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

Abstract

Megestrol acetate, an appetite stimulant with low bioavailability, shows increased bioavailability when taken together with food. However, the pharmacokinetic characteristics of megestrol acetate and its relation with food are not well understood. This study aimed to investigate the food effect on the pharmacokinetics (PK) of the recently developed nano-crystallized megestrol acetate (NCMA), using a model-based approach. Data were obtained from an NCMA PK study consisting of a single dose in fasting (39 individuals) and fed conditions (40 individuals). Plasma concentrations were measured up to 120 hr after dosing. With the incorporation of body-weight via allometry, NONMEM 7.3 was used to develop a PK model, which was then used to simulate an optimal fasting dose yielding an area under concentration (AUC) and maximum concentration (C ) of NCMA close to those obtained with the fed dose. NCMA concentrations were best characterized by a two-compartment model with first-order absorption linked to a recycling compartment to account for the multiple concentration peaks observed. Food increased bioavailability 2.2 times and decreased the absorption rate constant 0.58 times. Recycling event times were estimated to be 3.56, 7.99 and 24.0 hr. The optimal fast dose was 2.0 times higher than the fed dose, and the resulting difference in drug exposure between the fasting and fed dose was 7.5%. This work suggests that the PK model developed can be applied to an optimal dosage regimen design for NCMA treatment.

Comparison of the pharmacokinetic characteristics and bioequivalence between two nanosuspension formulations of megestrol acetate in healthy Korean male subjects

“…These characteristics include reduced bioavailability and susceptibility to food intake when taken orally [ 21 ]. Although megestrol acetate has increased bioavailability when administered after a high-fat meal [ 22 ], in clinical use, it is usually administered under fasting conditions because it is used in patients with cachexia. This has led to improvements in formulation by using a new formulation with higher absorption rates.…”