scholarly journals A First-in-Human Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Oral Dose Study of Novel Antimalarial Spiroindolone KAE609 (Cipargamin) To Assess Its Safety, Tolerability, and Pharmacokinetics in Healthy Adult Volunteers

2014 ◽  
Vol 58 (10) ◽  
pp. 6209-6214 ◽  
Author(s):  
F. Joel Leong ◽  
Ruobing Li ◽  
Jay Prakash Jain ◽  
Gilbert Lefèvre ◽  
Baldur Magnusson ◽  
...  
Keyword(s):  
Adverse Events ◽  
Oral Dose ◽  
Dose Range ◽  
Systemic Exposure ◽  
Moderate Intensity ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Time Zero ◽  
Dose Study ◽  
Dose Proportional

ABSTRACTThis first-in-human randomized, double-blind, placebo-controlled, ascending-single and -multiple oral dose study was designed to evaluate the safety, tolerability, and pharmacokinetics in healthy volunteers of KAE609 (cipargamin; formerly NITD609), a spiroindolone now in trials for malaria treatment. It was studied in single-dose cohorts (1 to 300 mg, including one 30-mg food effect cohort) with 4 to 10 subjects in each cohort and in multiple-dose cohorts (10 to 150 mg once daily for 3 days) with 8 subjects in each cohort. The follow-up period was 6 to 8 days post-last dose. Safety and pharmacokinetics were assessed at scheduled time points during the study. Systemic exposure in terms of the area under the concentration-time curve from 0 h extrapolated to infinity (AUC0–∞) increased in a dose-proportional manner over the dose range of 1 to 300 mg. The AUC from time zero to the time of the last quantifiable concentration (AUClast) and the maximum concentration of drug in plasma (Cmax) also increased in an approximately dose-proportional manner. When administered daily for 3 days, the accumulation ratio on day 3 (the AUC from time zero to 24 h postdosing [AUC0–24] on day 3/AUC0–24on day 1) was in the range of 1.5 to 2 in the studied dose range (10 to 150 mg) and was consistent with an elimination half-life of around 24 h. Urine analysis for unchanged KAE609 revealed negligible amounts (≤0.01%) were excreted renally. The high fat food intake did not affect the extent of KAE609 absorption (AUC); however, theCmaxwas reduced by around 27%. KAE609 was tolerated in this study, with transient gastrointestinal and genitourinary adverse events of mild to moderate intensity (semen discoloration, diarrhea, nausea and abdominal discomfort, dizziness and headache, catheter site hematoma). Gastrointestinal and genitourinary adverse events increased with rising doses.

scholarly journals A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza B Virus Monoclonal Antibody, MHAB5553A, in Healthy Volunteers

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Jeremy J. Lim ◽  
Michael A. Derby ◽  
Yaping Zhang ◽  
Rong Deng ◽  
Richard Larouche ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase 1 ◽  
Influenza B Virus ◽  
Influenza B ◽  
Double Blind ◽  
Double Blind Placebo ◽  
B Virus ◽  
Dose Study ◽  
Single Ascending Dose Study ◽  
Dose Proportional

ABSTRACT Influenza B can cause significant morbidity and mortality. MHAB5553A, a human monoclonal immunoglobulin G1 (IgG1) antibody that binds to a highly conserved region of the hemagglutinin protein of influenza B virus, is being examined as a novel therapeutic for the treatment of influenza B patients with severe disease. This phase 1, randomized, double-blind, placebo-controlled, single-ascending-dose study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of MHAB5553A. Twenty-six healthy male and female volunteers of >18 years of age were randomized into five cohorts receiving a single intravenous (i.v.) dose of 120, 1,200, 3,600, 8,400, or 10,800 mg MHAB5553A or placebo (four active:one placebo, except for the 120-mg cohort [4:2]). Subjects were followed for 120 days after dosing. No subject discontinued the study, no dose-limiting adverse events or serious adverse events were reported, and a maximum tolerated dose (MTD) was not defined. The most commonly reported adverse events were cold symptoms and headache; most were mild and occurred at a similar rate across all cohorts. MHAB5553A showed no relevant time- or dose-related changes in laboratory values or vital signs compared to the placebo. The observed serum PK was linear and generally dose proportional, and the observed nasal PK was nonlinear and generally non-dose proportional. MHAB5553A is generally well tolerated in healthy volunteers up to at least a single i.v. dose of 10,800 mg and demonstrated linear serum PK consistent with those of a human IgG1 antibody lacking known endogenous targets in humans. (This study has been registered at ClinicalTrials.gov under registration no. NCT02528903.)

