scholarly journals Safety, Tolerability and Pharmacokinetics of the Serotonin 5-HT6 Receptor Antagonist, HEC30654, in Healthy Chinese Subjects

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaojiao Li ◽  
Lei Gao ◽  
Jingrui Liu ◽  
Hong Zhang ◽  
Hong Chen ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Clinical Laboratory ◽  
Therapeutic Option ◽  
Dose Range ◽  
Stopping Rules ◽  
Pharmacokinetic Analysis ◽  
Controlled Clinical Trial ◽  
Double Blind ◽  
Healthy Chinese ◽  
Chinese Subjects

Background and Objective: HEC30654 is a selective 5-HT6 receptor antagonist that was safe and well-tolerated in preclinical models of Alzheimer’s disease. The objective of this double-blind, randomized, placebo-controlled clinical trial was to evaluate the safety, tolerability, and pharmacokinetic profile of HEC30654 after single ascending doses in healthy Chinese subjects.Methods: Healthy volunteers received a single oral dose of HEC30654 (5, 10, 15, 30, 60 mg). Safety and tolerability assessments included adverse events, vital signs, and findings on electrocardiograms, electroencephalograms, physical examination, and clinical laboratory tests. Pharmacokinetic analysis of HEC30654 and its major metabolite HEC93263 were conducted in blood, urine, and fecal samples.Results: Single doses of HEC30654 up to 30 mg were generally safe and well tolerated, but dose escalation was terminated early as the 60 mg HEC30654 treatment group met the pre-defined stopping rules specified in the protocol. Median tmax of HEC30654 was 6 h (range, 4–12 h), t1/2 of 10–60 mg HEC30654 ranged from 52.1 to 63.8 h. Exposure to HEC30654 across the dose range explored in this study increased more than in proportion to dose. Metabolism of HEC30654 to HEC93263 was slow (<10%), and HEC30654 was mainly eliminated unchanged through feces.Conclusion: Single doses of HEC30654 up to 30 mg were generally safe and well tolerated. Based on preclinical efficacy in various models of cognition, HEC30654 may represent a therapeutic option for symptomatic treatment of cognitive disorders.

scholarly journals First-in-human, phase I single-ascending-dose study of the safety, pharmacokinetics, and relative bioavailability of selatinib, a dual EGFR-ErbB2 inhibitor in healthy subjects

2020 ◽  
Vol 38 (6) ◽  
pp. 1826-1835
Author(s):  
Meng-na Wang ◽  
Yun Kuang ◽  
Li-ying Gong ◽  
Ye Hua ◽  
Qi Pei ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Dose Range ◽  
Placebo Control ◽  
Peak Time ◽  
Open Label ◽  
Double Blind ◽  
Healthy Chinese ◽  
Chinese Subjects

Summary We assessed the pharmacokinetics and safety of a single oral administration of selatinib to healthy Chinese subjects and evaluated the potential bioavailability advantage of selatinib relative to lapatinib. Healthy subjects aged 18–40 years were enrolled in this two-part study: Part 1, a single ascending dose (50–500 mg), randomized, double-blind, placebo-control study with 64 subjects; and Part 2, an open-label, positive control, randomized, three-treatment, three-period, three-sequence crossover design study, with 6 subjects administered a single 500-mg dose of selatinib tablets (A), selatinib suspension (B), or lapatinib tablets C) per cycle. In part 1, selatinib was well-tolerated up to the planned maximum dose of 500 mg; thus the maximum tolerated dose was not attained. Twenty-two adverse events were observed in 19 (36.5%) of the 52 subjects administered the test drug. The most common drug-related adverse event was diarrhea. The mean selatinib peak plasma concentration was 69.4–494 ng/mL, which was achieved in a median peak time of 3.5–4.5 h, with a mean elimination half-life between 13.8 and 15.8 h. In Part 2, A and B showed similar bioavailability. Plasma exposure to the active drug (selatinib plus the metabolite, lapatinib) after A intake was more than two-fold higher than that of the same dose of C. In the dose range of 50–500 mg, selatinib was safe and well-tolerated by healthy Chinese subjects, and it conformed with linear pharmacokinetics. Active exposure to selatinib was much greater than that to lapatinib, supporting its development as an adjuvant for anticancer treatment.

Toreforant, A Histamine H4 Receptor Antagonist, in Patients with Active Rheumatoid Arthritis Despite Methotrexate Therapy: Results of 2 Phase II Studies

2016 ◽  
Vol 43 (9) ◽  
pp. 1637-1642 ◽  
Author(s):  
Robin L. Thurmond ◽  
Andrew Greenspan ◽  
Waldemar Radziszewski ◽  
Xie L. Xu ◽  
Ye Miao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Receptor Antagonist ◽  
Active Rheumatoid Arthritis ◽  
Dose Range ◽  
Joint Disease ◽  
Double Blind ◽  
Once Daily ◽  
Double Blind Placebo ◽  
Range Finding ◽  
Phase Ii Studies

