see ADVERSE
REACTIONS section).
Megestrol Acetate Oral Suspension Clinical Efficacy Trials
|
Trial 1
Study Accrual Dates
11/88 to 12/90 |
Trial 2
Study Accrual Dates
5/89 to 4/91 |
Megestrol Acetate, mg/day |
0 |
100 |
400 |
800 |
0 |
800 |
Entered Patients |
38 |
82 |
75 |
75 |
48 |
52 |
Evaluable Patients |
28 |
61 |
53 |
53 |
29 |
36 |
Mean Change in Weight (lb.) |
Baseline to 12 Weeks |
0.0 |
2.9 |
9.3 |
10.7 |
-2.1 |
11.2 |
% Patients ≥ 5 Pound Gainat Last Evaluation in 12 Weeks |
21 |
44 |
57 |
64 |
28 |
47 |
Mean Changes in Body Composition*: |
Fat Body Mass (lb.) |
0.0 |
2.2 |
2.9 |
5.5 |
1.5 |
5.7 |
Lean Body Mass (lb.) |
-1.7 |
-0.3 |
1.5 |
2.5 |
-1.6 |
-0.6 |
Water (liters) |
-1.3 |
-0.3 |
0.0 |
0.0 |
-0.1 |
-0.1 |
% Patients With Improved Appetite: |
At Time of MaximumWeight Change |
50 |
72 |
72 |
93 |
48 |
69 |
At Last Evaluation in 12 Weeks |
50 |
72 |
68 |
89 |
38 |
67 |
Mean Change in Daily Caloric Intake: |
Baseline to Time of MaximumWeight Change |
-107 |
326 |
308 |
646 |
30 |
464 |
*Based on bioelectrical impedanceanalysisdeterminationsat
lastevaluationin 12weeks. |
The following figures are the results of mean weight changes for patients evaluable for efficacy in trials 1 and 2.
Animal Toxicology: Long-term treatment with megestrol acetate may increase
the risk of respiratory infections. A trend toward increased frequency of respiratory
infections, decreased lymphocyte counts and increased neutrophil counts was
observed in a two-year chronic toxicity/carcinogenicity study of megestrol acetate
conducted in rats.