The Science of Megestrol Acetate Delivery

1 Biodrugs 2005; 19 (3): 179-187 DRUG DELIVERY1173-8804/05/0003-0179/$ 2005 Adis Data Information BV. All rights Science of Megestrol Acetate DeliveryPotential to Improve Outcomes in CachexiaRobert A. Femia1 and Richert E. Goyette2 1 Scientific and Regulatory Affairs, Par Pharmaceutical, Inc., Spring Valley, New York, USA2 Consultant, Hematology/Oncology, Knoxville, Tennessee, Progesterone Modulation of Metabolic Pharmacodynamics of Megestrol General Anticytokine Properties of Megestrol Acetate in Orexigenic Effects of Megestrol Acetate in Tolerability of Megestrol Pharmacokinetics of Megestrol General Megestrol Acetate Megestrol Acetate Oral Megestrol Acetate Nanocrystal Oral Preclinical , usually defined as the loss of >5% of an individual s baseline bodyweight over 2 6 months, occursAbstractwith a number of diseases that includes not only AIDS and advanced cancer but also chronic heart failure.

2 Rheumatoid arthritis, chronic obstructive pulmonary disease, Crohn disease, and renal failure. Anorexia isconsidered 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 involvestimulation of appetite by both direct and indirect pathways and antagonism of the metabolic effects of theprincipal catabolic cytokines. Because the bioavailability of Megestrol Acetate directly affects its efficacy andsafety, the formulation was refined to enhance its efforts yielded Megestrol Acetate in a tablet form, followed by a concentrated oral suspension form, andan oral suspension form developed using nanocrystal technology.

3 Nanocrystal technology was designedspecifically to optimize drug Delivery and enhance the bioavailability of drugs that have poor solubility in Acetate nanocrystal oral suspension is currently under review by the US FDA for the treatment ofcachexia in patients with AIDS. Preclinical pharmacokinetic data suggest that the new Megestrol acetateformulation has the potential to significantly shorten the time to clinical response and thus may improveoutcomes in patients with & GoyetteProgestational agents are used to treat the anorexia-cachexiaCachexia is a condition of starvation characterized by depletionsyndrome and sometimes as salvage agents to treat hormone- of muscle mass and, to a lesser extent, adipose tissue.

4 Etymologi-sensitive breast cancer and cancers of the endometrium, ovary,cally, cachexia is derived from kakos and hexis Greek wordsprostate, and other organs. Because oral progesterone is poorlymeaning bad condition .[2] Although there are various definitionsabsorbed, the agent is usually delivered intramuscularly in an oilof cachexia in the medical literature, it commonly refers to ancarrier. Megestrol Acetate (Megace 1, Par Pharmaceutical, Inc.,involuntary loss of approximately 5% of an individual s baselineSpring Valley, NY, USA), a synthetic progestogen currently avail-bodyweight over a defined period, usually 2 6 months. Cachexiaable in tablet and suspension form, has physiologic activity similardevelops in approximately one half of patients with cancer, andto the natural hormone.

5 First used in humans in 1968, megestrolwhen it does, it can substantially shorten survival time.[2] It is oftenacetate tablets became commercially available in the US in 1971associated with other debilitating symptoms such as chronic nau-for the treatment of endometrial carcinoma. Since that time,sea, asthenia and weakness, autonomic failure, cognitive impair- Megestrol Acetate has been used as a component of oral contracep-ment, psychologic distress, and poor/unsatisfactory quality oftive pills and in the treatment of malignant and nonmalignantlife.[3] Tissue changes associated with cachexia predispose patientsconditions such as melanoma; cancers of the ovary, breast, kidney,to other comorbidities; for example, insufficient nutrition and lossand prostate; benign prostatic hypertrophy; and endometrial hy-perplasia.

6 [1]of fatty hip pads in patients with cachexia increase the risk of hipPatient withcachexiaFatty tissueMuscle tissueCNSM egestrol acetateTNFIL-6IL-1 Anti-TNFAnti-IL-6 Anti-IL-1 DirectOrexigenicCH3=OCH3CH3 HHCH3C=OOCOCH3 HFig. 1. The mechanism of action of Megestrol Acetate in anorexia/cachexia. IL = interleukin; TNF = tumor necrosis use of trade names is for product identification purposes only and does not imply endorsement. 2005 Adis Data Information BV. All rights 2005; 19 (3)Enhancing Megestrol Acetate Delivery for Cachexia181fractures due to falls, and compromise patients ability to retainbody heat.[4]The word cachexia often evokes the image of a patient withadvanced cancer or a disadvantaged individual with extensiveprotein-calorie malnutrition in a Third World nation; however,cachexia is common in devloped countries and in patients withdiseases other than cancer.

7 Cachexia is a manifestation of AIDS,CH3=OCH3CH3 HHCH3C=OOCOCH3 HFig. 2. Chemical structure of Megestrol heart failure, rheumatoid arthritis, chronic Modulation of Activitypulmonary disease, Crohn disease, chronic renal disease, and otherchronic disorders.[2,5-10]Progesterone enters the cell by passively diffusing through theAnorexia is a key component of cachexia, and accumulatingplasma membrane.[14] The actions of the hormone are mediated bydata suggest that the anorexia-cachexia syndrome is a cytokine-binding to progesterone receptor (PR)-A and -B, which arederived process manifested by loss of appetite and cytokine-drivenisoforms of the progesterone nuclear factor (NF) receptor codedhypercatabolism.

8 [11] Megestrol Acetate is commonly used to treatby a single PR gene. Unligated, the PR isoforms exist as mono-anorexia-cachexia and is the only FDA-approved treatment ofmers bound to heat shock proteins. These proteins dissociate aftercancer- and AIDS-related anorexia-cachexia syndrome. Other lessbinding, and the receptors are phosphorylated and dimerize ascommon interventions include dronabinol, glucocorticoids, ana-either homodimers or heterodimers. These dimers subsequentlybind to progesterone response elements on various target genesbolic steroids, antiserotonergic drugs, and prokinetic medica-and, through steps involving transcriptional activators and coac-tions.

9 [12] Until recently, the mechanism of action of megestroltivators and proteins with histone deacetylase activity, chromatinacetate in anorexia-cachexia was poorly understood, but it is nowis remodeled and general transcription factors become accessiblebelieved that Megestrol Acetate acts by stimulating appetite, byto transcription proteins such as RNA polymerase II. The biologicboth direct and indirect mechanisms, and by antagonizing theactivities of PR-A and -B are a function of the target effects of the main or most relevant catabolic cytokinesHowever, PR-A generally acts as a transcriptional inhibitor and(figure 1). Since the efficacy and safety of Megestrol Acetate isPR-B as a stimulator of other steroid response elements.

10 Althoughdirectly linked to the drug s bioavailability,[13] this article reviewsthe major activities of progesterone are mediated genomically,the Science of Megestrol Acetate Delivery and describes recentsome nongenomic mechanisms are also operative.[14]advances in the therapeutic area, focusing on the numerous meta-bolic effects of physiologic levels of progesterone and the Metabolic Activityeffects of pharmacologic amounts of the hormone on processesProgesterone exerts myriad metabolic effects on carbohydrateassociated with lipid metabolism.[14] Although the hormone does not alterglucose tolerance, it increases basal insulin levels and the insulin1. Progesterone Physiologyresponse to carbohydrate load.