Fossler Michael, Zhu John, Roehrborn Claus, McAleese Paul, Manyak Michael
Quantitative Sciences, Trevena, Inc., King of Prussia, PA, USA.
GlaxoSmithKline, King of Prussia, PA, USA.
Clin Drug Investig. 2016 Sep;36(9):763-767. doi: 10.1007/s40261-016-0419-6.
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.
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.
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.
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.
度他雄胺目前由葛兰素史克公司（GSK）销售，可作为单一疗法，也可与坦索罗辛组成固定剂量复方制剂。作为开发固定剂量复方产品项目的一部分，GSK制备了度他雄胺的替代剂型，并对其药代动力学特性进行了研究。
进行了两项单中心、开放标签、活性对照、随机、三周期交叉研究。第一项研究评估了0.5毫克度他雄胺软胶囊（市售剂型，对照）与0.5毫克度他雄胺硬胶囊及0.5毫克度他雄胺片剂的相对生物利用度。第二项研究评估了含300毫克或100毫克辛酸/癸酸甘油单酯和双酯（MDC8，一种乳化剂）的软胶囊中0.5毫克度他雄胺与市售剂型的相对生物利用度。
在第一项研究（n = 36）中，与市售软胶囊剂型相比，片剂剂型的生物利用度（最小二乘法[LS]均值比）为76%（90%CI 0.68 - 0.84），硬胶囊剂型为73%（90%CI 0.66 - 0.82）。相对于市售软胶囊，片剂（73%；90%CI 0.66 - 0.81）和硬胶囊（71%；90%CI 0.64 - 0.79）的峰暴露量也较低。在第二项研究（n = 37）中，与市售软胶囊剂型相比，300毫克MDC8胶囊剂型的生物利用度（LS均值比）为95%（90%CI 0.88 - 1.03），100毫克MDC8胶囊剂型为93%（90%CI 0.86 - 1.00）。300毫克MDC8（90%；90%CI 0.81 - 0.99）和100毫克MDC8（87%；90%CI 0.79 - 0.96）剂型的峰暴露量也较低。
度他雄胺的生物利用度和峰暴露量受给药制剂剂型的影响。这些研究证明了剂型对于获得度他雄胺最佳药代动力学特性的重要性。
