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5057 Background: Activating AR mutations ensure a continued AR activation by non-androgen steroid ligands, e.g. progesterone and glucocorticoids. CYP11A1 is the only enzyme that catalyzes the conversion of cholesterol to pregnenolone, from which all steroid hormones (glucocorticoids, mineralocorticoids, and sex steroids) are subsequently derived. ODM-208, an oral, selective inhibitor of CYP11A1, is being evaluated for safety and efficacy as a treatment of mCRPC in the ongoing CYPIDES phase I/II trial in men previously treated with both novel hormonal therapies and taxanes (ClinicalTrials.gov identifier: NCT03436485). Preliminary phase 1 results were previously reported (Fizazi K et al., ASCO GU 2022). Here we confirm that the in-vitro sensitivity of common AR mutations to ODM-208 treatment is mirrored in patient response in CYPIDES phase 1. Methods: ODM-208 was administered at daily doses between 6-150 mg (phase 2 dose: 10 mg) with dexamethasone and fludrocortisone, resulting in maximal suppression in all measured steroids at all doses. AR ligand-binding domain (LBD) mutations (L702H, V716M, W742L, W742C, H875Y, F877L, T878A, T878S, M896T, M896V) were assessed using a BEAMing assay (Sysmex Inostics) from plasma circulating cell-free DNA (cfDNA) collected before the first dose of ODM-208. The activation of wild-type (wt) and LBD mutated AR with various ligands was also studied in vitro using a luciferase reporter assay in AR negative PC3 cells. Results: 17 of 44 patients had at least one AR activating mutation, the most frequent being L702H (n = 11), T878A (n = 10), and H875Y (n = 6). Eleven out of the 16 evaluable patients (68%) with an AR LBD mutation achieved ≥50% reduction in serum PSA compared with 2 out of the 24 evaluable patients (8%) without an AR LBD mutation (P

18 Background: ODM-208 is a novel, oral, non-steroidal and selective inhibitor of CYP11A1, the first and rate-limiting enzyme of steroid biosynthesis. ODM-208 suppresses the production of all steroid hormones and their precursors that may activate the androgen receptor (AR) signalling pathway. This is particularly relevant in patients with AR ligand binding domain (LBD) activating somatic point mutations, a mechanism of resistance to hormone-based therapies in metastatic castration-resistant prostate cancer (mCRPC). We report the first results of the first-in-man phase I CYPIDES trial. Methods: ODM-208 was examined in a dose finding phase 1 trial with a 3+3 design in patients with progressive mCRPC who had previously received ≥1 line of AR signalling inhibitor and ≥1 line of taxane-based chemotherapy. ODM-208 was administered up to 150 mg/day with glucocorticoid (GC) and mineralocorticoid replacement therapy and androgen deprivation therapy (ADT). The phase 1 endpoints included dose-limiting toxicities (DLTs), adverse events, pharmacokinetics, pharmacodynamics, PSA and RECIST response, and exploratory genetic profiling. Results: By Jan 22 2021, 41 patients (median age 70 yrs.) had received ODM-208. The dose finding was completed and included doses ranging from 10 to 150 mg/day. 22 (54%) patients had previously received both abiraterone and enzalutamide, and 23 (56%) patients both docetaxel and cabazitaxel. Although tolerated by most patients, the main safety finding was adrenal insufficiency (AI). Overall, 15/41 (37%) patients experienced Grade 3 AI requiring short-term high-dose GC treatment. ODM-208 plasma exposure was dose proportional. Serum testosterone was undetectable after 4 weeks of start of ODM-208 in almost all patients, as were serum DHEA sulphate, androstenedione, 11β-hydroxyandrostenedione, 11-ketotestosterone and pregnenolone. Overall 12/36 (33%) evaluable patients achieved a PSA decline of ≥50%. In evaluable patients with AR LBD mutation 10/15 (67%) achieved a PSA decline of ≥50%. Clinical improvement in symptoms such as pain was also observed in some men. Conclusions: Administration of ODM-208 to mCRPC men pretreated with abiraterone/enzalutamide and taxanes was highly effective in blocking the production of steroid hormones and showed promising antitumor activity, especially in men with AR mutation-positive cancers. The phase 2 dose expansion part of CYPIDES is ongoing. Clinical trial information: NCT03436485.

