scholarly journals 628. Pharmacokinetics, Safety and Tolerability of Co-administration of Nacubactam and β-lactams after Multiple Doses in Japanese Healthy Subjects

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S418-S418
Author(s):  
Hiroki Sato ◽  
Jun Morita ◽  
Tatsuo Miura ◽  
Masayo Sumiya ◽  
Risako Takaya ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Plasma Concentrations ◽  
Vital Signs ◽  
Study Drug ◽  
Concomitant Administration ◽  
Remarkable Change ◽  
Double Blind ◽  
Carbapenem Resistant ◽  
Laboratory Test Results ◽  
Dose Study

Abstract Background Increase of carbapenem-resistant Enterobacterales (CRE) is a serious problem in the clinical setting and drugs which can treat patients with CRE are still limited. Nacubactam (OP0595) is a novel diazabicyclooctane-type β-lactamase inhibitor and being developed as a standalone drug to be co-administered with cefepime or aztreonam. Methods A randomized, double-blind multiple dose study of nacubactam in co-administration with cefepime (Cohort 1) or aztreonam (Cohort 2) in Japanese healthy subjects was performed to assess pharmacokinetics, safety, and tolerability of co-administrations of nacubactam and cefepime or aztreonam. In each cohort, 6 subjects received 2 g of nacubactam and 2 g of concomitant drug (cefepime or aztreonam) and 2 subjects received placebo (saline) intravenously over 60 minutes, three times daily every 8 hours for 7 days. Plasma samples were collected and concentrations of each drug were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and the evaluation of changes from baseline in safety laboratory test results, 12-lead electrocardiograms (ECGs), vital signs, and physical examinations. Results Profiles of Cmax, tmax, AUC0-8, AUC0-∞ and t1/2 for nacubactam, cefepime and aztreonam are summarized in Table 1. Summary of Ctrough for nacubactam, cefepime and aztreonam are summarized in Table 2. Plasma concentrations of nacubactam, cefepime and aztreonam reached the steady-state by Day 4, and the mean accumulation ratios of Cmax and AUC0-8 on Day 7 to those of Day 1 were in the range of 0.91 to 1.10. As for the safety, no serious adverse event was observed in this study. There was 1 TEAE (seborrhoeic dermatitis) leading to the discontinuation in 1 subject in nacubactam/cefepime group, but it was judged as “Not related to study drug”. Table 1. PK profiles of nacubactam and concomitant drugs on Day 1 and Day 7 Table 2. Summary of Ctrough of nacubactam and concomitant drugs Conclusion In conclusion, no remarkable change in pharmacokinetics was observed in each drug with multiple concomitant administration for 7 days and safety and tolerability of co-administrations of nacubactam and cefepime or aztreonam were confirmed. Based on these results, nacubactam is currently under further development. Disclosures All Authors: No reported disclosures

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.

MO258SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF VIS649, AN APRIL-NEUTRALIZING IGG2 MONOCLONAL ANTIBODY, IN HEALTHY VOLUNTEERS: PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE ASCENDING DOSE STUDY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Yusuke Suzuki ◽  
Mohit Mathur ◽  
Jonathan Barratt ◽  
Frank Engler ◽  
Jill Yarbrough ◽  
...  
Keyword(s):  
Phase 1 ◽  
Study Drug ◽  
Dependent Manner ◽  
Double Blind ◽  
Serum Iga ◽  
Dose Study ◽  
Dose Response Effect ◽  
Japanese Descent ◽  
Dose Dependent ◽  
Single Ascending Dose Study

