Impact of Formulation on the Pharmacokinetics of Dutasteride: Results from Two Phase I Studies

Background and Objectives: Dutasteride is currently marketed by GlaxoSmithKline (GSK), either as monotherapy or as a fixed-dose combination with tamsulosin. As part of the project to develop the fixed-dose combination product, alternative formulations of dutasteride were prepared by GSK, and their pharmacokinetic properties were investigated. Methods: Two single-centre, open-label, active-comparator, randomised, three-period crossover studies were performed. The first study evaluated the relative bioavailability of dutasteride 0.5 mg soft gelatin capsule (marketed formulation, reference) versus a dutasteride 0.5 mg hard gelatin capsule and a dutasteride 0.5 mg tablet. The second assessed the relative bioavailability of dutasteride 0.5 mg from soft gelatin capsules containing 300 or 100 mg of mono- and diglycerides of caprylic acid/capric acid (MDC8, an emulsifying agent) versus the marketed formulation. Results: In the first study (n = 36), compared with the marketed soft gelatin capsule formulation, the bioavailability (least squares [LS] means ratio) of the tablet formulation was 76 % (90 % CI 0.68–0.84), and that of the hard gelatin capsule was 73 % (90 % CI 0.66–0.82). Peak exposures were also lower for the tablet (73 %; 90 % CI 0.66–0.81) and hard capsule (71 %; 90 % CI 0.64–0.79) relative to the marketed soft gelatin capsule. In the second study (n = 37), compared with the marketed soft gelatin formulation, the bioavailability (LS means ratio) of the 300 mg MDC8 capsule formulation was 95 % (90 % CI 0.88–1.03), and that of the 100 mg MDC8 capsule formulation was 93 % (90 % CI 0.86–1.00). Peak exposures were also lower for the 300 mg MDC8 (90 %; 90 % CI 0.81–0.99) and 100 mg MDC8 (87 %; 90 % CI 0.79–0.96) formulations. Conclusions: The bioavailability of, and peak exposure to, dutasteride are influenced by the formulation of the administered medication. These studies demonstrate the importance of formulation for obtaining the optimal pharmacokinetic properties of dutasteride.