Optimization of LY545694 tosylate controlled release tablets through pharmacoscintigraphy

To optimize a controlled release (CR) matrix formulation with two goals: (1) effectively deliver a prodrug to a preferred absorption region of the upper GI tract, and (2) afford a PK profile similar to a "reference" CR formulation.

A pharmacoscintigraphic clinical study was conducted using a flexible formulation design space. A six-arm, three-prototype study was employed to cover the formulation design space and assess performance against the reference formulation. Pharmacokinetic and scintigraphic data from the first three dosing arms were used to select prototypes to be dosed in subsequent arms.

Of three prototypes tested, the third prototype had an optimal release rate. The in vivo erosion rate was observed via scintigraphy to reach 90% in 3 h. The AUC ratio relative to the reference for the prodrug was 1.25, while the C(max) ratio was 1.07. The ratios for the active moiety were 1.31 (AUC) and 1.01 (C(max)).

A single pharmacoscintigraphic study efficiently investigated a wide formulation design space and precisely optimized the release rate with few formulation iterations. The selected formulation provided the desired exposure at a 30% lower dose. The approach is beneficial when drug absorption is limited to a region of the GI tract.