Abstract Background and Aims Immunoglobulin A (IgA) nephropathy (IgAN) is a glomerulonephritis characterized by the presence of circulating and glomerular immune complexes containing galactose-deficient (Gd) IgA1. A proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor superfamily of ligands, is thought to play a key role in the pathogenesis of IgAN by virtue of its role in class-switching to IgA production. VIS649, a humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks the biological actions of APRIL, is in clinical development as a potential treatment for IgAN. The primary objective of this first-in-human study was to evaluate the safety and tolerability of VIS649 in healthy volunteers. Secondary objectives included characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) of VIS649. Method This was a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose study of VIS649 in healthy adult male and female volunteers (ClinicalTrials.gov identifier: NCT03719443). The study was conducted in sequential dosing cohorts. The first four cohorts (0.5, 2.0, 6.0, and 12.0 mg/kg, respectively) each enrolled 9 participants (4 of Japanese descent and 5 of non-Japanese descent) who were randomized to VIS649 or placebo in a ratio of 7:2. In addition, a fifth cohort enrolled 15 adults randomized to receive VIS649 6.0 mg/kg or placebo (10:5), followed by tetanus/diphtheria vaccine challenge after 28 days (TENIVAC®, Sanofi Pasteur Limited; the effect of APRIL inhibition on vaccine response is described in a companion abstract). Participants received intravenous administration of study drug on Day 1, were discharged from the institution on Day 2, and were followed for 16–24 weeks on an outpatient basis. Standard safety assessments and blood sampling for PK and PD were performed at regular intervals. Results 51 participants were randomized and dosed with study drug, of whom 47 (92.2%) completed the study. VIS649 was well tolerated, with no serious adverse events (AEs) or AEs that led to study discontinuation. Most treatment-emergent AEs (TEAEs) were mild; the incidence and severity of TEAEs were not dose dependent. One participant in the 2.0 mg/kg group experienced a severe TEAE of syncope following phlebotomy that the investigator considered unlikely to be related to study drug. There was no clinically relevant effect of treatment on laboratory tests, vital signs, electrocardiogram parameters, or physical examinations. VIS649 had non-linear PK: half-life (t½) increased with dose, while drug exposure (AUC) increased in a greater than dose proportional manner. Serum IgA, Gd-IgA1, IgG, and IgM were reversibly suppressed in a dose-dependent manner following VIS649 administration. The maximum mean percentage reductions from baseline occurred at Week 12 for the 12.0 mg/kg dose: IgA, -57.2% (Figure); Gd-IgA1, -71.6% (Figure); IgG, -33.6%; and IgM, -67.2%. These reductions were reversible and showed a dose-response effect with respect to time-to-recovery. Mean free (non-VIS649 bound) serum APRIL levels decreased to the lower limit of quantification (50 pg/mL) for all VIS649 doses at Week 1, and also showed a dose-response effect with respect to time-to-recovery. No depletions in circulating lymphocyte populations were observed. There were no significant PK or PD differences between Japanese and non-Japanese participants. Conclusion A single dose of VIS649, up to 12.0 mg/kg, was safe and well tolerated in healthy adults and was able to suppress free serum APRIL to the lower level of quantification. Serum Gd-IgA1 decreased in parallel with total serum IgA and recovered in a dose-dependent manner following reappearance of free APRIL in serum. These data support the further clinical development of VIS649 as a potential treatment for IgAN.

scholarly journals 1371. Safety, Tolerability, and Pharmacokinetics of Multiple Doses of TP-6076, a Novel, Fully Synthetic Tetracycline, in a Phase 1 Study

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S420-S420 ◽  
Author(s):  
Larry Tsai ◽  
Alison Moore
Keyword(s):  
Physical Examination ◽  
Bacterial Infections ◽  
Clinical Laboratory ◽  
Phase 1 ◽  
Geometric Mean ◽  
Vital Signs ◽  
Gastrointestinal Adverse Event ◽  
Double Blind ◽  
Dose Study

