nutritional status affects health , disease state outcomes , and quality of life.1,2 inadequate food intake that does not meet metabolic and caloric demands can lead to unintended weight loss ( uwl ) , a distinguishing clinical feature of cachexia.3 cachexia or wasting disease is associated with underlying illness such as aids , cancer , heart failure , kidney failure , copd , or rheumatoid arthritis,4 and is distinct from conditions such as starvation , malabsorption , age - related loss of muscle mass , or hyperparathyroidism.3 as many as 5 million people in the united states , or 20% to 40% of those affected with chronic conditions , may require treatment for cachexia.4 among patients with aids , cachexia is a prevalent comorbidity , affecting up to 35% of aids patients in the united states.4 diagnostic criteria for cachexia include uwl  5% in 12 months or less in the presence of underlying illness or body mass index ( bmi ) < 20 kg / m ; additional criteria are described by evans et al 2008.3 megestrol acetate oral suspension ( maos ) is an orexigenic agent indicated for the treatment of anorexia , cachexia , or an unexplained , significant weight loss in patients with aids . the original formulation of maos ( megace ; bristol - myers squibb , princeton , new jersey , usa ) is relatively more viscous than other liquid medications and the recommended dose of 800 mg/20 ml or 4 teaspoons,5 once daily may be limiting factors for patients with decreased appetite or difficulty swallowing . to improve the palatability of maos , nanocrystal technology ( elan pharma international limited , king of prussia , pennsylvania , usa ) was applied to produce a nanocrystal dispersion6 of megestrol acetate ( ma - es ; megace es ; par pharmaceutical , inc . , spring valley , new york , usa ) , which is a more concentrated suspension with improved dissolution and decreased viscosity . an initial pharmacokinetic ( pk ) study demonstrated that ma - es 625 mg/5 ml was bioequivalent to maos 800 mg/20 ml under fed conditions;5 however , when pk parameters were analyzed under fasting conditions , ma - es unexpectedly showed greater bioavailability than maos . bioavailability , or the amount of drug available to provide a therapeutic response , is dependent on absorption.7 since drug absorption and bioavailability under fasting conditions are particularly relevant to patients with cachexia , studies to characterize the pk profiles of ma - es and maos were undertaken . this paper describes results from three studies evaluating the food effect on bioavailability of ma - es 625 mg/5 ml and maos 800 mg/20 ml in healthy individuals under fed and fasting conditions . a prospective , randomized , open - label , two - way crossover study to evaluate the bioavailability of ma - es under fed and fasting conditions was conducted in healthy male volunteers , 18 to 55 years of age , with no clinically significant medical histories ( figure 1 ) . subjects were randomized to receive a single dose of ma - es 625 mg/5 ml after an overnight fast of at least 10 hours , or immediately after eating a standard , high - calorie , high - fat meal of 800 to 1000 calories consisting of 2 eggs fried in butter , 2 slices of toast with butter , 2 strips of bacon , 4 oz of hash brown potatoes , and 8 oz of whole milk.8 the study drug was administered orally with the standard 8 oz of water . following a 14-day washout period , subjects received a second single dose of ma - es under the crossover ( fed or fasting ) condition . during each treatment period , subjects remained at the study site for at least 10 hours pre - dose through 24 hours post - dose , after which they were discharged but returned at specified times for blood sample collection up to 120 hours post - dose . plasma concentrations of megestrol acetate were quantified by a validated liquid chromatography , tandem mass spectrometric method . the lower limit of quantification was 2 ng / ml . bioequiv ( release 3.50 ) proprietary software ( sfbc anapharm , sainte - foy , quebec , canada ) was used to calculate the following pk parameters : area under the plasma concentration - time curve ( auc ) from time 0 to the time of the last non - zero concentration of the study drug ( auc0t ) ; auc from time 0 to infinity ( auc0 ) ; maximum observed plasma concentration ( cmax ) ; time to cmax ( tmax ) ; and elimination half - life ( t1/2 ) . descriptive statistics were tabulated by treatment for all pk parameters , as applicable . for auc0t , auc0 , and cmax , analysis of variance ( sas general linear models procedure ) was used to compare logarithmic - transformed ( base ) values from the fed and fasting treatments . this model includes sequence , subject within sequence , study period , and treatment as factors . the 90% confidence intervals ( ci ) were estimated for the ratio ( fed / fasting ) of least - squares means ( lsm ) . vital signs , electrocardiograms ( ecg ) , and clinical laboratory parameters ( hematology , blood chemistry , and urinalysis ) were monitored , and adverse events were