Novel nanocrystal formulation of megestrol acetate has improved bioavailability compared with the conventional micronized formulation in the fasting state

Abstract

BackgroundMegestrol acetate is an effective treatment for improving appetite and increasing body weight in patients with cancer-associated anorexia. However, Megace® oral suspension (OS), a micronized formulation of megestrol acetate, has low bioavailability in the fasting state. To overcome this limitation, a nanocrystal formulation has been developed. This study was performed to evaluate the pharmacokinetics and tolerability of the nanocrystal formulation and to compare them with those of Megace® OS in the fed and fasting states.MethodsA randomized, open-label, two-treatment, two-period, two-sequence, crossover study was performed in three parts in 93 healthy subjects. A single 625 mg/5 mL oral dose of a nanocrystal formulation was administered in the fasting and fed states (part I). In parts II and III, a single 625 mg/5 mL oral dose of the nanocrystal formulation or Megace® OS 800 mg/20 mL was given in the fed and fasting states, respectively. Blood samples were collected for up to 120 hours post dose for pharmacokinetic analysis. Tolerability was evaluated throughout the entire study period.ResultsThe nanocrystal formulation of megestrol acetate was rapidly absorbed in both the fed and fasting states. In the fed state, systemic exposure was comparable between the nanocrystal formulation of megestrol acetate and Megace® OS. In the fasting state, however, the peak plasma concentration and area under the plasma concentration-time curve to the last measurable concentration of megestrol acetate was 6.7-fold and 1.9-fold higher, respectively, for the nanocrystal formulation than for Megace® OS. No serious adverse events were reported.ConclusionSystemic exposure to megestrol acetate is less affected by lack of concomitant food intake when it is administered using the nanocrystal formulation. The nanocrystal formulation of megestrol acetate could be more effective in treating patients with cachexia or anorexia.

Quantitative Assessment of Food Effect on the Pharmacokinetics of Nano‐Crystallized Megestrol Acetate

“…In the simulation, the dosing scheme chosen was multiple dosing for 7 days assuming a steady-state, based on the drug elimination half-life of 20-50 hr reported in the literature [6][7][8]. The optimal daily dose, D*, to be administered under fasting conditions, was defined as the dose that minimizes the absolute relative error (ERR, %), which is defined as follows:…”

“…Subsequently, with advancements in pharmaceutical science, nano-crystallized megestrol acetate (NCMA) has been developed. Through animal and human studies, nano-crystallization has been found to enhance bioavailability in a fasting administration to some extent, thereby compensating for reduced systemic exposure compared with that in a fed administration [5][6][7][8].…”

Novel Oral Drug Delivery Systems for Steroids: Overview and Recent Updates

“…Based on the above results the authors stated that, with oral administration of nanocrystal formulation, systemic exposure to megestrol acetate is less affected by the lack of concomitant intake of food and the authors concluded that megestrol acetate's nanocrystal formulation could be more effective in treating patients with cachexia. 22…”

Nanocrystalization: An Emerging Technology to Enhance the Bioavailability of Poorly Soluble Drugs

“…Conventional treatment and some novel carrier system have the disadvantage of stability efficacy, bioavailability and toxicity; therefore, some of the drugs are formulated in the NCs l form and commercialized for effective treatment. Some of the Marketed NCs and their method of preparation are summarized in Table 2 [93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108].…”