scholarly journals Pharmacokinetics of Ferroquine, a Novel 4-Aminoquinoline, in Asymptomatic Carriers of Plasmodium falciparum Infections

2012 ◽  
Vol 56 (6) ◽  
pp. 3165-3173 ◽  
Author(s):  
Christian Supan ◽  
Ghyslain Mombo-Ngoma ◽  
Matthias P. Dal-Bianco ◽  
Carmen L. Ospina Salazar ◽  
Saadou Issifou ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Oral Dose ◽  
Dose Range ◽  
Young Male ◽  
Double Blind ◽  
Time Curve ◽  
Blood Concentrations ◽  
Content Type ◽  
Dose Linearity ◽  
Dose Study

ABSTRACTFerroquine (SSR97193), a ferrocene-quinoline conjugate, is a promising novel antimalarial currently undergoing clinical evaluation. This study characterizes its pharmacokinetic properties. Young male African volunteers with asymptomaticPlasmodium falciparuminfection were administered a single oral dose (n= 40) or a repeated oral dose (n= 26) given over 3 days of ferroquine in two dose-escalation, double-blind, randomized, placebo-controlled clinical trials. In addition, a food interaction study was performed in a subsample of participants (n= 16). The studies were carried out in Lambaréné, Gabon. After single-dose administration of ferroquine, dose linearity was demonstrated in a dose range of 400 to 1,200 mg for maximum mean blood concentrations ([Cmax] 82 to 270 ng/ml) and in a dose range of 400 to 1,600 mg for overall exposure to ferroquine (area under the concentration-time curve [AUC], 13,100 to 49,200 ng · h/ml). Overall mean estimate for blood apparent terminal half-life of ferroquine was 16 days and 31 days for its active and major metabolite desmethylferroquine (SSR97213). In the 3-day repeated-dose study,Cmaxand overall cumulated exposure to ferroquine (AUCcum) increased in proportion with the dose from day 1 to day 3 between 400 and 800 mg. No major food effect on ferroquine pharmacokinetics was observed after single administration of 100 mg of ferroquine except for a slight delay of time to maximum blood concentration (tmax) by approximately 3 h. The pharmacokinetics of ferroquine and its active main metabolite are characterized by sustained levels in blood, and the properties of ferroquine as a partner drug in antimalarial combination therapy should be evaluated.

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.

scholarly journals A First-in-Human Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Oral Dose Study of Novel Imidazolopiperazine KAF156 To Assess Its Safety, Tolerability, and Pharmacokinetics in Healthy Adult Volunteers

2014 ◽  
Vol 58 (11) ◽  
pp. 6437-6443 ◽  
Author(s):  
F. Joel Leong ◽  
Rong Zhao ◽  
Shuqi Zeng ◽  
Baldur Magnusson ◽  
Thierry T. Diagana ◽  
...  
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Oral Dose ◽  
Maximum Concentration ◽  
Food Effect ◽  
Renal Elimination ◽  
Pharmacokinetic Data ◽  
Upper Respiratory Tract ◽  
Double Blind ◽  
Dose Study

ABSTRACTKAF156 belongs to a new class of antimalarial, the imidazolopiperazines, and is currently in clinical development for the treatment of uncomplicated malaria. This first-in-human, single- and multiple-ascending-dose study in 70 healthy male volunteers determined the maximum oral dose of KAF156 tolerated by healthy adults and derived pharmacokinetic data (including preliminary food effect) to enable dose calculations for malaria patients. KAF156 was studied in single-dose cohorts (10 to 1,200 mg, including one 400-mg food effect cohort (4 to 10 subjects/cohort), and in multiple-dose cohorts (60 to 600 mg once daily for 3 days; 8 subjects/cohort). The follow-up period was 6 to 14 days after the last dose. KAF156 was tolerated, with self-limited mild to moderate gastrointestinal and neurological adverse events. In treated subjects after single doses, headache (n= 4; 11.1%), diarrhea (n= 3; 8.3%), dizziness (n= 3; 8.3%), and abdominal pain (n= 2; 5.6%) were the most common adverse events. Headache (n= 4; 16.7%), nausea (n= 3; 12.5%), upper respiratory tract infection (n= 3; 12.5%), and dizziness (n= 2; 8.3%) were the most common adverse events following multiple doses. KAF156 time to maximum concentration (Tmax) was between 1.0 and 6.0 h. Both the area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased more than dose-proportionally in both single- and multiple-ascending-dose cohorts (terminal half-life, 42.5 to 70.7 h). There was no significant accumulation over 3-day repeated administration. The extent of absorption was not significantly affected by food at a single dose of 400 mg, while meanCmaxdecreased from 778 ng/ml to 627 ng/ml andTmaxwas delayed from a median of 3.0 h under fasting conditions to 6.0 h under fed conditions. Renal elimination is a minor route.

