scholarly journals 143 A Combination of Olanzapine and Samidorphan Has No Clinically Relevant Effect on QT Prolongation up to Supratherapeutic Doses

CNS Spectrums ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 291-291
Author(s):  
Lei Sun ◽  
Sergey Yagoda ◽  
Hongqi Xue ◽  
Randy Brown ◽  
Narinder Nangia ◽  
...  
Keyword(s):  
Geometric Mean ◽  
Plasma Concentrations ◽  
Double Blind ◽  
Assay Sensitivity ◽  
Mixed Effect ◽  
Matching Placebo ◽  
Relevant Effect ◽  
Parallel Group ◽  
Relationship Of ◽  
Funding Acknowledgements

Abstract:Background:ALKS 3831, a combination of olanzapine and samidorphan (OLZ/SAM) in development for schizophrenia, is intended to mitigate olanzapine-associated weight gain. This thorough QT (tQT) study evaluated OLZ/SAM effects on electrocardiogram parameters.Methods:In this randomized, double-blind, parallel-group study, 100 patients with stable schizophrenia were randomized 3:2 to either receive OLZ/SAM 10/10 mg (therapeutic dose) on days 2–4, 20/20 mg on days 5–8, and 30/30 mg (supratherapeutic dose) on days 9–13 with moxifloxacin-matching placebo on days 1 and 14, or a single dose of moxifloxacin 400 mg and matching placebo on days 1 and 14 (nested crossover design). Drug concentration relation to change from baseline in Fridericia-corrected QTc (ΔQTcF) was evaluated using a linear mixed-effect concentration-QTc (C-QTc) model. Adverse events were assessed.Results:The slope (90% CI) of the C-QTc was not significant for olanzapine or samidorphan (0.03 [−0.01, 0.08] and 0.01 [−0.01, 0.04] msec per ng/mL, respectively). Predicted placebo-corrected ΔQTcF (90% CI) was 2.33 (−2.72, 7.38) and 1.38 (−3.37, 6.12) msec at the observed geometric mean maximal concentration of olanzapine (62.6 ng/mL) and samidorphan (75.1 ng/mL), respectively, on day 13. A clinically relevant QT effect (ie, placebo-corrected ΔQTcF ≥10 msec) can be excluded for olanzapine and samidorphan concentrations up to ≈110 and ≈160 ng/mL, respectively. Assay sensitivity was confirmed by the C-QTc relationship of moxifloxacin. OLZ/SAM was well tolerated.Conclusions:OLZ/SAM, in doses and plasma concentrations up to supratherapeutic levels, was well tolerated and had no clinically relevant effects on electrocardiogram parameters, including QT interval, in patients with schizophrenia.Funding Acknowledgements:This study was funded by Alkermes, Inc.

Abstract 527: Vorapaxar Does Not Increase Bleeding Time

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Walter Kraft ◽  
Jocelyn Gilmartin ◽  
Derek L Chappell ◽  
Srikanth Nagalla ◽  
Uhlas P Naik ◽  
...  
Keyword(s):  
Bleeding Time ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Clinical Trial Data ◽  
Open Label ◽  
Period 2 ◽  
Parallel Group ◽  
The Us ◽  
Surgical Bleeding ◽  
Group 2

Vorapaxar is a novel PAR-1 inhibitor approved in the US and EU to reduce risk of thrombotic CV events in patients with a history of MI, and in the US also in patients with PAD. It does not affect coagulation tests (TT, PT, aPTT, ACT, ECT). Aspirin and P2Y 12 inhibitors prolong human bleeding time (BT); does vorapaxar? Methods: In this randomized, active controlled, parallel group, 2-period, single-blind, open-label trial, healthy men (n=31) and women (n=5), in Period 1, received either 81 mg aspirin (ASA) QD for 7 days (N=18), or a 7 day regimen of vorapaxar (N=18) achieving steady state plasma concentrations equivalent to chronic 2.5 mg QD doses. In Period 2, each group added 7 days of the therapy alternate to that of Period 1 without washout. BT and platelet aggregation (PA) using arachidonic acid, ADP, and TRAP agonists were collected predose in Periods 1 (baseline) and 2, and 24 h after Period 2 last dose. A linear mixed effects model with fixed effect for treatment analyzed data. Results: BT geometric mean ratio (90% CI) for (vorapaxar/baseline) was 1.01 (0.88, 1.15), (ASA/baseline) was 1.32 (1.15, 1.51), (vorapaxar+ASA/vorapaxar) was 1.47 (1.26, 1.70), (vorapaxar+ASA/ASA) was 1.12 (0.96, 1.30). Each antiplatelet inhibited PA only as expected. See figure. Conclusions: Unlike ASA, vorapaxar did not prolong BT compared to baseline. When given with ASA, there is a slight numerical increase in BT beyond that of ASA. Implications for clinical spontaneous or surgical bleeding await further analyses of clinical trial data.