Abstract Background TP-6076 is a novel, fully synthetic tetracycline being developed for the treatment of serious bacterial infections, including those caused by multidrug-resistant Acinetobacter baumannii. TP-6076 has demonstrated potent activity in vitro against carbapenem-resistant strains of A. baumannii, with MIC90 64 times lower compared with tigecycline and 256 times lower compared with minocycline. We now report the results of a multiple ascending dose study in normal healthy volunteers. Methods This was a phase 1, single-site, randomized, double-blind, placebo-controlled dose-escalating, multiple dose study in healthy adults who met the inclusion/exclusion criteria and provided informed consent prior to any study procedure. Cohorts of eight subjects each (six active and two placebo) received daily doses of 6.0 to 40.0 mg TP-6076 or placebo for 7 days. Plasma and urine samples for pharmacokinetic (PK) analyses were collected starting immediately prior to dosing until 96 hours after the last dose. Safety was assessed through collection of adverse events (AEs), clinical laboratories, vital signs, ECG, and physical examination data. Results The geometric mean derived PK parameters for TP-6076 were: There were no serious or severe AEs reported. The most frequently reported AEs were gastrointestinal events, including nausea and vomiting, and localized infusion site reactions. There were no clinically significant changes in clinical laboratory values, ECG parameters, or physical examination findings. Conclusion Following multiple IV doses of TP-6076, plasma exposure increased as dose increased. Multiple IV doses of TP-6076 were generally well tolerated, with higher gastrointestinal adverse event rates in the higher dose groups. Disclosures L. Tsai, Tetraphase Pharmaceuticals: Employee and Shareholder, Salary. A. Moore, Tetraphase Pharmaceuticals: Employee, Salary.

Prophylactic treatment of irinotecan-induced diarrhea with neomycin (a randomized, placebo-controlled, double-blind study)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3626-3626
Author(s):  
R. H. Mathijssen ◽  
F. A. De Jong ◽  
D. F. Kehrer ◽  
R. H. Van Schaik ◽  
J. Verweij ◽  
...  
Keyword(s):  
Prophylactic Treatment ◽  
Plasma Concentrations ◽  
Aminoglycoside Antibiotic ◽  
Concomitant Administration ◽  
Patient Characteristics ◽  
Common Side Effect ◽  
Double Blind Study ◽  
Double Blind ◽  
Severe Diarrhea ◽  
Grade 3

3626 Background: Delayed-type diarrhea is a common side-effect of irinotecan, and is associated with a bacterial-mediated formation of the active irinotecan metabolite SN-38 from its glucuronide conjugate in the intestines. We hypothesized that concomitant administration of the aminoglycoside antibiotic neomycin would diminish exposure of the gut to SN-38, ameliorating the incidence of diarrhea. Methods: Patients were treated with irinotecan in a randomized, placebo-controlled, double-blind trial. In arm A, patients received irinotecan (350 mg/m2 i.v. for 90 minutes once every 3 weeks) combined with neomycin (660 mg orally 3 times daily for 3 consecutive days, starting 2 days before chemotherapy). In arm B, patients received the same irinotecan regimen with placebo. To detect a 50% reduction to less than grade 2 diarrhea (power=.80; P=.05), 60 patients had to be studied. Blood samples for additional pharmacokinetic and pharmacogenetic analyses were obtained after separate informed consent. Results: Sixty-two patients were evaluable for toxicity analysis. Relevant baseline patient characteristics (P>.06), SN-38 plasma concentrations (P=.80; N=43), and UGT1A1*28 genotype status (P=.58; N=52) were similar in both arms. Distribution, severity, and duration of diarrhea did not differ significantly between both arms (P>.32), although grade 3 diarrhea tended to be less frequent in the neomycin arm (45% reduction; P=.19). Grade 2 nausea was more common in this arm (39% vs. 9%; P<.01). The presence of at least one UGT1A1*28 allele was strongly related to the incidence of grade 2–3 diarrhea (69% vs. 34%; P=.01). Conclusions: Our results do not suggest a role for neomycin in the prophylactic treatment of irinotecan-induced diarrhea. In addition, neomycin does not influence systemic SN-38 pharmacokinetics. Also, it is suggested that each patient’s UGT1A1*28 genotype status could be used as a prospective screening tool to prevent severe diarrhea. No significant financial relationships to disclose.

scholarly journals 1099. Evaluation of the Safety and Pharmacokinetics (PK) following Administration of Single and Multiple Doses of Anti-Staphylococcal Lysin, LSVT-1701, in Healthy Adult Subjects

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S641-S641
Author(s):  
Mary Beth Wire ◽  
Soo youn Jun ◽  
In-Jin Jany ◽  
Jun Gi Hwang ◽  
David Huang
Keyword(s):  
Single Dose ◽  
Healthy Adult ◽  
Phase 1 ◽  
Vital Signs ◽  
Time Data ◽  
Serum Samples ◽  
Double Blind ◽  
Dose Study ◽  
Clinically Significant ◽  
New Treatments