Aims Dexmedetomidine (dexdor®) is approved in the European Union (EU) for sedation of adults in the intensive care unit (ICU). The present observational, retrospective study was requested by the European Medicines Agency to investigate dexmedetomidine use in clinical practice, with a particular focus on off-label use, including the paediatric population. Methods Study countries and sites were chosen from those with highest dexmedetomidine use, based on sales. Site selection (blind) was conducted by a multispecialist, independent group. Anonymized data on demographics, treatment indication, dexmedetomidine dosing, concomitant medications and treatment effectiveness were collected retrospectively from records of all dexmedetomidine-treated patients at the site during the enrolment period. Informed consent was waived, to avoid influencing the prescribing of dexmedetomidine. Recruitment was completed within 18 months of first site initiation. Results Data from 2000 patients were collected from 16 hospitals in four EU countries (Finland 750, Poland 505, Germany 470, Austria 275). The median age was 62 years, with more males (70.2%) than females. Dexmedetomidine was primarily used in the adult ICU (86.0%) for ICU sedation (78.6%) and mostly dosed according the product label. The intended sedative effect was obtained in 84.9% of administrations. Paediatric use (5.9% of patients, mostly in Austria and Finland) occurred mainly in the adult or paediatric ICU (75.6%) for sedation (67.2%). Conclusions Overall, most patients were treated with dexmedetomidine according to the product labelling. Use in children was limited but significant and similar in scope to that in adults. Administrations not fully according to the product labelling usually occurred in an ICU environment and reflected extensively investigated clinical uses of dexmedetomidine.

Background: ODM-201 is a novel second-generation androgen receptor inhibitor for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Objective: To evaluate the pharmacokinetics of ODM-201 tablet products and preliminary long-term safety, tolerability, and antitumor activity of ODM-201 in chemotherapy-naive men with mCRPC. Design, setting, and participants: Thirty patients were enrolled in this open-label phase 1 trial. Patients received a single 600-mg dose of ODM-201 in capsules with food and one 600-mg dose of ODM-201 tablet product (TabA or TabB) with food and in the fasted state in a random order. In the extension, patients received 600 mg twice daily ODM-201 taken with food in capsules. Outcome measurements and statistical analysis: We analyzed the pharmacokinetics of ODM-201 tablet formulations. Safety and tolerability were assessed until disease progression or an intolerable adverse event (AE). Antitumor activity was assessed by prostate-specific antigen (PSA) levels and imaging. Results and limitations: The capsule: TabA ratio of area under the concentration-time curve from time zero to the last sample at 48 h was 1.06 (90% confidence interval [CI], 0.91-1.24); the capsule: TabB ratio was 0.97 (90% CI, 0.82-1.14). At week 12, 25 of 30 patients (83%) had a PSA response (>= 50% reduction from baseline). Median time to radiographic progression was 66 wk (95% CI, 41-79). Most common AEs were fatigue (n = 4 [13%]) and nausea (n = 4 [13%]). Conclusions: The study showed that the tablet formulation of ODM-201 had similar pharmacokinetics compared with the capsule. Treatment with a 600-mg twice daily dose of ODM-201 provided anticancer activity and was well tolerated in men with chemotherapy-naive mCRPC. Patient summary: The findings of this study showed that ODM-201 is well tolerated and provided antitumor activity in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC) and that the 300-mg tablet formulation can be used in further clinical studies. A phase 3 trial with ODM-201 600 mg twice daily in patients with non-mCRPC is ongoing. (C) 2015 European Association of Urology. Published by Elsevier B.V.