scholarly journals First Assessment in Humans of the Safety, Tolerability, Pharmacokinetics, and Ex Vivo Pharmacodynamic Antimalarial Activity of the New Artemisinin Derivative Artemisone

2008 ◽  
Vol 52 (9) ◽  
pp. 3085-3091 ◽  
Author(s):  
Johannes Nagelschmitz ◽  
Barbara Voith ◽  
Georg Wensing ◽  
Axel Roemer ◽  
Burkhard Fugmann ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Ex Vivo ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Artemisinin Derivative ◽  
Active Metabolites ◽  
Multiple Dosing ◽  
Serious Adverse Events ◽  
Double Blind

ABSTRACT In preclinical studies, artemisone (BAY 44-9585), a new artemisinin derivative, was shown to possess enhanced efficacy over artesunate, and it does not possess the neurotoxicity characteristic of the current artemisinins. In a phase I program with double-blind, randomized, placebo-controlled, single and multiple ascending oral-dose studies, we evaluated the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamic antimalarial activity of artemisone. Single doses (10, 20, 30, 40, and 80 mg) and multiple doses (40 and 80 mg daily for 3 days) of artemisone were administered orally to healthy subjects. Plasma concentrations of artemisone and its metabolites were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS). Artemisone was well tolerated, with no serious adverse events and no clinically relevant changes in laboratory and vital parameters. The pharmacokinetics of artemisone over the 10- to 80-mg range demonstrated dose linearity. After the single 80-mg dose, artemisone had a geometric mean maximum concentration of 140.2 ng/ml (range, 86.6 to 391.0), a short elimination half-life (t 1/2) of 2.79 h (range, 1.56 to 4.88), a high oral clearance of 284.1 liters/h (range, 106.7 to 546.7), and a large volume of distribution of 14.50 liters/kg (range, 3.21 to 51.58). Due to artemisone's short t 1/2, its pharmacokinetics were comparable after single and multiple dosing. Plasma samples taken after multiple dosing showed marked ex vivo pharmacodynamic antimalarial activities against two multidrug-resistant Plasmodium falciparum lines. Artemisone equivalent concentrations measured by bioassay revealed higher activity than artemisone measured by LC/MS-MS, confirming the presence of active metabolites. Comparable to those of other artemisinin's, artemisone's t 1/2 is well suited for artemisinin-based combination therapy for the treatment of P. falciparum malaria.

Safety, Tolerability, and Pharmacokinetics of Telacebec (Q203), a New Antituberculosis Agent, in Healthy Subjects

2021 ◽  
Author(s):  
Jeongjun Kim ◽  
Jinho Choi ◽  
Hwankyu Kang ◽  
Jiye Ahn ◽  
Jane Hutchings ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Drug Candidate ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Time Curve ◽  
Exponential Decline ◽  
Potent Drug

Telacebec (Q203) is a potent drug candidate under clinical development for the treatment of drug-naïve and drug-resistant tuberculosis. The first-in-human randomized, placebo-controlled, double-blind, dose-escalation Phase 1A trial (Q203-TB-PI-US001) was conducted to evaluate the safety, tolerability, and pharmacokinetics of telacebec. A total of 56 normal, healthy, male and female subjects (42 active and 14 placebo) were enrolled in the study. The doses of telacebec were 10 mg (Cohort 1), 30 mg (Cohort 2), 50 mg (Cohort 3), 100 mg (Cohort 4), 200 mg (Cohort 5), 400 mg (Cohort 6), and 800 mg (Cohort 7) in a fasted state. Subjects participating in Cohort 4 were also enrolled in Cohort 8 to investigate the food effect on the pharmacokinetics of telacebec after a high-fat meal. In all subjects dosed with telacebec (10 – 800 mg), telacebec was well tolerated and did not lead to any significant or serious adverse events. Following a single oral administration of telacebec (10 – 800 mg), telacebec plasma concentration reached the maximal plasma concentration (C max ) in average 2.0 – 3.5 h and showed multi-exponential decline thereafter. The area under the plasma concentration vs. time curve (AUC) was approximately dose-proportional. A significant increase in plasma concentrations was observed in the fed condition compared with the fasted condition with the geometric mean ratio of 3.93 for C max . Moderate delay in T max (4.5 h) was also observed in the fed condition. These results, combined with the demonstrated activity against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis , support further investigation of telacebec for the treatment of tuberculosis.

