scholarly journals First-in-Human Study of the Safety, Tolerability, Pharmacokinetics and - Preliminary Dynamics of Neuroprotectant 2-Iminobiotin in Healthy Subjects

2020 ◽  
Vol 15 (2) ◽  
pp. 152-163 ◽  
Author(s):  
Ewoud-Jan van Hoogdalem ◽  
Cacha M.P.C.D. Peeters-Scholte ◽  
Paul W.T.J. Leufkens ◽  
Jan Hartstra ◽  
Jan J. van Lier ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Cell Injury ◽  
Human Study ◽  
Volume Of Distribution ◽  
Water Volume ◽  
Cerebral Hypoxia ◽  
Healthy Male ◽  
Dose Escalation Study ◽  
Hypoxia Ischemia ◽  
Male Subjects

Background: 2-iminobiotin (2-IB) is an investigational neuroprotective agent in development for the reduction of brain cell injury after cerebral hypoxia-ischemia. Objective: The present first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK) and -dynamics (PD) of 2-IB in healthy male subjects, intravenously infused with or without Captisol® as a solubilizing agent. Methods: This randomized, double-blind, placebo-controlled, dose-escalation study was executed in 2 groups of 9 healthy male subjects. A single dose of 2-IB 0.6 mg/kg or placebo was infused over periods between 15 min and 4 h, and repeated doses escalating from 0.6 mg/kg to 12 mg/kg, or placebo were infused every 4 h for 6 administrations in total. Results: Single and multiple doses of 2-IB up to 6 doses of 6 mg/kg with and without Captisol® were safe and well-tolerated in healthy male subjects. 2-IB proved to be a high-clearance drug with a volume of distribution slightly exceeding total body water volume, and with linear PK that appeared not to be affected by the presence of Captisol®. Conclusion: Sulfobutyletherbeta-cyclodextrin (SBECD) in Captisol® had a low-clearance profile with a small volume of distribution, with time-independent PK. Preliminary PD characterization of repeated iv dosing of 2-IB in an acute peripheral hypoxic ischemia model in healthy subjects did not reveal any notable effects of 2-IB, noting that this model was not selected to guide efficacy in the currently pursued indication of cerebral hypoxia-ischemia.

Effect of Valine on 5-HT-mediated Prolactin Release in Healthy Volunteers, and on Mood in Remitted Depressed Patients

1995 ◽  
Vol 167 (2) ◽  
pp. 238-242 ◽  
Author(s):  
D. J. Williamson ◽  
S. F. B. McTavish ◽  
S. B. G. Park ◽  
P. J. Cowen
Keyword(s):  
Depressive Symptoms ◽  
Healthy Subjects ◽  
Antidepressant Drug ◽  
Experimental Studies ◽  
Healthy Male ◽  
Prolactin Release ◽  
Depressed Patients ◽  
Symptomatic Relapse ◽  
Male Subjects ◽  
Antidepressant Drug Treatment

BackgroundAnimal experimental studies suggest that the amino acid valine may decrease brain serotonin (5-HT) function by inhibiting the transport of the 5-HT precursor, L-tryptophan, across the blood barrier. The aim of the present study was to assess whether valine could decrease brain 5-HT function in healthy subjects and provoke symptomatic relapse in recently remitted depressed patients taking antidepressant drug treatment.MethodWe studied the effect of valine (30 g) on the prolactin (PRL) response to the 5-HT releasing agent, d-fenfluramine, in healthy male subjects and on the mood of 12 remitted depressed patients taking either selective serotonin re-uptake inhibitors (n = 10) or lithium and amitriptyline (n = 2).ResultsValine significantly lowered the PRL response to d-fenfluramine in healthy subjects. In the remitted depressives, valine caused a mild but detectable lowering of mood on a number of measures but only one patient experienced a significant relapse in mood.ConclusionsValine administration may decrease brain 5-HT neurotransmission in humans. This effect could explain the mild increase in depressive symptoms in patients taking 5-HT-potentiating drugs.