Abstract Background LSVT-1701 is an anti-staphylococcal phage lysin being developed for treatment of MRSA infections in combination with SoC antibiotics. The safety and PK of single ascending doses of LSVT-1701 0.1 to 10 mg/kg in healthy adult volunteers were previously described (Jun, et.al, AAC 2017;61:e02629-16). We further evaluated the safety and PK of multiple ascending doses of LSVT-1701 in healthy adult subjects. Methods Study ITB-101-1b was a Phase 1, randomized, double-blind, placebo-controlled, multiple ascending dose study. 8 subjects were randomized 3:1 to active:placebo in each cohort. LSVT-1701 was administered as a 6 mg/kg single dose and twice daily (BID) doses of 1.5, 3.0, and 4.5 mg/kg for 4 days (24h between Doses 1-2, 12h between Doses 2-6). Study drugs were administered as a 1-hour IV infusion. Serial serum samples were collected over 24 hours following the first and last doses for measurement of LSVT-1701 concentrations by a validated ELISA method. PK analysis of LSVT-1701 concentration-time data was done using noncompartmental methods. Safety was assessed by AEs, clinical labs, vital signs, and ECG. Results 30/32 (94%) subjects completed the study. No subjects withdrew due to AEs, and there were no severe AEs, no serious AEs, and no deaths. AEs were of mild (97%) to moderate (3%) intensity and were reported by all subjects in the LSVT-1701 6 mg/kg single dose group and 1-3 (17-50%) of subjects receiving 1.5 to 4.5 mg/kg BID or placebo. The most common AEs of headache, chills, rigors, and fever generally lasted for ≤2 days with or without acetaminophen treatment, and no clinically significant changes in blood pressure, heart rate, ECG, or clinical labs (other than transient increases in CRP) were observed. Infusion site reactions (erythema, pain, induration, warmth) were observed with BID administration of LSVT-1701, but not with the single 6 mg/kg dose or placebo. LSVT-1701 exposure increased greater than in proportion to dose and t1/2 was concentration-dependent, increasing with higher doses. No accumulation in LSVT-1701 exposure was observed. Summary of LSVT-1701 PK Parameters Summary of LSVT-1701 PK Parameters Conclusion The safety and PK profile of LSVT-1701 is favorable for evaluation in patients with S. aureus infections, including bacteremia and infective endocarditis, for which new treatments are needed. Disclosures Mary Beth Wire, Pharm#, Lysovant (Consultant) Soo youn Jun, PhD, iNtRON Biotechnology (Consultant) In-Jin Jany, PhD, iNtRON (Consultant) Jun Gi Hwang, PhD, Lysovant (Consultant) David Huang, MD, PhD, Lysovant (Consultant)

Effect of Infusion Rate on the Pharmacokinetics and Tolerance of Intravenous Dolasetron Mesylate

1998 ◽  
Vol 32 (1) ◽  
pp. 39-44
Author(s):  
Dan C Dimmitt ◽  
Thomas L Hunt ◽  
Anthony J Spalitto ◽  
Michael B Cramer ◽  
Ajit K Shah ◽  
...  
Keyword(s):  
Infusion Rate ◽  
Vital Signs ◽  
Correlation Coefficients ◽  
Study Drug ◽  
Pharmacokinetic Parameters ◽  
Least Squares Regression ◽  
Double Blind ◽  
Elimination Half ◽  
Parallel Group ◽  
Before And After

