Pharmacokinetics, Antitumor Activity, and Safety of ODM-201 in Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer : An Open-label Phase 1 Study

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.Peer reviewe

Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer

Targeted Inhibition of CYP11A1 in Prostate CancerIn this single-arm, multicenter, combined phase 1 and phase 2 study, patients with metastatic prostate adenocarcinoma with progression on prior androgen receptor pathway inhibitors and taxane-based chemotherapy were treated with ODM-208. A decrease in prostate-specific antigen levels of 50% or more occurred in 16/42 (38.1%) and 24/45 (53.3%) in phase 1 and 2 respectively. Responses mainly occurred in patients with androgen receptor mutations. Adrenal insufficiency was the dose-limiting toxicity.</p

Liver function abnormalities, clinical profile, and outcome in acute decompensated heart failure

AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: 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 patient

ODM-204, a Novel Dual Inhibitor of CYP17A1 and Androgen Receptor: Early Results from Phase I Dose Escalation in Men with Castration-resistant Prostate Cancer

Background: Most prostate cancer patients develop castration-resistant prostate cancer (CRPC) after androgen deprivation therapy treatment. CRPC growth is mediated mostly by androgen receptor signalling driven by primary androgens synthesised largely by the CYP17A1 enzyme. Objective: To evaluate the safety profile and dose-limiting toxicities of ODM-204. Design, setting, and participants: In this open, uncontrolled, nonrandomised, multi-centre, tolerability and pharmacokinetic first-in-man phase I dose escalation study, patients with metastatic CRPC were randomised to receive ODM-204 in sequential cohorts of five dose levels (ie, 50, 100, 200, 300, and 500 mg twice daily) concomitantly with prednisone. Intervention: ODM-204, a novel, orally administered, investigational, nonsteroidal dual inhibitor of CYP17A1 and androgen receptor. Outcome measurements and statistical analysis: ODM-204 plasma concentrations, serum testosterone, and prostate-specific antigen (PSA) levels were evaluated and imaging of lesions was performed. Results and limitations: Of the 23 patients enrolled into the study, 60.9% experienced mild adverse effects considered to be related to the study treatment, which were fatigue, increased/decreased appetite, nausea, asthenia, diarrhoea, and weight decrease. ODM-204 area under the curve (AUC(0-12)) values increased dose dependently until the 300 mg dose. The AUC was lower on day 8 after repeated dosing compared with day 1 from the 200 mg dose upwards. Decreases in testosterone levels were seen with ODM-204 treatment confirming androgen deprivation. Of the patients, 13% also demonstrated a >50% decrease in PSA at week 12 and continued ODM-204 treatment for over a year. Conclusions: ODM-204 was well tolerated up to the highest evaluated dose. There were decreases in both testosterone and PSA levels, suggesting preliminary antitumour activity in the treatment of CRPC. The pharmacokinetic properties of the molecule, however, prevent further development. Patient summary: This study looked at the safety of ODM-204, a novel dual inhibitor of CYP17A1 and the androgen receptor, in castration-resistant prostate cancer patients. ODM-204 treatment was found to be well tolerated, and it also reduced both serum testosterone and prostate-specific antigen levels, but the properties of the molecule prevent further development. (C) 2018 European Association of Urology. Published by Elsevier B.V.Peer reviewe

A multinational, drug utilization study to investigate the use of dexmedetomidine (Dexdor\uae) in clinical practice in the EU

Aims: Dexmedetomidine (dexdor\uae) 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\ua0months 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\ua0years, 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

Oral Levosimendan Increases Cerebral Blood Flow Velocities in Patients with a History of Stroke or Transient Ischemic Attack: A Pilot Safety Study

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