Assessment of quality and clinical similarity (pharmacokinetic and safety) of HD204, a biosimilar of bevacizumab.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21556-e21556
Author(s):  
Jocelyn Hii ◽  
Martin Demarchi ◽  
Pierre Coliat ◽  
Michael J Kim ◽  
Kuo Wei Chan ◽  
...  
Keyword(s):  
Clinical Study ◽  
Cancer Progression ◽  
Neutralizing Antibodies ◽  
Volume Of Distribution ◽  
Prospective Clinical Study ◽  
Healthy Male ◽  
Clinical Phase ◽  
Humanized Monoclonal Antibody ◽  
The Impact ◽  
Male Subjects

e21556 Background: Prestige Biopharma Pte Ltd is developing HD204, a biosimilar candidate of Bevacizumab (Avastin). Bevacizumab has been approved in the treatment of a variety of metastatic tumours. Bevacizumab, a recombinant humanized monoclonal antibody block angiogenesis which is required for cancer progression by preventing binding of soluble vascular endothelial growth factor (VEGF) to VEGF receptors. Due to heterogeneity nature of antibody therapeutic, the impact on quality of HD204 on safety and pharmacokinetic (PK) was reaffirmed through clinical study to establish clinical similarity between HD204 and Avastin. Methods: Quality attributes identified to influence PK and safety established through comprehensive analytical characterization was used to correlate any potential differences (structural or biological) between the two compounds if any, could result in any clinical meaningful differences in safety and PK in the clinical settings. The PK and safety equivalence of HD204 relative to Avastin was demonstrated in a randomized, single-blind, single-dose, three-arm and parallel-group study clinical Phase I (SAMSON). A total of 120 healthy male subjects randomized 1:1:1 were to receive 1 mg/kg intravenous infusion of either HD204, EU- or US-Avastin. Various PK parameters, safety assessments not limiting to adverse events (AE) and measurement of antidrug antibodies (ADA) and neutralizing antibodies (NAb) were evaluated. Results: The pairwise comparisons of Exposure (AUC0-inf and AUC0-last), maximal concentration (Cmax) established equivalence between the 3 arms. All other PK parameters including half-life, clearance and volume of distribution were comparable between HD204 and Avastin treatment groups. Treatment related TEAEs reported for each group were 25.0%, 30.0% and 25.6% respectively and comparable. There were no treatment-emergent SAEs. Furthermore, none of the subjects treated with HD204 was ADA positive. Conclusions: HD204 demonstrated equivalent PK and safety profile to both US-Avastin and EU-Avastin at 1mg/kg administered as a 90-minute IV infusion to healthy male subjects. A prospective clinical study aimed to demonstrate equivalence in terms of efficacy, PK and safety is currently ongoing. Clinical trial information: 2017-005174-19.

Phase 1 Rising Multiple-Dose Study of Talabostat (PT-100) in Healthy Subjects.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4215-4215 ◽  
Author(s):  
Margaret J. Uprichard ◽  
Barry Jones
Keyword(s):  
Adverse Events ◽  
Healthy Subjects ◽  
Significant Inhibition ◽  
Average Increase ◽  
Healthy Male ◽  
Post Dose ◽  
Peripheral Edema ◽  
Dpp Iv ◽  
Limit Of Quantitation ◽  
Male Subjects

