scholarly journals Randomized, Double-Blind, Placebo-Controlled Studies of the Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Eravacycline

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Joseph V. Newman ◽  
Jian Zhou ◽  
Sergey Izmailyan ◽  
Larry Tsai
Keyword(s):  
Healthy Subjects ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Maximum Plasma ◽  
Double Blind ◽  
Time Curve ◽  
Concentration Time ◽  
Dosing Regimens ◽  
Aerobic And Anaerobic

ABSTRACT Eravacycline is a novel, fully synthetic fluorocycline antibiotic with in vitro activity against aerobic and anaerobic Gram-positive and Gram-negative pathogens, including multidrug-resistant (MDR) bacteria. The pharmacokinetics (PK), urinary excretion, and safety/tolerability of intravenous (i.v.) eravacycline were evaluated in single- and multiple-ascending-dose studies. Healthy subjects received single i.v. doses of 0.1 to 3 mg/kg of body weight or 10 days of treatment with 0.5 or 1.5 mg/kg every 24 h (q24h) over 30 min, 1.5 mg/kg q24h over 60 min, or 1 mg/kg q12h over 60 min. After single doses, total exposure (the area under the plasma concentration-time curve [AUC]) and the maximum plasma concentrations (Cmax) of eravacycline increased in an approximately dose-proportional manner. After multiple doses, steady state was achieved within 5 to 7 days. Accumulation ranged from approximately 7% to 38% with the q24h dosing regimens and was 45% with 1 mg/kg q12h. Eravacycline was generally well tolerated, with dose-related nausea, infusion site effects, and superficial phlebitis that were mild or moderate occurring. These results provide support for the 1-mg/kg q12h regimen used in clinical studies of eravacycline.

Effects of Ginkgo biloba Extract Ingestion on the Pharmacokinetics of Talinolol in Healthy Chinese Volunteers

2009 ◽  
Vol 43 (5) ◽  
pp. 944-949 ◽  
Author(s):  
Lan Fan ◽  
Gong-You Tao ◽  
Guo Wang ◽  
Yao Chen ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Ginkgo Biloba ◽  
High Performance ◽  
Plasma Concentrations ◽  
Ginkgo Biloba Extract ◽  
Maximum Plasma ◽  
Time Curve ◽  
P Glycoprotein

Background Ginkgo biloba extract (GBE), the best selling herbal medicine in the world, has been reported to inhibit P-glycoprotein in vitro. However, the effects of GBE on P-glycoprotein activity in humans have not been clarified. Objective To investigate the effects of single and repeated GBE ingestion on the oral pharmacokinetics of talinolol, a substrate drug for P-glycoprotein in humans. Methods Ten unrelated healthy male volunteers were selected to participate in a 3-stage sequential study. Plasma concentrations of talinolol from 0 to 24 hours were measured by high-performance liquid chromatography after talinolol 100 mg was administrated alone, with a single oral dose of GBE (120 mg), and after 14 days of repeated GBE ingestion (360 mg/day). Results A single oral dose of GBE did not affect the pharmacokinetics of talinolol. Repeated ingestion of GBE increased the talinolol maximum plasma concentration (Cmax) by 36% (90% CI 10 to 68; p = 0.025), the area under the concentration-time curve (AUC)0-24 by 26% (90% CI 11 to 43; p = 0.008) and AUC0-∞ by 22% (90% CI 8 to 37; p = 0.014), respectively, without significant changes in elimination half-life and the time to Cmax. Conclusions Our results suggest that long-term use of GBE significantly influenced talinolol disposition in humans, likely by affecting the activity of P-glycoprotein and/or other drug transporters.