scholarly journals Phase 1, randomized, parallel-group, double-blind, placebo-controlled trial to evaluate the effects of erenumab (AMG 334) and concomitant sumatriptan on blood pressure in healthy volunteers

Cephalalgia ◽  
2018 ◽  
Vol 39 (1) ◽  
pp. 100-110 ◽  
Author(s):  
Jan de Hoon ◽  
Anne Van Hecken ◽  
Corinne Vandermeulen ◽  
Marissa Herbots ◽  
Yumi Kubo ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mean Arterial Pressure ◽  
Confidence Interval ◽  
Arterial Pressure ◽  
Phase 1 ◽  
Geometric Mean ◽  
Double Blind ◽  
Parallel Group ◽  
Resting Blood Pressure ◽  
Subcutaneous Sumatriptan

Objectives The aim of this study was to assess the effects of concomitant administration of erenumab and sumatriptan on resting blood pressure, pharmacokinetics, safety, and tolerability in healthy subjects. Methods In this phase 1, parallel-group, one-way crossover, double-blind, placebo-controlled study, healthy adult subjects were randomized (1:2) to receive either intravenous placebo and subcutaneous sumatriptan 12 mg (i.e. two 6-mg injections separated by 1 hour) or intravenous erenumab 140 mg and subcutaneous sumatriptan 12 mg. Blood pressure was measured pre-dose and at prespecified times post-dose. The primary endpoint was individual time-weighted averages of mean arterial pressure, measured from 0 hours to 2.5 hours after the first dose of sumatriptan. Pharmacokinetic parameters for sumatriptan were evaluated by calculating geometric mean ratios (erenumab and sumatriptan/placebo and sumatriptan). Adverse events and anti-erenumab antibodies were also evaluated. Results A total of 34 subjects were randomized and included in the analysis. Least squares mean (standard error) time-weighted averages of mean arterial pressure were 87.4 (1.0) mmHg for the placebo and sumatriptan group and 87.4 (1.2) mmHg for the erenumab and sumatriptan group. Mean difference in mean arterial pressure between groups was −0.04 mmHg (90% confidence interval: −2.2, 2.1). Geometric mean ratio estimates for maximum plasma concentration of sumatriptan was 0.95 (90% confidence interval: 0.82, 1.09), area under the plasma concentration–time curve (AUC) from time 0 to 6 hours was 0.98 (90% confidence interval: 0.93, 1.03), and AUC from time 0 to infinity was 1.00 (90% confidence interval: 0.96, 1.05). No clinically relevant safety findings for co-administration of sumatriptan and erenumab were identified. Conclusion Co-administration of erenumab and sumatriptan had no additional effect on resting blood pressure or on pharmacokinetics of sumatriptan. Trial registration: ClinicalTrials.gov, NCT02741310.

Modification of bronchial reactivity by physiological concentrations of plasma epinephrine

1992 ◽  
Vol 73 (3) ◽  
pp. 1004-1007 ◽  
Author(s):  
A. J. Knox ◽  
H. Campos-Gongora ◽  
A. Wisniewski ◽  
I. A. MacDonald ◽  
A. E. Tattersfield
Keyword(s):  
Geometric Mean ◽  
Plasma Concentrations ◽  
Challenge Test ◽  
Forced Expiratory Volume ◽  
Bronchial Reactivity ◽  
Plasma Epinephrine ◽  
Double Blind ◽  
Bronchial Responsiveness ◽  
Mean Values ◽  
Epinephrine Concentration

