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Our objectives were to stabilize a non-clinical suspension for use in toxicological studies and to develop methods to investigate the stability of the formulation in terms of salt disproportionation. The compound under research was a hydrochloride salt of a practically insoluble discovery compound ODM-203. The first of the three formulation approaches was a suspension prepared and stored at room temperature. The second formulation was stabilized by pH adjustment. In the third approach cooling was used to prevent salt disproportionation. 5 mg/mL aqueous suspension consisting of 20 mg/mL PVP/VA and 5 mg/mL Tween 80 was prepared for each of the approaches. The polymer was used as precipitation inhibitor to provide prolonged supersaturation while Tween 80 was used to enhance dissolution and homogeneity of the suspension. The consequences of salt disproportionation were studied by a small-scale in vitro dissolution method and by an in vivo pharmacokinetic study in rats. Our results show that disproportionation was successfully suppressed by applying cooling of the suspension in an ice bath at 2-8 degrees C. This procedure enabled us to proceed to the toxicological studies in rats. The in vivo study results obtained for the practically insoluble compound showed adequate exposures with acceptable variation at each dose level.

1. Darolutamide is a novel selective androgen receptor antagonist consisting of two pharmacologically equipotent diastereoisomers. The absorption, distribution, metabolism and excretion properties of darolutamide in rats are reported.2. Non- or [

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.

Neoplasia and other histopathological lesions in flounder (Platichthys flesus) liver have been investigated in several European sea areas, including the Baltic Sea. Several studies have been able to link neoplasm epizootics in fish with the exposure to genotoxins such as polycyclic aromatic hydrocarbons (PAHs). The level of hydrophobic DNA adducts in tissue DNA reflects the exposure of the organism to PAHs. Using hydrophobic DNA adduct levels as biomarkers, possible PAH exposure was assessed in flounder from 10 different sites in the Baltic Sea, collected during the years 1995-1997. The results show that the overall levels of hepatic DNA adducts were low and, in general, the chromatograms appeared clean. The highest levels of DNA adducts were found at two sites in the southern Baltic Sea. There were no statistically significant differences in adduct levels between the sites. Our results indicate that flounder from studied off shore sites of the Baltic Sea had not been exposed to a greater extent to large polycyclic hydrophobic hydrocarbons in their environment.

230 Background: Castration-resistant prostate cancer (CRPC) is characterized by high androgen receptor (AR) expression and persistent activation of AR signaling axis by residual tissue androgens. Inhibiting AR and androgen biosynthesis together may be more effective than inhibiting either alone to treat CRPC. ODM-204 is a potent, orally administered investigational non-steroidal dual inhibitor of CYP17A1 and AR. In vivo, ODM-204 shows favourable pharmacokinetic/ pharmacodynamics (PK/PD) properties in intact mature male monkeys and strong antitumor activity in VCaP xenograft. Methods: The inhibition of CYP17A1 by ODM-204 was studied by using human testicular microsomes and adrenal cortex cell line. Potency to human AR was demonstrated in cells stably transfected with the full-length AR and androgen-responsive reporter gene constructs. PK/PD relationships were evaluated in intact male mature monkeys after single and multiple doses of ODM-204 (10-30 mg/kg/day) by measuring plasma PK after several time points and serum testosterone (T), dehydroepiandrosterone (DHEA), luteinizing hormone (LH), aldosterone, and cortisol 5 hours after the daily dose. Efficacy was further studied in VCaP xenograft in intact male nude mice treated with ODM-204, enzalutamide (enza), abiraterone (abi), or enza+abi-combination for 28 days. Results: ODM-204 binds to AR with a high affinity (Ki47 nM) and selectivity, and has a high potency towards CYP17A1 (IC5022 nM). In intact monkeys, ODM-204 was well tolerated and showed good oral bioavailability with linear and dose proportional pharmacokinetics. Already after a single oral dose of ODM-204, serum T and DHEA were markedly suppressed. After multiple days of dosing, LH was increased, however, changes in cortisol and aldosterone were only minimal. In VCaP xenograft model, ODM-204 showed significant antitumor activity, better than single agent enza or abi, or their combination. Conclusions: ODM-204 is a novel, dual CYP17A1 and AR inhibitor for the treatment of CRPC. A clinical phase 1/2 dose-escalation trial (NCT02344017) is ongoing in patients with mCRPC to determine PK, PD, safety and anti-tumor activity of ODM-204.

Estrogen receptor (ER) ligands that are able to prevent postmenopausal bone loss, but have reduced activity in the uterus and the mammary gland might be of great value for hormone therapy. It is well established that the classical ER can activate genomic as well as nongenomic signal transduction pathways. In this study, we analyse the in vivo behaviour of ER ligands that stimulate nongenomic ER effects to the same extent as estradiol, but show clearly reduced activation of genomic ER effects in vitro. Using different readout parameters such as morphological changes, cellular proliferation, and target gene induction, we are able to demonstrate that ER ligands with reduced genomic activity in vitro show a better dissociation of bone versus uterine and mammary gland effects than estradiol that stimulates genomic and nongenomic effects to the same extent. We conclude that pathway-selective ER ligands may represent an interesting option for hormone therapy.