recorded throughout the study . an open - label study to assess the bioavailability of maos under fed conditions ( study 2 ) was performed in healthy males at least 18 years of age , with no clinically significant medical histories . subjects received a single , 800 mg/20 ml dose of maos within 30 minutes of consuming a standard high - calorie , high - fat meal as described previously.8 blood samples were collected pre - dose , then sequentially for up to 96 hours post - dose . plasma concentrations of megestrol acetate were measured by liquid chromatography with tandem mass spectrometry detection , and pk parameters ( cmax , tmax , auc0t , auc0 , and t1/2 ) were determined . any adverse events reported throughout the study period were recorded . an open - label study to assess the bioavailability of maos under fasting conditions ( study 3 ) was similarly performed in healthy males , at least 18 years of age , with no clinically significant medical histories . subjects received a single , 800 mg/20 ml dose of maos after an overnight fast of at least 10 hours . the protocol for blood sampling and plasma concentration measurement was identical to the fed study , and the same pk parameters were evaluated . all three studies received institutional review board approval , and were conducted in accordance with good clinical practice guidelines as required by the declaration of helsinki . a prospective , randomized , open - label , two - way crossover study to evaluate the bioavailability of ma - es under fed and fasting conditions was conducted in healthy male volunteers , 18 to 55 years of age , with no clinically significant medical histories ( figure 1 ) . subjects were randomized to receive a single dose of ma - es 625 mg/5 ml after an overnight fast of at least 10 hours , or immediately after eating a standard , high - calorie , high - fat meal of 800 to 1000 calories consisting of 2 eggs fried in butter , 2 slices of toast with butter , 2 strips of bacon , 4 oz of hash brown potatoes , and 8 oz of whole milk.8 the study drug was administered orally with the standard 8 oz of water . following a 14-day washout period , subjects received a second single dose of ma - es under the crossover ( fed or fasting ) condition . during each treatment period , subjects remained at the study site for at least 10 hours pre - dose through 24 hours post - dose , after which they were discharged but returned at specified times for blood sample collection up to 120 hours post - dose . plasma concentrations of megestrol acetate were quantified by a validated liquid chromatography , tandem mass spectrometric method . the lower limit of quantification was 2 ng / ml . bioequiv ( release 3.50 ) proprietary software ( sfbc anapharm , sainte - foy , quebec , canada ) was used to calculate the following pk parameters : area under the plasma concentration - time curve ( auc ) from time 0 to the time of the last non - zero concentration of the study drug ( auc0t ) ; auc from time 0 to infinity ( auc0 ) ; maximum observed plasma concentration ( cmax ) ; time to cmax ( tmax ) ; and elimination half - life ( t1/2 ) . descriptive statistics were tabulated by treatment for all pk parameters , as applicable . for auc0t , auc0 , and cmax , analysis of variance ( sas general linear models procedure ) was used to compare logarithmic - transformed ( base ) values from the fed and fasting treatments . this model includes sequence , subject within sequence , study period , and treatment as factors . the 90% confidence intervals ( ci ) were estimated for the ratio ( fed / fasting ) of least - squares means ( lsm ) . vital signs , electrocardiograms ( ecg ) , and clinical laboratory parameters ( hematology , blood chemistry , and urinalysis ) were monitored , and adverse events were recorded throughout the study . an open - label study to assess the bioavailability of maos under fed conditions ( study 2 ) was performed in healthy males at least 18 years of age , with no clinically significant medical histories . subjects received a single , 800 mg/20 ml dose of maos within 30 minutes of consuming a standard high - calorie , high - fat meal as described previously.8 blood samples were collected pre - dose , then sequentially for up to 96 hours post - dose . plasma concentrations of megestrol acetate were measured by liquid chromatography with tandem mass spectrometry detection , and pk parameters ( cmax , tmax , auc0t , auc0 , and t1/2 ) were determined . any adverse events reported throughout the study period were recorded . an open - label study to assess the bioavailability of maos under fasting conditions ( study 3 ) was similarly performed in healthy males , at least 18 years of age , with no clinically significant medical histories . subjects received a single , 800 mg/20 ml dose of maos after an overnight fast of at least 10 hours . the protocol for blood sampling and plasma concentration measurement was identical to the fed study , and the same pk parameters were evaluated . all three studies received institutional review board approval , and