Predicting the effect of prandial stage and particle size on absorption of ODM-204.

The prediction of absorption properties plays a key role in formulation development when the compound under development shows poor solubility and its absorption is therefore presumed to be solubility limited. In our work, we combined and compared data obtained from in vitro dissolution tests, transit intestinal model studies (TIM -1) and physiologically based pharmacokinetic modelling. Our aim was to determine the ability of these methods to predict performance of poorly soluble lipophilic weak base in vivo. The validity of the predictive methods was evaluated against the in vivo clinical pharmacokinetic (PK) data obtained after administration of the first test formulation, Tl. The aim of our study was to utilize the models in evaluating absorption properties of the second test formulation, T2, which has not yet been clinically administered. The compound in the studies was ODM-204, which is a novel, orally administered, investigational, nonsteroidal dual inhibitor of CYP17A1 and androgen receptor. Owing to its physicochemical properties ODM-204 is prone to low or variable bioavailability. The models examined provided congruent data on dose dependent absorption, food effect at a dose of 200 mg and on the effect of API (active pharmaceutical ingredient) particle size on absorption. Our study shows that the predictive tools of in vitro dissolution, TIM-1 system and the PBPK (physiologically based pharmacokinetic) simulation, showed predictive power of different mechanisms of bioavailability and together provided valuable information for decision making.Peer reviewe

Discovery and development of ODM-204: A Novel nonsteroidal compound for the treatment of castration-resistant prostate cancer by blocking the androgen receptor and inhibiting CYP17A1

We report the discovery of a novel nonsteroidal dual-action compound, ODM-204, that holds promise for treating patients with castration-resistant prostate cancer (CRPC), an advanced form of prostate cancer characterised by high androgen receptor (AR) expression and persistent activation of the AR signaling axis by residual tissue androgens. For ODM-204, has a dual mechanism of action. The compound is anticipated to efficiently dampen androgenic stimuli in the body by inhibiting CYP17A1, the prerequisite enzyme for the formation of dihydrotestosterone (DHT) and testosterone (T), and by blocking AR with high affinity and specificity. In our study, ODM-204 inhibited the proliferation of androgen-dependent VCaP and LNCaP cells in vitro and reduced significantly tumour growth in a murine VCaP xenograft model in vivo. Intriguingly, after a single oral dose of 10-30 mg/kg, ODM-204 dose-dependently inhibited adrenal and testicular steroid production in sexually mature male cynomolgus monkeys. Similar results were obtained in human chorionic gonadotropin-treated male rats. In rats, leuprolide acetate-mediated (LHRH agonist) suppression of the circulating testosterone levels and decrease in weights of androgen-sensitive organs was significantly and dose-dependently potentiated by the co-administration of ODM-204. ODM-204 was well tolerated in both rodents and primates. Based on our data, ODM-204 could provide an effective therapeutic option for men with CRPC.</p