scholarly journals Pharmacokinetics and Safety of an Antirhinoviral Agent, Ruprintrivir, in Healthy Volunteers

2002 ◽  
Vol 46 (2) ◽  
pp. 392-397 ◽  
Author(s):  
Poe-Hirr Hsyu ◽  
Yazdi K. Pithavala ◽  
Merril Gersten ◽  
Carol A. Penning ◽  
Bradley M. Kerr
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Systemic Exposure ◽  
Upper Respiratory Tract ◽  
Irreversible Inhibitor ◽  
Double Blind ◽  
Measured Concentration ◽  
Single Dose Study ◽  
Multiple Doses ◽  
Dose Study

ABSTRACT A single-dose study and a multiple-dose study of the safety and pharmacokinetics of ruprintrivir, a new selective irreversible inhibitor of human rhinovirus 3C protease, were conducted with healthy adult volunteers. Both studies were double-blind, randomized, placebo-controlled, parallel-group investigations of ruprintrivir administered intranasally at two dose levels. The parent drug and its acid metabolite, AG7185, were measured in plasma samples and nasal washings, and the safety of the treatments was monitored. Intranasal ruprintrivir, administered as single doses of 4 and 8 mg or every 3 h, six times per day, for 7 days was safe and well tolerated. Adverse events were mild, short-lived, and confined to the upper respiratory tract (i.e., nose and throat, taste and smell perceptions). Adverse events were similar after placebo and after single or multiple doses of active drug. Systemic exposure to ruprintrivir was rarely detectable with the highest measured concentration of ≤0.52 ng/ml; the assay had a lower limit of quantification of 0.2 ng/ml. Systemic exposure to the metabolite was also low, with a highest measured concentration of 3.25 ng/ml. Concentrations of AG7185 observed during multiple dosing were higher than those observed after the first dose but were no more than predicted from the single-dose study. Substantial amounts of ruprintrivir were observed intranasally for at least 9 h after multiple doses of ruprintrivir.

ACE-536 Increases Hemoglobin in Healthy Postmenopausal Women: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3194-3194
Author(s):  
Kenneth M Attie ◽  
Ingrid E Boyd ◽  
Dawn M Wilson ◽  
Mark J Allison ◽  
Matthew L Sherman
Keyword(s):  
Blood Pressure ◽  
Adverse Events ◽  
Phase 1 ◽  
Vital Signs ◽  
Ineffective Erythropoiesis ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Dose Study ◽  
The Mean ◽  
Dose Levels