Pharmacokinetics, safety and tolerability of ravidasvir, with and without danoprevir/ritonavir, in healthy subjects

2021 ◽  
Author(s):  
Guolan Wu ◽  
Huili Zhou ◽  
Jing Wu ◽  
Duo Lv ◽  
Lihua Wu ◽  
...  
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Fold Increase ◽  
Sequential Design ◽  
Maximum Plasma ◽  
Double Blind ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Multiple Doses

Ravidasvir (RDV) is a novel oral hepatitis C virus NS5A inhibitor. This study aimed to evaluate the pharmacokinetics and safety of RDV and the drug–drug interaction between RDV and ritonavir-boosted danoprevir (DNVr) in healthy adults. In 1 st study, healthy volunteers were administered oral single doses of 100, 200 and 300 mg RDV and 200 mg once daily for 7 days. The 2 nd study was randomized, double-blind and placebo-controlled sequential design (day 1 for 200 mg RDV alone, day 7 for 100 mg/100 mg DNVr, day 13 for 200 mg RDV plus 100mg/100mg DNVr, followed by RDV 200 mg once daily with DNVr 100mg/100mg twice daily for 10 days). The results showed that RDV exposure increased in a dose-proportional manner following a single dose with no evidence of accumulation with multiple doses. Co-administration with DNVr regimen (100 mg/100 mg, twice daily) resulted in a 2.92- and 1.99-fold increase in minimum plasma concentration at steady state (C min,ss ) and area under the concentration–time curve at steady state (AUC τ ) of RDV. With co-administration of RDV, maximum plasma concentration (C max ) and area under the concentration curve from zero to 12 h (AUC 0-12 ) of DNV increased 1.71-fold and 2.33-fold, respectively. We did not observe any significant changes in ritonavir exposure. Both single and multiple doses of RDV with or without DNVr were well tolerated. The favorable pharmacokinetic and safety results support ravidasvir’s continued clinical development and treatment.

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 Pharmacokinetics-Pharmacodynamics of a Novel β-Lactamase Inhibitor, CB-618, in Combination with Meropenem in anIn VitroInfection Model

2016 ◽  
Vol 60 (7) ◽  
pp. 3891-3896 ◽  
Author(s):  
Brian D. VanScoy ◽  
Michael Trang ◽  
Jennifer McCauley ◽  
Haley Conde ◽  
Sujata M. Bhavnani ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Dose Fractionation ◽  
Infection Model ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Wide Range ◽  
Dosing Regimens ◽  
Lactamase Inhibitor

ABSTRACTThe usefulness of β-lactam antimicrobial agents is threatened as never before by β-lactamase-producing bacteria. For this reason, there has been renewed interest in the development of broad-spectrum β-lactamase inhibitors. Herein we describe the results of dose fractionation and dose-ranging studies carried out using a one-compartmentin vitroinfection model to determine the exposure measure for CB-618, a novel β-lactamase inhibitor, most predictive of the efficacy when given in combination with meropenem. The challenge panel includedEnterobacteriaceaeclinical isolates, which collectively produced a wide range of β-lactamase enzymes (KPC-2, KPC-3, FOX-5, OXA-48, SHV-11, SHV-27, and TEM-1). Human concentration-time profiles were simulated for each drug, and samples were collected for drug concentration and bacterial density determinations. Using data from dose fractionation studies and a challengeKlebsiella pneumoniaeisolate (CB-618-potentiated meropenem MIC = 1 mg/liter), relationships between change from baseline in log10CFU/ml at 24 h and each of CB-618 area under the concentration-time curve over 24 h (AUC0–24), maximum concentration (Cmax), and percentage of the dosing interval that CB-618 concentrations remained above a given threshold were evaluated in combination with meropenem at 2 g every 8 h (q8h). The exposure measures most closely associated with CB-618 efficacy in combination with meropenem were the CB-618 AUC0–24(r2= 0.835) andCmax(r2= 0.826). Using the CB-618 AUC0–24indexed to the CB-618-potentiated meropenem MIC value, the relationship between change from baseline in log10CFU/ml at 24 h and CB-618 AUC0–24/MIC ratio in combination with meropenem was evaluated using the pooled data from five challenge isolates; the CB-618 AUC0–24/MIC ratio associated with net bacterial stasis and the 1- and 2-log10CFU/ml reductions from baseline at 24 h were 27.3, 86.1, and 444.8, respectively. These data provide a pharmacokinetics-pharmacodynamics (PK-PD) basis for evaluating potential CB-618 dosing regimens in combination with meropenem in future studies.