OBJECTIVE To evaluate the safety, tolerance, and pharmacokinetics of dolasetron mesylate and its active metabolite hydrodolasetron when dolasetron mesylate was administered intravenously at increasing infusion rates. DESIGN: A double-blind, placebo-controlled, parallel-group study. METHODS: Forty-nine healthy nonsmoking male volunteers were randomly assigned to receive intravenous doses of dolasetron mesylate 100 mg or placebo. Three groups of 16 subjects each (12 dolasetron mesylate, 4 placebo) received escalating infusion rates (50, 100, then 200 mg/min). Physical examinations, vital signs, laboratory tests, and adverse events were recorded before and after administration of the study drug. Serial blood samples and 12-lead electrocardiogram measurements were obtained for 24 hours after the infusion. Plasma samples were analyzed for dolasetron and hydrodolasetron. RESULTS Dolasetron mesylate was well tolerated, with no apparent differences in vital signs or adverse event profiles among the different rates of infusion. In general, the pharmacokinetics of dolasetron and hydrodolasetron were superimposable among the three infusion rate groups. Plasma dolasetron concentrations declined rapidly in all three infusion rate groups, with mean elimination half-life (t1/2) of less than 10 minutes. The reduced metabolite hydrodolasetron, which accounts for most pharmacologic activity, formed rapidly, with maximum concentrations occurring between 0.4 and 0.5 hours and disappeared with a mean t1/2 of 8–9 hours. The correlation coefficients of least-squares regression analysis between the pharmacokinetic parameters and the infusion rate of dolasetron were less than 0.083 and the slopes were not significantly different from 0, suggesting that none of the hydrodolasetron pharmacokinetic parameters were affected by rate of infusion. CONCLUSIONS The intravenous administration of dolasetron 100 mg over 0.5–2 minutes did not significantly alter the pharmacokinetic profiles of either dolasetron or hydrodolasetron. In addition, the safety profile of dolasetron did not change with increasing rate of infusion. Therefore, the rate of infusion of dolasetron mesylate appears to have no pharmacokinetic or clinical implications when assessed over a 0.5- to 2-minute time period. OBJETIVO Evaluar la seguridad, tolerabilidad, y farmacocinética del dolasetrón mesilato y la de su metabolito activo hidrodolasetrón cuando se administra dolasetrón mesilato por vía intravenosa a una frecuencia de infusión creciente. DISEÑO Estudio a doble-ciego, controlado con placebo, y grupos paralelos. MÉTODO Cuarenta y nueve hombres voluntarios sanos no fumadores fueron asignados de forma aleatorizada para recibir el tratamiento intravenoso con la dosis de 100 mg de dolasetrón mesilato o con placebo. Tres grupos de 16 sujetos cada uno (12 tratados con dolasetrón mesilato y 4 con placebo) recibieron frecuencias de infusión crecientes (50, 100, y 300 mg/min). La exploración física, signos vitales, analítica de laboratorio, y efectos adversos se registraron antes y tras la administración del fármaco. Se tomaron muestras seriadas de sangre y se determinó el electrocardiograma de 12 derivaciones durante 24 horas tras la infusión. Se analizaron los niveles plasmáticos de dolasetrón y de hidrodolasetrón. RESULTADOS Dolasetrón mesilato fue bien tolerado sin diferencias aparentes en el perfil de los signos vitales o efectos adversos entre las diferentes frecuencias de infusión. En general la farmacocinética del dolasetrón e hidrodolasetrón resulte superponible entre los tres grupos de infusión. Las concentraciones plasmáticas de dolasetrón disminuyeron rápidamente en los tres grupos, con una vida media de eliminación (t1/2) inferior a 10 minutos. El metabolito reducido hidrodolasetrón que posee la mayor parte de la actividad aparece con rapidez, con una concentración máxima alcanzada entre 0.4 y 0.5 horas y desaparece con una t1/2 de 8 a 9 horas. El coeficiente de correlación (r) del análisis de regresión por mínimos cuadrados entre los parámetros farmacocinéticos y la frecuencia de infusión de dolasetrón, fue inferior a 0.083 y las pendientes no difirieron significativamente de cero, súgiriendo que ninguno de los parámetros farmacocinéticos de hidrodolasetrón resultó afectado por la frecuencia de infusión. CONCLUSIONES La administración intravenosa de 100 mg de dolasetrón entre 0.5 a 2 minutos no altera significativamente el perfil farmacocinético del dolasetrón ni del hidrodolasetrón. Además, el perfil de seguridad del dolasetrón no cambia con el aumento de la frecuencia de infusión. Así pues, la frecuencia de infusión del dolasetrón mesilato parece carecer de implicaciones farmacocinéticas o clínicas cuando se administra en un período de tiempo comprendido entre 0.5 y 2 minutos.

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