were conducted in accordance with good clinical practice guidelines as required by the declaration of helsinki . a total of 24 subjects were randomized to the study ; the analysis population included 23 subjects . one subject who did not follow protocol and received treatment under the wrong condition was discontinued from the study . megestrol acetate plasma concentrations were zero in all subjects prior to dosing in both study periods . the pk parameters for ma - es 625 mg/5 ml administered under fed and fasting conditions are shown in table 1 . auc0 decreased from 16,268 ngh / ml in the fed state to 12,095 ngh / ml in the fasting state . the mean cmax decreased from 1,618 ng / ml in the fed to 1,133 ng / ml in the fasting state . absorption of ma - es based on auc and cmax showed a decrease of 26% and 30% , respectively , in the fasting compared with the fed state . the fed to fasting ratios ( 90% ci ) of least - squares means for auc0t , auc0 , and cmax , were 1.36 ( 1.26 to 1.47 ) , 1.36 ( 1.26 to 1.47 ) , and 1.48 ( 1.28 to 1.71 ) , respectively , indicating that consumption of a high - fat meal increased the rate and extent of absorption of ma - es . figure 2 shows the profile for mean plasma concentration over time for ma - es administered under fed or fasting conditions . each adverse event was reported once , except for increased blood pressure , which was reported in 2 subjects . all adverse events were mild to moderate in intensity , except for an incident of severe vomiting reported by 1 patient during the fed condition of the crossover treatment . the frequency and severity of adverse events were similar under fed and fasting conditions , and the majority of adverse events had resolved spontaneously by the end of the study . changes in ecgs , clinical laboratory values , and vital signs were unremarkable and not considered related to therapy . in study 2 , 40 healthy volunteers were enrolled to evaluate maos bioavailability under fed conditions . one subject withdrew due to clinically significant hematology results , and another subject withdrew due to diarrhea . study 3 also enrolled 40 healthy male subjects , who were evaluated for maos bioavailability under fasting conditions . four subjects were not included in the statistical analysis due to protocol deviations resulting in 36 subjects with evaluable data . the pk parameters for an 800 mg/20 ml dose of maos given under fed or fasting conditions are summarized in table 1 . in the fed state , ngh / l and the mean cmax was 1,364 ng / ml . in the fasting state , auc0 only reached 8,942 ngh / l with a cmax of 187 ng / ml . relative to the fed state , auc0 and cmax were decreased by 52% and 86% , respectively , in the fasting state . the mean plasma concentration - time profiles for maos after administration of a high - fat meal and during a fasting state are shown in figure 3 . for the 32 subjects included in the safety population of the study conducted under fed conditions , adverse events were generally mild or moderate in severity . there was 1 unrelated severe adverse event of vomiting , 13 days post - dose . no serious adverse events were reported , and all adverse events were considered unlikely to be related to the study medication . for the 36 subjects included in the safety population of the study conducted under fasting conditions , adverse events were mild or moderate in severity . as shown in figure 4 , single doses of ma - es 625 mg/5 ml and maos 800 mg/20 ml have comparable bioavailability under fed conditions , but under fasting conditions the bioavailability of ma - es is greater than that of maos . a total of 24 subjects were randomized to the study ; the analysis population included 23 subjects . one subject who did not follow protocol and received treatment under the wrong condition was discontinued from the study . megestrol acetate plasma concentrations were zero in all subjects prior to dosing in both study periods . the pk parameters for ma - es 625 mg/5 ml administered under fed and fasting conditions are shown in table 1 . auc0 decreased from 16,268 ngh / ml in the fed state to 12,095 ngh / ml in the fasting state . the mean cmax decreased from 1,618 ng / ml in the fed to 1,133 ng / ml in the fasting state . absorption of ma - es based on auc and cmax showed a decrease of 26% and 30% , respectively , in the fasting compared with the fed state . the fed to fasting ratios ( 90% ci ) of least - squares means for auc0t , auc0 , and cmax , were 1.36 ( 1.26 to 1.47 ) , 1.36 ( 1.26 to 1.47 ) , and 1.48 ( 1.28 to 1.71 ) , respectively , indicating that consumption of a high - fat meal increased the rate and extent of absorption of ma - es . figure 2 shows the profile for mean plasma concentration over time for ma - es administered under fed or fasting conditions . each adverse event was reported once , except for increased blood pressure , which was reported in 2 subjects . all adverse events were mild to moderate in intensity , except for an incident of severe vomiting reported by 1 patient during the fed condition