scholarly journals Increased Doses Lead to Higher Drug Exposures of Levofloxacin for Treatment of Tuberculosis

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Charles A. Peloquin ◽  
Patrick P. J. Phillips ◽  
Carole D. Mitnick ◽  
Kathleen Eisenach ◽  
Ramonde F. Patientia ◽  
...  
Keyword(s):  
South Africa ◽  
Multidrug Resistant ◽  
Maximum Plasma ◽  
Second Line ◽  
Time Curve ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Concentration Time ◽  
Nominal Dose ◽  
Median Maximum

ABSTRACTPatients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to a weight-banded nominal dose of 11, 14, 17, or 20 mg/kg/day levofloxacin (minimum, 750 mg) in combination with other second-line agents. A total of 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median areas under the concentration-time curve from 0 to 24 h (AUC0−24) were 109.49, 97.86, 145.33, and 207.04 μg · h/ml. Median maximum plasma concentration (Cmax) were 11.90, 12.02, 14.86, and 19.17 μg/ml, respectively. Higher levofloxacin doses, up to 1,500 mg daily, resulted in higher exposures. (This study has been registered at ClinicalTrials.gov under identifier NCT01918397.)

scholarly journals Pharmacokinetics and Safety of Single and Multiple Doses of ACHN-490 Injection Administered Intravenously in Healthy Subjects

2011 ◽  
Vol 55 (12) ◽  
pp. 5874-5880 ◽  
Author(s):  
Robert T. Cass ◽  
Carter D. Brooks ◽  
Nancy A. Havrilla ◽  
Kenneth J. Tack ◽  
Marie T. Borin ◽  
...  
Keyword(s):  
Steady State ◽  
Healthy Subjects ◽  
Clinical Laboratory ◽  
Vestibular Function ◽  
Multidrug Resistant ◽  
Volume Of Distribution ◽  
Reporting Standard ◽  
Double Blind ◽  
Time Curve ◽  
Multiple Doses

ABSTRACTACHN-490 is an aminoglycoside with activity against multidrug-resistant pathogens, including those resistant to currently used aminoglycosides. Two randomized, double-blind, placebo-controlled clinical studies investigated the pharmacokinetics (PK), safety, and tolerability of ACHN-490 injection in healthy subjects. Study 1 used a parallel-group design with escalating single (SD) and multiple doses (MD). Study 2 explored a longer duration of the highest dose tolerated in the first study. Subjects were randomly assigned to receive either ACHN-490 injection or a placebo administered by a 10-min intravenous infusion. Study 1 enrolled 39 subjects (30 active and 9 placebo) and consisted of a single dose of 1 mg/kg body weight followed by ascending SD and MD cohorts of 4, 7, 11, and 15 mg/kg for 10, 10, 5, and 3 days, respectively. Study 2 enrolled 8 subjects (6 active and 2 placebo) who received 15 mg/kg for 5 days. Safety was assessed from adverse event (AE) reporting, standard clinical laboratory procedures, and testing for renal, cochlear, and vestibular function. ACHN-490 exhibited linear and dose-proportional PK, with agreement between the studies for PK parameters assessed. The 15-mg/kg dose did not accumulate with repeated dosing over 5 days. Mean steady-state (±standard deviation) area under the concentration-time curve from 0 to 24 h (AUC0-24), maximum concentration of drug in serum (Cmax), half-life (t1/2), clearance, and volume of distribution at steady state (Vss) for the 15-mg/kg, day 5 dose were 239 ± 45 h·mg/liter, 113 ± 17 mg/liter, 3 ± 0.3 h, 1.1 ± 0.1 ml/min/kg, and 0.24 ± 0.04 liters/kg, respectively. AEs were mild to moderate and rapidly resolved. No evidence of nephrotoxicity or ototoxicity was observed.

scholarly journals Pharmacokinetics and Pharmacodynamics of Minocycline against Acinetobacter baumannii in a Neutropenic Murine Pneumonia Model

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Jian Zhou ◽  
Kimberly R. Ledesma ◽  
Kai-Tai Chang ◽  
Henrietta Abodakpi ◽  
Song Gao ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Multidrug Resistant ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Dose Linearity ◽  
Unit Reduction ◽  
The Relationship