Abstract Background: Talabostat (PT-100) is an orally available small molecule that competitively inhibits dipeptidyl peptidases such as DPP-IV/CD26 and fibroblast activation protein (FAP). In vitro, talabostat promotes proliferation of hematopoietic progenitor cells. In vivo it stimulates expansion of progenitors in both white and red cell lineages and causes tumor regression in mouse models. Talabostat has also been shown to accelerate neutrophil recovery in patients and mice receiving myelosuppressive chemotherapy. Its activity appears to be mediated via rapid upregulation of cytokine and chemokine (e.g., G-CSF, IL-6, IL-8) production. Methods: This randomized, placebo-controlled, sequential, dose-escalation study was conducted to evaluate the pharmacodynamics and safety of talabostat in healthy male subjects. 48 healthy male subjects aged 19 to 44 years were randomized to receive daily doses of either 25-, 100-, 300-, 600-, 1200-, 1800μg talabostat or placebo for 7 days. Subjects were randomized in cohorts of 8 subjects each in a 6:2 (talabostat: placebo) scheme. Pharmacodynamics were assessed by measurement of plasma DPP-IV activity, plasma G-CSF, IL-6 and IL-11, and white blood cell (WBC), and absolute neutrophil counts (ANC) at specified timepoints intervals during the study. Clinical examinations, laboratories, vitals, ECG, and adverse events (AEs) were evaluated at specified intervals. Results: At 30 minutes post-dose, talabostat doses ≥ 100μg showed a dose-related, sustained, significant inhibition of DPP-IV activity to 75% to 95% of baseline (p<0.001) in healthy subjects. On Day 1, there was a significant increase in IL-6 at 6 and 12 hours post-dose across all dose cohorts (p<0.01). At 6 and 12 hours, respectively, an average increase in IL-6 of 1426% and 2130% relative to baseline was observed (p<0.05). There was a dose-related increase in G-CSF, with significant increases at doses ≥600μg noted pre-dose on Day 4 (p<0.05). Across all groups on Day 1, an average increase in G-CSF of 132% was noted at 6 hours. Only modest changes in WBC and ANC were noted in these healthy subjects. IL-11 remained unchanged or below the limit of quantitation. The most frequent AEs across all cohorts were (talabostat vs placebo): headache 19/36 (53%) vs 4/12 (33%), myalgia 9/36 (25%) vs 1/12 (8%), nausea 6/36 (17%) vs 0, vomiting 5/36 (14%) vs 1/12 (8%), peripheral edema 5/36 (14%) vs 0, rigors 5/36 (14%) vs 0, sore throat 4/36 (11%) vs 1 (8%)., and arthralgia 4/36 (11%) vs 0. Peripheral edema, myalgia, arthralgia, and rigors were dose-related with all but one event of peripheral edema occurring at talabostat single doses ≥1200μg. There were no serious AEs. The talabostat 1800μg dose cohort was terminated after 2 doses due to adverse events of edema, and talabostat 1200μg was considered the maximum tolerated dose. Conclusion: Talabostat doses ≥100μg showed significant inhibition of DPP-IV activity. Significant dose-related increases in IL-6 and G-CSF were observed. ANC and WBC counts did not change significantly in healthy subjects over the 7-day study. Multiple doses of talabostat were well-tolerated. These results support conducting additional clinical studies in patients to further evaluate the hematopoietic effects of talabostat.

scholarly journals Safety, tolerability and pharmacokinetic characterisation of DACRA KBP-042 in healthy male subjects

2021 ◽  
Author(s):  
Kim Henriksen ◽  
Karen Broekhuizen ◽  
Wadim de Boon ◽  
Morten Karsdal ◽  
Asger Bihlet ◽  
...  
Keyword(s):  
Human Study ◽  
Pharmacokinetic Profile ◽  
Healthy Male ◽  
Double Blind ◽  
Linear Pharmacokinetic ◽  
Dose Study ◽  
Dose Levels ◽  
Dose Dependent ◽  
Male Subjects ◽  
Single Ascending Dose Study