Levosimendan is an inodilator indicated for acute heart failure (AHF). Its vasodilatory and anti-ischemic effects are mediated by the opening of ATP-dependent potassium channels (K(ATP) channels). Diabetes mellitus is common in AHF patients and sulfonylureas are often prescribed. Sulfonylureas act by blocking the K(ATP) channels. An interaction between levosimendan and sulfonylureas has been shown in preclinical models and could be hypothesized in clinical practice.We produced a pooled analysis of six randomized levosimendan trials (in total of 3004 patients of which 1700 were treated with levosimendan and 226 both with levosimendan and sulfonylureas) with the aim to study the influence of concurrent sulfonylurea treatment to the levosimendan effects. Invasive and non-invasive hemodynamics, biomarkers (BNP), adverse events related to myocardial ischemia, and survival were evaluated.In our relatively small data set, we could not detect any clinically relevant interactions between the sulfonylureas and levosimendan. Similar decreases in systolic and diastolic blood pressure, pulmonary capillary wedge pressure and BNP, and similar survival and adverse event profiles were seen in sulfonylurea users and non-users exposed to levosimendan.Concomitant use of sulfonylureas with levosimendan does not attenuate the hemodynamic or other effects of levosimendan.

Background Intravenous levosimendan is indicated for acute heart failure. The compound has shown promising beneficial effects in ischemic stroke models. Objective We evaluated the efficacy and safety of oral levosimendan in patients with a history of cerebral ischemia. Methods In a randomized, double-blind, placebo-controlled, parallel-group study, 16 patients with a history of ischemic stroke/transient ischemic attack received oral levosimendan in 5 escalating doses from 0.125 to 2.0 mg daily for 18-day intervals of each dose; 5 patients received placebo. Twenty-four-hour ambulatory ECG and cerebral blood flow velocities using transcranial Doppler ultrasound were recorded at baseline and at the end of each dosing period. Vasomotor reactivity was assessed via the breath holding index. In addition, plasma levels of N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) and the metabolites of levosimendan were determined. Results Levosimendan induced an increase in cerebral blood flow velocities and a decrease in NT-pro-BNP compared with placebo. There was no significant effect on breath holding index. Doses ≥0.5 mg increased heart rate by 5 to 9 beats/min. The dose level of 2.0 mg exceeded the preset safety margin of ventricular extrasystoles per hour (ie, upper 90% CI of the ratio of levosimendan to placebo above 2) with an estimate of 3.10 (90% CI, 0.95–10.07). Conclusions Oral levosimendan increases cerebral blood flow velocities and diminishes NT-pro-BNP levels in patients with earlier ischemic cerebrovascular event. Daily doses up to 1.0 mg were well tolerated, whereas the 2.0 mg dose level induced an increase in ventricular extrasystoles. ClinicalTrials.gov identifier: NCT00698763.

WOS: 000316128800011, PubMed ID: 23091203, The aim of this study was to assess the prevalence of abnormal liver function tests (LFTs) and the associated clinical profile and outcome(s) in acute decompensated heart failure (ADHF) patients. Alteration in LFTs is a recognized feature of ADHF, but prevalence and outcomes data from a broad contemporary cohort of ADHF are scarce and the mechanism(s) of ADHF-induced cholestasis is unknown. We conducted a post hoc analysis of SURVIVE, a large clinical trial including ADHF patients treated with levosimendan or dobutamine. All LFTs were available in 1134 patients at baseline. Abnormal LFTs were seen in 46 of ADHF patients: isolated abnormal alkaline phosphatase (AP) was noted in 11, isolated abnormal transaminases in 26, and a combination of abnormal AP and transaminases in 9. Abnormal AP was associated with marked signs of systemic congestion and elevated right-sided filling pressure. Abnormal AP had no relationship with 31-day mortality but was associated with worse 180-day mortality (23.5 vs. 34.9, P 0.001 vs. patients with normal AP). Abnormal transaminases were associated with clinical signs of hypoperfusion and with greater 31-day and 180-day mortality compared with normal transaminase profiles (17.6 vs. 8.4 and 31.6 vs. 22.4, respectively; both P 0.001). There was no additive value of abnormal AP plus abnormal transaminase on a long-term outcome. Abnormal LFTs were present in about a half of patients presenting with ADHF treated with inotropes. Abnormal AP and abnormal transaminases were associated with specific clinical, biological, and prognostic features, including a short-term overmortality with increased transaminases but not with biological signs of cholestasis, in ADHF patients., Abbott; Orion Pharma, SURVIVE study was sponsored by Abbott and Orion Pharma.