ABSTRACT Multidrug-resistant (MDR) Acinetobacter baumannii is increasingly more prevalent in nosocomial infections. Although in vitro susceptibility of A. baumannii to minocycline is promising, the in vivo efficacy of minocycline has not been well established. In this study, the in vivo activity of minocycline was evaluated in a neutropenic murine pneumonia model. Specifically, we investigated the relationship between minocycline exposure and bactericidal activity using five A. baumannii isolates with a broad range of susceptibility (MIC ranged from 0.25 mg/liter to 16 mg/liter). The pharmacokinetics of minocycline (single dose of 25 mg/kg of body weight, 50 mg/kg, 100 mg/kg, and a humanized regimen, given intraperitoneally) in serum and epithelial lining fluid (ELF) were characterized. Dose linearity was observed for doses up to 50 mg/kg and pulmonary penetration ratios (area under the concentration-time curve in ELF from 0 to 24 h [AUCELF,0–24]/area under the concentration time curve in serum from 0 to 24 h [AUCserum,0–24]) ranged from 2.5 to 2.8. Pharmacokinetic-pharmacodynamics (PK-PD) index values in ELF for various dose regimens against different A. baumannii isolates were calculated. The maximum efficacy at 24 h was approximately 1.5-log-unit reduction of pulmonary bacterial burdens from baseline. The AUC/MIC ratio was the PK-PD index most closely correlating to the bacterial burden (r 2 = 0.81). The required AUCELF,0–24/MIC for maintaining stasis and achieving 1-log-unit reduction were 140 and 410, respectively. These findings could guide the treatment of infections caused by A. baumannii using minocycline in the future. Additional studies to examine resistance development during therapy are warranted.

Comparative Bioavailability and Safety of Two Intramuscular Ceftriaxone Formulations

1996 ◽  
Vol 30 (11) ◽  
pp. 1223-1226 ◽  
Author(s):  
Encarnación C Suárez ◽  
Jana R Grippi
Keyword(s):  
Plasma Concentration ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Double Blind ◽  
Time Curve ◽  
Mean Values ◽  
Concentration Time ◽  
Clinical Research Center ◽  
Comparative Bioavailability ◽  
Concentrated Solution

OBJECTIVE: To determine if two ceftriaxone solutions of different concentrations are bioequivalent when administered intramuscularly. DESIGN: Double-blind, single-dose, two-period, randomized crossover study. SETTING: A clinical research center. SUBJECTS: Seventeen healthy volunteers. INTERVENTION: Ceftriaxone 500 mg administered in either 2 or 1.4 mL of lidocaine 1% solution, with final ceftriaxone concentrations of 250 and 350 mg/mL, respectively. MAIN OUTCOME MEASURES: Blood samples were assayed for ceftriaxone concentrations with HPLC and pharmacokinetic parameters were calculated from the resulting plasma—concentration time profiles: maximum plasma concentration (Cmax) of ceftriaxone and areas under the concentration-time curve (AUC) from 0 to 36 h and 0 to infinity were the primary parameters considered in the determination of bioequivalence. RESULTS: The two solutions were generally well tolerated and had similar safety profiles. Administration of both solutions resulted in similar mean values for all pharmacokinetic parameters. Statistical analysis showed no significant differences between the two solutions in any pharmacokinetic parameter, indicating that the two solutions are statistically bioequivalent (p ≤ 0.05). The 90% CI for the ratio of the means for AUC0-36 (0.86 to 1.11), AUC0-∞. (0.89 to 1.14), and Cmax (0.84 to 1.12) are within the Food and Drug Administration range of bioequivalence (0.80 to 1.25). CONCLUSIONS: These results demonstrate that the more concentrated solution of ceftriaxone (350 mg/mL) is bioequivalent to the currently marketed solution of 250 mg/mL.