of the crossover treatment . the frequency and severity of adverse events were similar under fed and fasting conditions , and the majority of adverse events had resolved spontaneously by the end of the study . changes in ecgs , clinical laboratory values , and vital signs were unremarkable and not considered related to therapy . in study 2 , 40 healthy volunteers were enrolled to evaluate maos bioavailability under fed conditions . one subject withdrew due to clinically significant hematology results , and another subject withdrew due to diarrhea . study 3 also enrolled 40 healthy male subjects , who were evaluated for maos bioavailability under fasting conditions . four subjects were not included in the statistical analysis due to protocol deviations resulting in 36 subjects with evaluable data . the pk parameters for an 800 mg/20 ml dose of maos given under fed or fasting conditions are summarized in table 1 . in the fed state , ngh / l and the mean cmax was 1,364 ng / ml . in the fasting state , auc0 only reached 8,942 ngh / l with a cmax of 187 ng / ml . relative to the fed state , auc0 and cmax were decreased by 52% and 86% , respectively , in the fasting state . the mean plasma concentration - time profiles for maos after administration of a high - fat meal and during a fasting state are shown in figure 3 . for the 32 subjects included in the safety population of the study conducted under fed conditions , adverse events were generally mild or moderate in severity . there was 1 unrelated severe adverse event of vomiting , 13 days post - dose . no serious adverse events were reported , and all adverse events were considered unlikely to be related to the study medication . for the 36 subjects included in the safety population of the study conducted under fasting conditions , adverse events were mild or moderate in severity . as shown in figure 4 , single doses of ma - es 625 mg/5 ml and maos 800 mg/20 ml have comparable bioavailability under fed conditions , but under fasting conditions the bioavailability of ma - es is greater than that of maos . bioequivalence of ma - es 625 mg/5 ml to maos 800 mg/20 ml is seen under fed conditions ; however , the bioavailability of a poorly water soluble10 lipophilic drug , such as megestrol acetate,11 is greatly impacted under fasting conditions . drugs with poor water - solubility are frequently associated with highly variable absorption based upon food intake.10 the enhanced bioavailability of maos when taken with a high - fat meal is predictable , as the lipophilic drug dissolves readily in the fat content of food . in the fasting state , maos demonstrates poor bioavailability , probably due to its poor water solubility , which contributes to reduced dissolution . the change in the absorption profile of maos between fed and fasting states had not been characterized when the drug was initially approved for marketing in 1993 . solubility , and thus absorption and bioavailability , of lipophilic drug molecules can be improved with a reduction in particle size to submicron levels.12 to improve the solubility of megestrol acetate , nanocrystal technology was applied to the original formulation to reduce the drug particle size to 80 to 400 nm in diameter ( up to 50 times smaller than the micronized particles in maos ) , thus increasing the total surface area of drug particles and improving dissolution of ma - es . when the pk data for ma - es was compared to that of maos , the difference between drug absorption of the two formulations under fasting conditions became apparent . results from the current studies demonstrate that cmax and total absorption ( auc0 ) of maos are markedly reduced ( by 86% and 52% , respectively ) in fasting versus fed subjects . since cachectic patients can have minimal appetite , and are often in the fasted state , the poor bioavailability of maos in this state may be a significant impediment . graham et al report in their 21-day study of aids patients with cachexia that there is a significant correlation between sustained plasma concentrations of maos above a threshold of 300 ng / ml and weight gain.13 patients in the study were administered maos 800 mg/20 ml , once daily , prior to breakfast . we report a cmax value of 187 ng / ml for maos in the fasting state , which is below the 300 ng / ml threshold suggested for weight gain to occur . cmax and total absorption of ma - es in fasting versus fed subjects are reduced by much smaller margins ( 30% and 26% , respectively ) . since absorption of ma - es is less profoundly affected by the presence or absence of food , this formulation may offer potential clinical benefit for cachectic patients with impaired appetite and low caloric intake . hiv - positive patients ( n = 63 ) with 10% unintended weight loss were randomized to once daily treatment with ma - es 575 mg/5 ml or maos 800 mg/20 ml for 12 weeks.14 although ma - es 575 mg/5 ml is not an fda - approved dose , it is formulated using nanocrystal technology . patients receiving ma - es 575 mg/5 ml showed statistically significant weight