Levosimendan is indicated for acute heart failure. The formation of levosimendan's active metabolite OR-1896 is dependent on the acetylator status. We evaluated whether acetylator status affects the hemodynamic responses after levosimendan infusion.Forty-one NYHA III to IV heart failure patients were divided into rapid and slow acetylators by population kinetic modeling. Invasive hemodynamics and plasma concentrations of levosimendan and its metabolites were followed serially.Fifty-six percent of the patients were rapid and 44% slow acetylators. Levosimendan induced increases in heart rate and cardiac output, and decreases in pulmonary capillary wedge pressure (PCWP) and blood pressure, which were sustained at 24 hours after stopping the infusion. At this time, levosimendan levels were undetectable, and OR-1896 levels were about two-fold higher in rapid acetylators. However, hemodynamic effects were similar; mean(SEM) change from baseline in cardiac output was +2.0(0.3) vs. +1.6(0.3) l/min (p = 0.309), and in PCWP -8(2) vs. -7(1) mmHg (p = 0.536), in rapid and slow acetylators, respectively.The sustained hemodynamic effects of levosimendan are similar irrespective of acetylator status.

Repetitive dosing of intravenous levosimendan improves pulmonary hemodynamics in patients with pulmonary hypertension : results of a pilot study

230 Background: The open phase I trial, ARAFOR, with long-term extension evaluated pharmacokinetics (PK), antitumor activity and safety of ODM-201 in chemotherapy-naïve patients with progressive mCRPC. Methods: PK phase: Patients received one 600 mg dose of ODM-201 capsules (6 x 100 mg) in fed state and one dose of either tablet formulation (TabA or TabB, 2 x 300 mg) in fed and fasted state in random order. Extension: Patients received ODM-201 600 mg (capsule) twice daily until disease progression/ intolerable adverse event (AE). A data cut-off date Apr 4, 2014 was used for analyses. Results: 30 patients were enrolled in PK and treated in the extension phase. Baseline characteristics: median age 68 yrs, ECOG score 0 in 67%, and ECOG 1 in 33% patients, median PSA 18.2 ng/mL. Median time from PC diagnosis to start of ODM-201 treatment was 39 months. Median time on ODM-201 treatment was 9.5 months (trial is on-going). ODM-201 plasma concentration–time curves were similar for the capsule, TabA, and TabB at fed state. Median tmax at fed state was longer than in fasted state (5–6 h vs. 4 h). Absorption was slower and plasma exposure about 2-fold greater at fed state compared to fasted state (AUCt, AUC¥ and Cmax values). All 30 patients completed the first 12 weeks of the extension phase. Prostate-specific antigen (PSA) responses (≥50% reduction from baseline) were seen in 25 (83%) patients (PSA reductions ≥90% in 9 [30%] patients). At 12 weeks, RECIST responses in soft tissue were noted in 6 patients (29%) and stable disease in 13 (62%) patients, 3 (11%) had improvement in skeletal metastases and 18 (67%) stabilised bone disease. 21 (70%) reported at least 1 AE, and treatment-related AEs occurred in 6 (20%) patients. No treatment-related AEs of grade 2 or higher were reported. Conclusions: Tablet and capsule formulations showed comparable single-dose pharmacokinetics. Dose level of 600 mg twice daily (capsule) showed significant antitumor activity and had a favourable safety profile. Updated results from the extension phase will be presented. A phase 3 ARAMIS trial at a dose of 600 mg twice daily in men with non-metastatic CRPC is currently ongoing. Clinical trial information: NTC01784757.

The purpose of the study was to characterize the pharmacokinetics of levosimendan and its metabolites OR-1855 and OR-1896 in patients with congestive heart failure.Levosimendan was administered as a continuous intravenous infusion for 7 days. Twelve subjects received the drug at an infusion rate of 0.05 micro g kg(-1) min(-1) and 12 at a rate 0.1 micro g kg(-1) min(-1).Steady state concentrations of levosimendan were achieved within 4 h. Peak concentrations of the metabolites occurred after termination of the infusion. The mean (+/- SD) half-life of the active metabolite OR-1896 was 81 +/- 37 h after the lower dose and 81 +/- 28 h after the higher dose (P = 0.992, 95% confidence interval on the difference -27.5, 27.7).The metabolites of levosimendan, OR-1855 and OR-1896, were formed and eliminated slowly, their peak concentrations occurring after termination of the 7-day infusion of the drug.