Circulating epinephrine concentrations are altered in certain pathophysiological states, but whether such changes in epinephrine concentrations can alter bronchial responsiveness in subjects with asthma has not been studied. We studied 10 subjects with asthma in a double-blind crossover study on 4 nonconsecutive days. After measurement of baseline forced expiratory volume in 1 s (FEV1) and plasma epinephrine concentration, subjects were given placebo or 4, 16, or 64 ng.kg-1.min-1 epinephrine by intravenous infusion for 45 min. Blood was taken for plasma epinephrine concentration before the infusion and at 30 min, when a histamine challenge test was performed. Mean plasma epinephrine concentrations ranged from 0.37 nmol/l on placebo to 3.76 nmol/l with the 64-ng/kg infusion. FEV1 increased progressively with increasing concentrations of infused epinephrine, the mean change ranging from -0.051 on placebo to 0.331 after the highest concentration of epinephrine. The provocative dose of histamine causing a 20% fall in FEV1 increased progressively with increasing concentrations of infused epinephrine, geometric mean values ranging from 0.61 mumol with placebo to 1.7 mumol after the highest dose of epinephrine. Thus epinephrine, at physiological plasma concentrations, can modify bronchial reactivity.

scholarly journals Assessment of morning sleep propensity with lemborexant in adults with insomnia disorder in a randomized, placebo-controlled crossover study

2021 ◽  
Author(s):  
David Mayleben ◽  
Russell Rosenberg ◽  
Kate Pinner ◽  
Ziad Hussein ◽  
Margaret Moline
Keyword(s):  
Crossover Study ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Sleep Onset ◽  
Sleep Onset Latency ◽  
Open Label ◽  
Double Blind ◽  
Assay Sensitivity ◽  
Insomnia Disorder ◽  
Sleep Propensity

Abstract Objective To evaluate effects of lemborexant (LEM), a dual orexin receptor antagonist, on next-morning sleep propensity assessed by a modified Multiple Sleep Latency Test (M-MSLT) in adults with insomnia disorder. Methods Study 107 (E2006-A001-107) was a phase 1, randomized, double-blind, four-period crossover study. Subjects (n=69) received oral single-dose placebo, LEM 5 mg (LEM5), and LEM 10 mg (LEM10) at bedtime in periods 1–3 in a randomized crossover and open-label flurazepam 30 mg in period 4. After an 8-h overnight sleep opportunity, the M-MSLT measured average sleep onset latency (SOL). Mean change from baseline in average SOL vs. placebo of -6.0 min or more was considered clinically meaningful. Other sleep propensity assessments included the proportion of subjects with average SOL >6 min shorter than placebo. LEM plasma concentrations, safety, and tolerability were also assessed. Results M-MSLT assay sensitivity was confirmed by a clinically meaningful decrease in average SOL with flurazepam vs. placebo (least squares mean [LSM] difference –6.06 min; 1-sided p<0.0001). In contrast, decreases in average SOL with LEM5 (LSM difference vs. placebo –1.15 min; 1-sided p=0.0262) and LEM10 (–3.48 min; p<0.0001) did not meet the pre-defined threshold for a clinically meaningful effect (LEM5, –2.12; LEM10, –4.46). Some individuals did experience higher sleep propensity (average SOL >6.0 min shorter than placebo), particularly with LEM10 (LEM10, 29.4%; LEM5, 13.2%). Conclusions In contrast to flurazepam, LEM5 and LEM10 did not show clinically meaningful mean increases in next-morning sleep propensity vs. placebo. The possibility that some subjects may experience residual morning effects cannot be excluded.

scholarly journals Evaluation of the Effect of a Supratherapeutic Dose of Intravenous Ceftaroline Fosamil on the Corrected QT Interval

2013 ◽  
Vol 57 (4) ◽  
pp. 1777-1783 ◽  
Author(s):  
Todd A. Riccobene ◽  
Ludmyla Rekeda ◽  
Douglas Rank ◽  
Lily Llorens
Keyword(s):  
Qt Interval ◽  
Plasma Concentrations ◽  
Vital Signs ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Qtc Interval ◽  
Double Blind ◽  
Assay Sensitivity ◽  
Ceftaroline Fosamil ◽  
Supratherapeutic Dose