scholarly journals Rational dosing of HCQ for COVID-19_pre-print

2020 ◽  
Author(s):  
Kevin Downes ◽  
Kathleen Chiotos ◽  
Julie Fitzgerald ◽  
Marc H Scheetz ◽  
Athena F. Zuppa
Keyword(s):  
Plasma Concentrations ◽  
Safety Data ◽  
Loading Dose ◽  
Maximal Concentration ◽  
In Vitro Activity ◽  
Time Curve ◽  
First Order ◽  
Concentration Time ◽  
Autoimmune Conditions

Background: Hydroxychloroquine (HCQ) has in vitro activity against SARS-CoV-2. However, datato inform optimal human dosing are limited.Methods: We conducted Monte Carlo simulations of HCQ sulfate using a published populationpharmacokinetic model. The model informing our simulations described a 2-compartmentlinear model with first-order absorption with a lag, derived from plasma HCQ concentrationdata from 22 healthy adults and 69 patients with malaria. Using the final PK model, we performed 1000 simulations for the plasma concentrations of HCQ sulfate based on various approved dosages (i.e. acute malaria, autoimmune conditions) and proposed dosing regimensfor treatment of COVID-19. The results of simulations were used to derive the area under the concentration-time curve (AUC), maximal concentration, and time to maximal concentration for each evaluated regimen.Results: The use of a loading dose, as with acute malaria dosing, resulted in rapid achievementof maximal concentrations early in the treatment course, which were maintained with dailydosing thereafter. The use of once or twice daily doses without a loading dose led to slowlyincreasing plasma concentrations through day 10. Simulated regimens that employed an 800mg loading dose for adults (13 mg/kg for children) followed by 400 mg at 6 or 12 hours (6.5mg/kg for children) achieved the greatest AUC0-24.Conclusions: Based on our findings, along with established safety data from malarial studies,we believe that approved dosing for treatment acute malaria is the most reasonable and safestapproach if HCQ will be used to treat COVID-19.

scholarly journals Plasma and Intrapulmonary Concentrations of ETX2514 and Sulbactam following Intravenous Administration of ETX2514SUL to Healthy Adult Subjects

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Keith A. Rodvold ◽  
Mark H. Gotfried ◽  
Robin D. Isaacs ◽  
John P. O'Donnell ◽  
Emily Stone
Keyword(s):  
Healthy Adult ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Content Type ◽  
Liquid Chromatography Tandem Mass ◽  
Repeated Dosing ◽  
Sampling Times

ABSTRACT ETX2514 is a novel β-lactamase inhibitor that broadly inhibits Ambler class A, C, and D β-lactamases. ETX2514 combined with sulbactam (SUL) in vitro restores sulbactam activity against Acinetobacter baumannii. ETX2514-sulbactam (ETX2514SUL) is under development for the treatment of A. baumannii infections. The objective of this study was to determine and compare plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations following intravenous (i.v.) ETX2514 and sulbactam. Plasma, ELF, and AM concentrations of ETX2514 and sulbactam were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 30 healthy adult subjects following repeated dosing (ETX2514 [1 g] and sulbactam [1 g] every 6 h [q6h], as a 3-h i.v. infusion, for a total of 3 doses). A bronchoalveolar lavage (BAL) was performed once in each subject at either 1, 2.5, 3.25, 4, or 6 h after the start of the last infusion. Penetration ratios were calculated from area under the concentration-time curve from 0 to 6 h (AUC0–6) values for total plasma and ELF using mean and median concentrations at the BAL fluid sampling times. Respective ELF AUC0–6 values, based on mean and median concentrations, were 40.1 and 39.4 mg · h/liter for ETX2514 and 34.7 and 34.5 mg · h/liter for sulbactam. Respective penetration ratios of ELF to total/unbound plasma concentrations, based on mean and median AUC0–6 values, of ETX2514 were 0.37/0.41 and 0.36/0.40, whereas these same ratio values were 0.50/0.81 and 0.50/0.80 for sulbactam. ETX2514 and sulbactam concentrations in AM were measurable and fairly constant throughout the dosing interval (median values of 1.31 and 1.01 mg/liter, respectively). These data support further study of ETX2514SUL for the treatment of pneumonia caused by multidrug-resistant A. baumannii. (This study has been registered at ClinicalTrials.gov under identifier NCT03303924.)

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