Publications by authors named "Pasi Pohjanjousi"

11 Publications

  • Page 1 of 1

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.

Eur Urol Focus 2020 01 5;6(1):63-70. Epub 2018 Sep 5.

Drug Development Department (DITEP), Inserm Unit U981, Université Paris Saclay, Université Paris-Sud, Gustave Roussy, Villejuif, France.

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, multicentre, 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 500mg 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) values increased dose dependently until the 300mg dose. The AUC was lower on day 8 after repeated dosing compared with day 1 from the 200mg 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.
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http://dx.doi.org/10.1016/j.euf.2018.08.022DOI Listing
January 2020

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

Br J Clin Pharmacol 2017 Sep 10;83(9):2066-2076. Epub 2017 May 10.

RTI Health Solutions, Av. Diagonal 605, 9-1, 08028, Barcelona, Spain.

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.
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http://dx.doi.org/10.1111/bcp.13293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555873PMC
September 2017

Effects of dexmedetomidine and propofol on patient-ventilator interaction in difficult-to-wean, mechanically ventilated patients: a prospective, open-label, randomised, multicentre study.

Crit Care 2016 Jul 2;20(1):206. Epub 2016 Jul 2.

Department of Intensive Care and Anaesthesia, Catholic University of Rome, Policlinico A. Gemelli, Largo F. Vito 1, Rome, 00168, Italy.

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 < 0.05). No further difference was observed at 18 and 24 h.

Conclusions: When sedation with propofol and dexmedetomidine was compared at similar RASS scores of patients in whom first weaning trial had failed, the AI was lower with dexmedetomidine than with propofol, and this difference was statistically significant at 12 h. These results suggest that sedation with dexmedetomidine may offer some advantages in terms of patient-ventilator synchrony.
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http://dx.doi.org/10.1186/s13054-016-1386-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930611PMC
July 2016

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

Eur Urol 2016 05 17;69(5):834-40. Epub 2015 Oct 17.

Institut Gustave Roussy, University of Paris Sud, Villejuif, France. Electronic address:

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 600mg 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 48h 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 600mg twice daily in patients with non-mCRPC is ongoing.
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http://dx.doi.org/10.1016/j.eururo.2015.09.046DOI Listing
May 2016

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

Curr Ther Res Clin Exp 2015 Dec 29;77:46-51. Epub 2015 Jan 29.

Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland.

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.
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http://dx.doi.org/10.1016/j.curtheres.2015.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461857PMC
December 2015

Population pharmacokinetics of dexmedetomidine in critically ill patients.

Clin Drug Investig 2013 Aug;33(8):579-87

Faculty of Health Sciences, School of Pharmacy, University of Eastern Finland, PO Box 1624, 70211, Kuopio, Finland.

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.
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http://dx.doi.org/10.1007/s40261-013-0101-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3717151PMC
August 2013

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

Eur Heart J 2013 Mar 22;34(10):742-9. Epub 2012 Oct 22.

UMRS 942 Inserm, F-75010 Paris, France.

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 patients.
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http://dx.doi.org/10.1093/eurheartj/ehs332DOI Listing
March 2013

The clinical effects of levosimendan are not attenuated by sulfonylureas.

Scand Cardiovasc J 2012 Dec 25;46(6):330-8. Epub 2012 Sep 25.

Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.

Objectives: 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.

Design: 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.

Results: 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.

Conclusions: Concomitant use of sulfonylureas with levosimendan does not attenuate the hemodynamic or other effects of levosimendan.
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http://dx.doi.org/10.3109/14017431.2012.725206DOI Listing
December 2012

Acetylation status does not affect levosimendan's hemodynamic effects in heart failure patients.

Scand Cardiovasc J 2011 Apr 7;45(2):86-90. Epub 2010 Dec 7.

Helsinki University Central Hospital, Department of Cardiology, HUS, Helsinki, Finland.

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: The sustained hemodynamic effects of levosimendan are similar irrespective of acetylator status.
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http://dx.doi.org/10.3109/14017431.2010.540762DOI Listing
April 2011

Pharmacokinetics of levosimendan and its circulating metabolites in patients with heart failure after an extended continuous infusion of levosimendan.

Br J Clin Pharmacol 2004 Apr;57(4):412-5

Orion Pharma, Research Centre, Espoo, Finland.

Aims: 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.

Methods: 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).

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1111/j.1365-2125.2003.02043.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1884479PMC
April 2004