Objective.To assess toreforant (selective histamine H4 receptor antagonist) in active rheumatoid arthritis (RA).Methods.In a phase IIa, double-blind, placebo-controlled test, 86 patients were randomized (2:1) to once-daily toreforant 100 mg or placebo for 12 weeks. In phase IIb, double-blind, placebo-controlled, dose-range–finding evaluations, 272 patients were randomized (1:1:1:1) to once-daily placebo or toreforant 3/10/30 mg. Primary efficacy endpoints for both studies were Week 12 changes in 28-joint Disease Activity Score–C-reactive protein (DAS28-CRP).Results.Phase IIa testing was terminated prematurely (patient fatality; secondary hemophagocytic lymphohistiocytosis). Posthoc analyses indicated toreforant 100 mg/day reduced RA signs/symptoms through Week 12. Phase IIb testing, however, showed no significant Week 12 improvement in DAS28-CRP with toreforant.Conclusion.Toreforant was not effective in phase IIb testing.

scholarly journals Safety, tolerability, pharmacokinetics and immunogenicity of a monoclonal antibody (SCTA01) targeting SARS-CoV-2 in healthy adults: A randomized, double-blind, placebo-controlled, phase I study

2021 ◽  
Author(s):  
Yinjuan Li ◽  
Lu Qi ◽  
Haihong Bai ◽  
Chunyun Sun ◽  
Shuping Xu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Clinical Laboratory ◽  
Therapeutic Potential ◽  
Dose Range ◽  
Healthy Adults ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Linear Dose ◽  
Dose Proportional

SCTA01 is a novel monoclonal antibody with promising prophylactic and therapeutic potential for COVID-19. This study aimed to evaluate the safety, tolerability, pharmacokinetics (PK) and immunogenicity of SCTA01 in healthy adults. This was a randomized, double-blind, placebo-controlled, dose-escalation phase I clinical trial. Healthy adults were randomly assigned into the following four cohorts, Cohort 1 (n=5, 3:2), Cohort 2 (n=8, 6:2), Cohort 3 and Cohort 4 (both n=10, 8:2), to receive SCTA01 (5, 15, 30 and 50 mg/kg, respectively) versus placebo. All participants were followed up for clinical, laboratory, PK and immunogenicity assessments for 84 days. The primary outcomes were the dose-limiting toxicity (DLT) and maximal tolerable dose (MTD), and the secondary outcomes included PK parameters, immunogenicity and adverse events (AE). Of the 33 participants, 18 experienced treatment-related AEs; the frequency was 52.0% (13/25) in participants receiving SCTA01 and 62.5% (5/8) in those receiving placebo. All AEs were mild. There was no serious AE or death. No DLT was reported, and MTD of SCTA01 was not reached. SCTA01 with a dose range 5-50mg/kg had nearly linear dose-proportional increases in C max and AUC parameters. An anti-drug antibody response was detected in four (16.0%) participants receiving SCTA01, with low titers, between the baseline and day 28, but all became negative later. In conclusion, SCTA01 up to 50mg/kg was safe and well-tolerated in healthy participants. Its PK parameters were nearly linear dose-proportional.

Ginger for chemotherapy-related nausea in cancer patients: A URCC CCOP randomized, double-blind, placebo-controlled clinical trial of 644 cancer patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9511-9511 ◽  
Author(s):  
J. L. Ryan ◽  
C. Heckler ◽  
S. R. Dakhil ◽  
J. Kirshner ◽  
P. J. Flynn ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Receptor Antagonist ◽  
Cancer Patients ◽  
Rating Scale ◽  
Zingiber Officinale ◽  
Time Of Day ◽  
Nausea And Vomiting ◽  
Analysis Of Covariance ◽  
Controlled Clinical Trial ◽  
Double Blind

9511 Background: Despite the widespread use of antiemetics, post-chemotherapy nausea and vomiting continue to be reported by up to 70% of patients receiving chemotherapy. Ginger (Zingiber Officinale), an ancient spice, is used by practitioners worldwide to treat nausea and vomiting. We conducted a multi-site, phase II/III randomized, placebo-controlled, double-blind clinical trial to assess the efficacy of ginger for chemotherapy-related nausea in cancer patients at the University of Rochester-affiliated Community Clinical Oncology Program (CCOP) member sites. Methods: Cancer patients who experienced nausea following any chemotherapy cycle and were scheduled to receive at least three additional cycles were eligible. Patients were randomized into four arms: 1) placebo, 2) 0.5g ginger, 3) 1.0g ginger, or 4) 1.5g ginger. All patients received 5-HT3 receptor antagonist antiemetics on Day 1 of all cycles and took three 250mg capsules of ginger or placebo twice daily for six days starting three days before the first day of the next two cycles. Patients reported the severity of nausea during the morning, afternoon, evening, and night on a 7-point semantic rating scale (‘1' = ‘Not at all Nauseated' and ‘7' = “Extremely Nauseated”) for Days 1–4 of each cycle. The goal was to determine if ginger was more effective than placebo in controlling chemotherapy-related nausea in participants given a 5-HT3 receptor antagonist antiemetic. Results: A total of 644 patients were accrued (90% female, mean age = 53). Breast (66%), alimentary (6.5%), and lung (6.1%) cancers were the most common cancer types. Analysis of covariance (ANCOVA) examined change in nausea in the four study arms on Day 1 of cycles 2 and 3. All doses of ginger significantly reduced nausea (p=0.003). The largest reduction in nausea occurred with 0.5g and 1.0g of ginger. Also, time of day had a significant effect on nausea (p<0.001) with a linear decrease over 24 hours for patients using ginger. Conclusions: Ginger supplementation at daily dose of 0.5g-1.0g significantly aids in reduction of nausea during the first day of chemotherapy. Supported by NCI PHS grants 1R25CA10618 and U10CA37420. No significant financial relationships to disclose.

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