Abstract Abstract 3194 Background: ACE-536 is a recombinant fusion protein consisting of a modified form of the extracellular domain of the human activin receptor type IIB (ActRIIB) linked to the human IgG1 Fc domain. ACE-536 acts as a ligand trap for members of the TGF-β superfamily involved in erythropoiesis. ACE-536 promotes late-stage erythrocyte precursor cell differentiation by inhibiting specific TGF-β family ligands. Studies of ACE-536 in wild type animals across several species demonstrated an erythroid response that was rapid in onset, robust, and sustained. ACE-536 was also shown to significantly improve hematologic parameters and correct ineffective erythropoiesis in mouse models of myelodysplastic syndromes (MDS) and β-thalassemia. This study is the first human clinical trial of ACE-536. Methods: This was a single-center, randomized, double-blind, placebo-controlled, multiple ascending dose study to evaluate the safety, tolerability, PK, and PD effects of ACE-536 in healthy, postmenopausal women. Screening and baseline hemoglobin values were to be between 11.0 and 14.5 g/dL. Sequential cohorts of 8 subjects each were randomized to receive either ACE-536 (n=6) or placebo (n=2) administered as SC injections on Day 1 and Day 15. ACE-536 dose levels tested (prior to halting dose escalation per protocol due to positive hemoglobin response) were 0.0625, 0.125 and 0.25 mg/kg. The study included pre-specified individual stopping rules for the Day 15 dose for increases in hemoglobin, changes in blood pressure, or ≥ grade 3 adverse events. From Day 1 through Day 57, subjects were assessed for safety by monitoring adverse events, clinical laboratory tests, ECG, vital signs and physical examination. Longer-term follow up visits occurred on Days 71 and 127. Results: A total of 32 subjects were enrolled. The mean (SD) age was 59.4 (5.8) yr (range: 49–71 yr). All subjects in the first cohort (0.0625 mg/kg or placebo) received both doses of ACE-536; all subjects in the second cohort (0.125 mg/kg or placebo) received only one dose of ACE-536 due to study interruption. This dose level was repeated for the third cohort in which subjects received 2 doses; 1 subject in that cohort did not receive the second dose due to elevated blood pressure. Four subjects in the fourth cohort (0.25 mg/kg or placebo) did not receive the second dose due to hemoglobin increase ≥ 1.0 g/dL and one additional subject did not receive the second dose due to an AE of papular rash. There were no serious adverse events or study discontinuations reported. The majority of AEs were considered mild in severity. No clinically meaningful abnormalities in laboratory measures, vital signs, physical exam, or ECG were observed, and no anti-drug antibodies were detected. The mean serum ACE-536 Cmax and AUC after the first dose increased in a dose-proportional manner, with mean time to Cmax 7.7–11.7 days and mean elimination T½ 15.5–18.5 days. The maximum hemoglobin increase from baseline at any timepoint for subjects in the 0.25 mg/kg cohort ranged from 0.6 to 2.0 g/dL (5 of 6 subjects increased ≥1.1 g/dL), with a mean maximum increase of 1.3 g/dL (p<0.001 vs placebo). Mean hemoglobin levels increased in that dose group by at least 0.6 g/dL from Day 8 through Day 57, compared with a mean decrease in the placebo group of up to 0.6 g/dL through Day 43 (see Figure). Small increases in mean reticulocyte count and EPO levels were seen in groups treated with higher doses of ACE-536 as compared with the placebo group. Conclusions: The preliminary results from this first-in-human phase 1 study show that ACE-536 is associated with a robust and sustained increase in hemoglobin levels in healthy subjects. Dose levels up to 0.25 mg/kg were generally safe and well-tolerated. The PK results support SC dosing of ACE-536 every 3 weeks. These data warrant further evaluation of ACE-536 in clinical trials in patients with disease-associated ineffective erythropoiesis and anemia, such as MDS and β-thalassemia. Disclosures: Attie: Acceleron Pharma, Inc.: Employment. Boyd:Acceleron Pharma, Inc.: Employment. Wilson:Acceleron Pharma, Inc.: Employment. Sherman:Acceleron Pharma, Inc.: Employment.

scholarly journals A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Biapenem in Healthy Adult Subjects

2021 ◽  
Author(s):  
David C. Griffith ◽  
Elizabeth E. Morgan ◽  
Michael N. Dudley ◽  
Jeffery S. Loutit
Keyword(s):  
Adverse Events ◽  
Healthy Adult ◽  
Phase 1 ◽  
Urinary Recovery ◽  
Phase 1 Study ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Multiple Doses ◽  
Dose Study ◽  
Dose Proportional

The pharmacokinetics and safety of biapenem were studied in 36 healthy adult subjects in a randomized, placebo-controlled, double blind, sequential single and multiple-ascending dose study using doses from 250 to 1250 mg administered three times a day using 3-hour infusions. Maximum concentrations for biapenem were achieved at the end of the 3-hour infusion. Biapenem exposure (AUC) increased in a slightly greater than dose-proportional manner following single and multiple doses with no evidence of accumulation with multiple doses. Plasma AUCs increased from 18 mg*h/L at 250 mg to 150 mg*h/L at 1250 mg. Urinary recovery ranged from 14.2% at 250 mg to 42.3% at 1250 mg. Biapenem was well tolerated up to 1000 mg administered every 8 hours by 3-hour infusion for 7 days; however, a higher incidence of nausea, vomiting, and rash was reported at 1250 mg. There were no serious adverse events (SAEs) reported following either single or multiple doses of biapenem and all AEs were mild or moderate in severity.

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