There is a need for anti-diabetic agents successfully targeting insulin sensitivity and treating obesity control at the same time. The aim of this first-in-human study was 1) to evaluate safety and tolerability; 2) to evaluate pharmacokinetics and 3) to assess indications of receptor engagement of single ascending doses of KBP-042, a Dual Amylin and Calcitonin Receptor Agonists (DACRA) that has shown promising preclinical data, with superior activity in terms of typical amylin-induced responses including reduction of food intake, weight loss and gluco-regulatory capacities. A randomised double-blind placebo-controlled single ascending dose study was performed with six dose levels of KBP-042 (5, 7.5, 10, 20, 20 evening and 40µg) in healthy male adults. KBP-042 or placebo was administered as a single dose after an overnight fast, followed by a standardized lunch after four hours. KBP-042 was associated with dose-dependent complaints of nausea and vomiting, with a lack of tolerability at doses of 20µg and above. Doses of 5 to 40 μg KBP-042 were behaved according to a linear pharmacokinetic profile. Indications of target receptor engagement were observed at the level of glucose control and lowering of bone resorption, compared to placebo. The results of this study showed that doses up to 40 μg were safe, although tolerability was not present at the highest doses. The study confirmed target receptor engagement at the studied doses.

scholarly journals Co-Administration of Vonoprazan, Not Tegoprazan, Affects the Pharmacokinetics of Atorvastatin in Healthy Male Subjects

2021 ◽  
Vol 12 ◽  
Author(s):  
Sejung Hwang ◽  
Jae-Wook Ko ◽  
Heechan Lee ◽  
Seokuee Kim ◽  
Bongtae Kim ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Clinical Laboratory ◽  
Systemic Exposure ◽  
Cytochrome P450 3A4 ◽  
Healthy Male ◽  
Open Label ◽  
Once Daily ◽  
New Class ◽  
Inhibitory Activities ◽  
Male Subjects

Potassium-competitive acid blocker is a new class of drugs inhibiting gastric acid. It is controversial that vonoprazan showed the inhibitory activities of cytochrome P450 3A4. This study aimed to evaluate the pharmacokinetics (PK) of atorvastatin and safety when atorvastatin was administered alone and co-administered with vonoprazan or tegoprazan. An open-label, multiple-dose, 3-intervention, 4-sequence, 4-period, partial replicate crossover study was conducted, and three interventions were; one is orally administered atorvastatin 40 mg alone once daily for 7 days, another is atorvastatin co-administered with vonoprazan 20 mg, and the other is atorvastatin co-administered with tegoprazan 50 mg. PK blood samples were collected up to 24 h after the last dose, and PK parameters for atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were estimated by a non-compartmental method. Safety was evaluated, including adverse events and clinical laboratory tests. A total of 28 subjects completed the study. When atorvastatin was co-administered with vonoprazan, the systemic exposures of atorvastatin and atorvastatin lactone significantly increased, and the metabolic ratio of 2-hydroxyatorvastatin significantly decreased. Hypergastrinemia only occurred when atorvastatin was co-administered with vonoprazan. However, the plasma concentration profiles of atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were similar when atorvastatin was administered alone or co-administered with tegoprazan. In conclusion, after multiple doses of atorvastatin co-administered with vonoprazan in healthy subjects, the systemic exposure of atorvastatin and the incidence of hypergastrinemia increased. With tegoprazan, however, those interactions were not observed.

scholarly journals Pharmacokinetics and Safety of Intravenous Murepavadin Infusion in Healthy Adult Subjects Administered Single and Multiple Ascending Doses

2018 ◽  
Vol 62 (4) ◽  
pp. e02355-17 ◽  
Author(s):  
Achim Wach ◽  
Klaus Dembowsky ◽  
Glenn E. Dale
Keyword(s):  
Bacterial Pneumonia ◽  
Protein Targeting ◽  
Geometric Mean ◽  
Volume Of Distribution ◽  
Healthy Male ◽  
Double Blind ◽  
Content Type ◽  
Dosing Regimens ◽  
Hospital Acquired ◽  
Male Subjects