ABSTRACTA randomized, double-blind, placebo-controlled, 3-period crossover study was conducted in 54 healthy adults to assess the effect of ceftaroline fosamil on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using an individual correction formula (QTcIb), was determined predose and at 1, 1.25, 1.5, 2, 4, 8, 12, and 24.5 h after intravenous dosing with a supratherapeutic dose (1,500 mg) of ceftaroline fosamil, 400 mg moxifloxacin (positive control), and placebo. The pharmacokinetic profile of ceftaroline was also evaluated. At each time point following ceftaroline fosamil administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from predose baseline in QTcIb (ΔΔQTcIb) was below 10 ms (maximum, 3.4 ms at 1.5 h after dosing), indicating an absence of clinically meaningful QTc increase. The lower limit of the 90% CI of ΔΔQTcIb for moxifloxacin versus placebo was greater than 5 ms at 5 time points (maximum, 12.8 ms at 1 h after dosing), demonstrating assay sensitivity. There was no apparent correlation between ceftaroline plasma concentrations and ΔΔQTcIb. The supratherapeutic dose of ceftaroline fosamil (1,500 mg) resulted in substantially greater systemic exposure to ceftaroline than previously observed with standard therapeutic doses. Ceftaroline fosamil was well tolerated after a single 1,500-mg intravenous dose, and no clinically meaningful abnormalities in laboratory values or vital signs were observed.

Chocolate is a Migraine-Provoking Agent

Cephalalgia ◽  
1991 ◽  
Vol 11 (2) ◽  
pp. 93-95 ◽  
Author(s):  
CM Gibb ◽  
PTG Davies ◽  
V Glover ◽  
TJ Steiner ◽  
F Clifford Rose ◽  
...  
Keyword(s):  
Migraine Attack ◽  
Median Time ◽  
Double Blind ◽  
Matching Placebo ◽  
Parallel Group Study ◽  
Parallel Group ◽  
Objective Evidence ◽  
Migraine Episode

Patients with migraine who believed that chocolate could provoke their attacks were challenged with either chocolate or a closely matching placebo. In a double-blind parallel group study, chocolate ingestion was followed by a typical migraine episode in 5 out of 12 patients, while none of the 8 patients challenged with placebo had an attack ( p = 0.051). The median time to the onset of the attack was 22 h. This brief study provides some objective evidence that chocolate is able to provoke a migraine attack in certain patients who believe themselves sensitive to it.

scholarly journals A Thorough QT Study To Evaluate the Effects of Therapeutic and Supratherapeutic Doses of Delafloxacin on Cardiac Repolarization

2015 ◽  
Vol 59 (6) ◽  
pp. 3469-3473 ◽  
Author(s):  
Jeffrey S. Litwin ◽  
Michael S. Benedict ◽  
Michael D. Thorn ◽  
Laura E. Lawrence ◽  
Sue K. Cammarata ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Vital Signs ◽  
Study Drug ◽  
Pharmacokinetic Profile ◽  
Positive Control ◽  
Qtc Interval ◽  
Double Blind ◽  
Assay Sensitivity ◽  
Thorough Qt Study ◽  
Time Point

ABSTRACTA randomized, double-blind, placebo-controlled, 4-period crossover study was conducted in 52 healthy adults to assess the effect of delafloxacin on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using Fridericia's formula (QTcF), was determined predose and at 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 12, 18, and 24 h after dosing with delafloxacin at 300 mg intravenously (i.v.; therapeutic), delafloxacin at 900 mg i.v. (supratherapeutic), moxifloxacin at 400 mg orally (p.o.; positive control), and placebo. The pharmacokinetic profile of delafloxacin was also evaluated. At each time point after delafloxacin administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from the predose baseline in QTcF (ΔΔQTcF) was less than 10 ms (maximum, 3.9 ms at 18 h after dosing), indicating an absence of a clinically meaningful increase in the QTc interval. The lower limit of the 90% CI of ΔΔQTcF for moxifloxacin versus placebo was longer than 5 ms at all 5 time points selected for assay sensitivity analysis, demonstrating that the study was adequately sensitive to assess QTc prolongation. There was no positive relationship between delafloxacin plasma concentrations and ΔΔQTcF. Treatment-emergent adverse events (AEs) were more frequent among subjects receiving a single supratherapeutic dose of 900 mg delafloxacin. There were no deaths, serious AEs, or AEs leading to study discontinuation and no clinically meaningful abnormalities in laboratory values or vital signs observed at any time point after any dose of the study drug.

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