gain from baseline as early as week 1 . at the end of 12 weeks patients gained an average of 10% ( 11.9 lbs ; 5.4 kg ) of their baseline weight , which was statistically significant ( p < 0.05 ) . in addition , weight gain from baseline during the study was statistically significant at several time points . patients receiving maos did not show weight gain until week 2 . at the end of 12 weeks , patients gained an average of 6% ( 7.7 lbs ; 3.5 kg ) of their baseline weight , but weight gain was not statistically significant at any time point from baseline . at study end , ma - es 575 mg/5 ml patients did gain the 10% weight they had lost at baseline , and weight gain occurred more rapidly at each time point than for ma - os . the difference in weight gain results between ma - es 575 mg/5 ml and ma - os may be due to the improved absorption of the ma - es formulation in people who have not eaten , although this study was not controlled for food or caloric intake . most studies evaluating orexigenic agents for treatment of unintended weight loss are 12 weeks in duration.1518 the improved bioavailability of ma - es may facilitate earlier weight gain , and potentially shorten treatment duration . the ma - es formulation is associated with other properties that may be important to patients or caregivers . since the ma - es formulation is more concentrated at 125 mg / ml than maos , which is 40 mg / ml , the recommended dose of ma - es is delivered in a smaller volume of 5 ml ( 1 teaspoonful ) , once daily ; whereas , the recommended dose of maos is 20 ml ( 4 teaspoonsful ) , once daily.19 the reduction in megestrol acetate particle size in the ma - es formulation also resulted in a suspension that is much less viscous than maos ( 10 centipoise versus 163 centipoise , respectively [ data on file , par pharmaceutical , inc . , these factors may make ma - es more palatable for patients who lack appetite and/or may have difficulty swallowing . although maos and ma - es contain the same active ingredient , they are not considered therapeutic equivalents20 because of the differences in concentration and fasting bioavailability between each drug . the pk profile for maos under fed and fasted conditions ( study 2 and study 3 ) was needed for the ma - es new drug application submitted to the fda . fda approval was based on bioequivalence of ma - es to maos under fed conditions . subsequently , study 1 was conducted to further characterize the food - effect bioavailability of ma - es . since the pk profile for maos was already established , the results were evaluated relative to the pk profile of ma - es from study 1 . although these 3 pk studies described in the current report were conducted in a similar manner among healthy male subjects , the potential for differences between the study populations , assays , and sampling techniques these studies are also limited by the absence of female subjects from the study populations . a further limitation of these studies is that pk parameters in healthy volunteers may not be generalizable to cachectic patients , who suffer from underlying disease , take concomitant medications , and may be elderly . studies evaluating food effects and the effect of variable caloric intake on the bioavailability of ma - es and maos , and correlation with clinical improvement in patients with cachexia would be of interest . this is a particularly important consideration when treating patients with cachexia or uwl because they often have low caloric intake . ma - es is an improved formulation that is more readily absorbed and has improved bioavailability in the fasting state as compared to the original megestrol acetate oral suspension .
objective : megestrol acetate oral suspension ( maos ) is an appetite stimulant indicated for cachexia in patients with aids . 
 it is available in its original formulation , megace ( maos ) , and as a nanocrystal dispersion , megace es ( ma - es ) . 
 three studies were conducted to evaluate the pharmacokinetic properties of these formulations under fed and fasting conditions.methods:an open - label , crossover trial was conducted in 24 healthy males randomized to ma - es 625 mg/5 ml given with a high - calorie , high - fat meal , or after an overnight fast . 
 blood samples were drawn at multiple time points and pharmacokinetic parameters were determined . 
 two separate , open - label reference studies evaluated maos 800 mg/20 ml in 40 fed or 40 fasting healthy male volunteers.results:in fasting ma - es subjects , the average maximum concentration ( cmax ) was 30% less than the fed cmax value . for maos , 
 fasting cmax was 86% less than fed cmax . 
 in fasting subjects , the area under the curve was 12,095 ngh / ml for ma - es , and 8,942 ngh / ml for maos . 
 in fed subjects , the absorption of the two formulations was comparable.conclusion:bioavailability and absorption are greater for ma - es than maos in fasting subjects . 
 ma - es may be a preferred formulation of megestrol acetate when managing cachectic patients whose caloric intake is reduced .