ABSTRACT Murepavadin is the first in class of the outer membrane protein-targeting antibiotics (OMPTA) and a pathogen-specific peptidomimetic antibacterial with a novel, nonlytic mechanism of action targeting Pseudomonas aeruginosa. Murepavadin is being developed for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The pharmacokinetics (PK) and safety of single and multiple doses of murepavadin were investigated in healthy male subjects. Part A of the study was a double-blind, randomized, placebo-controlled, single-ascending-dose investigation in 10 sequential cohorts where each cohort comprised 6 healthy male subjects; 4 subjects were randomized to murepavadin, and 2 subjects were randomized to placebo. Part B was a double-blind, randomized, placebo-controlled, multiple-ascending-dose investigation in 3 sequential cohorts. After a single dose of murepavadin, the geometric mean half-life (2.52 to 5.30 h), the total clearance (80.1 to 114 ml/h/kg), and the volume of distribution (415 to 724 ml/kg) were consistent across dose levels. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Murepavadin was well tolerated, adverse events were transient and generally mild, and no dose-limiting toxicity was identified.

scholarly journals Tazemetostat– A Drug review

2021 ◽  
Vol 12 (1) ◽  
pp. 894-898
Author(s):  
Anju K Paul ◽  
Hridya Jayamohanan ◽  
Keechilat Pavithran
Keyword(s):  
Phase 1 ◽  
Epithelioid Sarcoma ◽  
Locally Advanced ◽  
Human Study ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Open Label ◽  
Dose Escalation Study ◽  
Teenagers And Young Adults ◽  
Proteins Metabolism

Epithelioid sarcoma affects three in 10 million people, usually teenagers and young adults. Tumours grow under the skin of the extremities or they can affect the trunk, head, or neck. It grows slowly, but can infiltrate surrounding tissues, later on, it frequently metastasis to lymph nodes. For advanced case, doxorubicin-based chemotherapy regimen is recommended. In January 2020, FDA approved the first-in-class, small molecule enhancer of zeste homolog 2 (EZH2) inhibitor, tazemetostat (Tazverik) to treat adults and paediatric patients aged 16 years and older with locally advanced or metastatic epithelioid sarcoma not suitable for complete resection. The recommended dosage is 800 mg twice daily until disease progression or unacceptable toxicity.  The first-in-human study of tazemetostat was a phase 1 open-label multi-centered dose-escalation study. Tazemetostat is having an oral bioavailability of approximately 33%. Apparent volume of distribution at steady-state (Vss/F) is 1230 L (46%) with 88% bound to human plasma proteins. Metabolism takes place via CYP3A. 15% and 79% of radioactivity is excreted through urine and feces respectively. ≥20% of the adverse reactions and above was fatigue, pain, constipation, nausea, anorexia and vomiting. This article summarizes the history, chemistry, physical properties, mechanism of action, indications, and drug–drug interactions of tazemetostat and we also discuss briefly the results of various clinical trials.

Absorption, Metabolism and Excretion of GBT440, a Novel Hemoglobin S (HbS) Polymerization Inhibitor for the Treatment of Sickle Cell Disease (SCD), in Healthy Male Subjects

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2487-2487 ◽  
Author(s):  
Peter Rademacher ◽  
Athiwat Hutchaleelaha ◽  
Carla Washington ◽  
Josh Lehrer ◽  
Eleanor Ramos
Keyword(s):  
Steady State ◽  
Adverse Events ◽  
Phase Ii ◽  
Whole Blood ◽  
Healthy Subjects ◽  
Total Radioactivity ◽  
Healthy Male ◽  
Employment Equity ◽  
Equity Ownership ◽  
Male Subjects