Background and Objectives Although the pharmacokinetics of dexmedetomidine in healthy volunteers have been studied, there are limited data about the pharmacokinetics of long-term administration of dexmedetomidine in critically ill patients. Methods This population pharmacokinetic analysis was performed to quantify the pharmacokinetics of dexmedetomidine in critically ill patients following infusions up to 14 days in duration. The data consisted of three phase III studies (527 patients with sparse blood sampling, for a total of 2,144 samples). Covariates were included in a full random-effects covariate model and the most important covariate relationships were tested separately. The linearity of dexmedetomidine clearance was evaluated by observing steady-state plasma concentrations acquired at various infusion rates. Results The data were adequately described with a one-compartment model. The clearance of dexmedetomidine was 39 (95 % CI 37–41) L/h and volume of distribution 104 (95 % CI 93–115) L. Both clearance and volume of distribution were highly variable between patients (coefficients of variation of 62 and 57 %, respectively), which highlights the importance of dose titration by response. Covariate analysis showed a strong correlation between body weight and clearance of dexmedetomidine. The clearance of dexmedetomidine was constant in the dose range 0.2–1.4 μg/kg/h. Conclusions The pharmacokinetics of dexmedetomidine are dose-proportional in prolonged infusions when dosing rates of 0.2–1.4 μg/kg/h, recommended by the Dexdor® summary of product characteristics, are used.

Background Dexmedetomidine can be used for sedation of mechanically ventilated patients and has minor respiratory effects. The aim of this study was to compare the incidence of patient-ventilator dyssynchronies during sedation with dexmedetomidine or propofol. Methods We conducted a multicentre, prospective, open-label, randomised clinical trial, comparing dexmedetomidine with standard propofol sedation at three intensive care units of university hospitals in Italy. Twenty difficult-to-wean patients for whom the first weaning trial had failed and who were on pressure support ventilation were randomised to receive sedation with either dexmedetomidine or propofol at a similar level of sedation (Richmond Agitation-Sedation Scale [RASS] score +1 to −2). The asynchrony index (AI) was calculated using tracings of airflow, airway pressure and electrical activity of the diaphragm sampled at 0, 0.5, 1, 2, 6, 12, 18 and 24 h. Results The mean AI was lower with dexmedetomidine than with propofol from 2 h onwards, although the two groups significantly differed only at 12 h (2.68 % vs 9.10 %, p

Aims Dexmedetomidine (dexdor®) is approved in the European Union (EU) for sedation of adults in the intensive care unit (ICU). The present observational, retrospective study was requested by the European Medicines Agency to investigate dexmedetomidine use in clinical practice, with a particular focus on off‐label use, including the paediatric population. Methods Study countries and sites were chosen from those with highest dexmedetomidine use, based on sales. Site selection (blind) was conducted by a multispecialist, independent group. Anonymized data on demographics, treatment indication, dexmedetomidine dosing, concomitant medications and treatment effectiveness were collected retrospectively from records of all dexmedetomidine‐treated patients at the site during the enrolment period. Informed consent was waived, to avoid influencing the prescribing of dexmedetomidine. Recruitment was completed within 18 months of first site initiation. Results Data from 2000 patients were collected from 16 hospitals in four EU countries (Finland 750, Poland 505, Germany 470, Austria 275). The median age was 62 years, with more males (70.2%) than females. Dexmedetomidine was primarily used in the adult ICU (86.0%) for ICU sedation (78.6%) and mostly dosed according the product label. The intended sedative effect was obtained in 84.9% of administrations. Paediatric use (5.9% of patients, mostly in Austria and Finland) occurred mainly in the adult or paediatric ICU (75.6%) for sedation (67.2%). Conclusions Overall, most patients were treated with dexmedetomidine according to the product labelling. Use in children was limited but significant and similar in scope to that in adults. Administrations not fully according to the product labelling usually occurred in an ICU environment and reflected extensively investigated clinical uses of dexmedetomidine.