Abstract Background: SCD is caused by a point mutation in the β-globin gene producing hemoglobin S (HbS) that polymerizes upon deoxygenation with subsequent formation of sickled red blood cells (RBCs). GBT440 is a novel, orally bioavailable small molecule that inhibits HbS polymerization by increasing the affinity of O2 to hemoglobin (Hb). Methods: The pharmacokinetics, mass balance, and metabolite profile of [14C]-GBT440 were evaluated in 7 healthy male subjects in this open-label study. In order to evaluate the disposition kinetics of GBT440 at steady-state concentrations, a loading/maintenance dose schema was employed. Each subject received an oral loading dose of 2000 mg GBT440 on Day 1 followed by oral maintenance doses of 400 mg once daily on Day 2 to Day 4. Once the target steady-state was achieved, a single [14C]-GBT440 400 mg dose (approximately 100 μCi) was administered orally on Day 5. Blood, plasma, urine and feces were collected serially up to 26 days postdose. Results: There were no serious adverse events or discontinuations due to adverse events for any of the healthy subjects participating in this study. GBT440 reached Cmax in plasma and whole blood with median time to maximum concentration (Tmax) values of 2.00 hours in plasma and whole blood and in 6.00 hours in RBCs. After reaching Cmax, GBT440 concentrations appeared to decline in a monophasic manner, with the terminal elimination phase for GBT440 in plasma, whole blood, and RBCs appearing to decline in a parallel manner, with geometric mean T1/2 values of 98.0 hours in plasma, 66.3 hours in whole blood, and 65.8 hours in RBCs. This study achieved 98.0% average recovery of total radioactivity in urine and feces over the course of the study. Most of the administered radioactivity (88.2%) was recovered by 144 hours postdose (Day 7). GBT440 was eliminated primarily in feces (62.6% of the total radioactive dose) with urinary excretion accounting for 35.4% of the total radioactive dose. In whole blood, the majority of the total radioactivity (TRA) was unchanged GBT440 (97.5%) while three metabolites accounted for the remaining TRA (2.5%). In plasma, unchanged GBT440 was the prominent circulating radioactive component, accounting for 48.8% of the TRA. Eleven circulating metabolites with corresponding radioactive peaks were identified. There was one major Phase II metabolite (GBT440 O-dealkylation-sulfation), accounting for 16.8% of the TRA. Two potential active metabolites were identified but only accounted for 2.5% of the dose in whole blood. GBT440 was eliminated predominately in feces. Unchanged GBT440 was the most abundant radioactive component, accounting for 33.3% of the administered dose. Four metabolites were identified, each accounting for 5.62%, 2.66%, 1.66% and less than 6% of the dose in the 0-216-hr human feces. Urine was a relatively minor excretion route for GBT440 in humans. An average of 34.3% of the dose was recovered in the urine samples. Unchanged GBT440 accounted for 0.08% of the administered dose and the rest were metabolites. GBT440 glucuronidation and reduction-glucuronidation products, which are Phase II metabolites, were the most abundant metabolites in urine, accounting for a combined 9.22% of dose. Because GBT440 does not undergo renal elimination, patients with renal disorders should not experience changes in pharmacokinetics of GBT440. Conclusions: Although GBT440 has high specific binding to hemoglobin, it was completely excreted from the body with a half-life of approximately three days in healthy subjects. Since the half-life of GBT440 was much shorter than RBC lifespan (~ 120 days), this supports the hypothesis that the binding between GBT440 to hemoglobin is a reversible process. Following an oral administration, approximately one-third of the dose was excreted as the unchanged drug into the feces (unabsorbed and/or via biliary excretion). Two-thirds of the administered dose was metabolized and excreted into urine and feces. The major metabolic pathway was via Phase I and Phase II metabolism. Because GBT440 was not excreted directly into the urine, the pharmacokinetics are unlikely to be affected in patients with renal disorders. Disclosures Rademacher: Global Blood Therapeutics: Employment, Equity Ownership. Hutchaleelaha:Global Blood Therapeutics: Employment, Equity Ownership. Washington:Global Blood Therapeutics: Employment, Equity Ownership. Lehrer:Global Blood Therapeutics: Employment, Equity Ownership. Ramos:Global Blood Therapeutics: Employment, Equity Ownership.

Sign in / Sign up

Export Citation Format

Share Document