scholarly journals Nonclinical Pharmacokinetics, Protein Binding, and Elimination of KBP-7072, an Aminomethylcycline Antibiotic, in Animal Models

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Xiaojuan Tan ◽  
Min Zhang ◽  
Qingmei Liu ◽  
Ping Wang ◽  
Tian Zhou ◽  
...  
Keyword(s):  
Animal Models ◽  
Protein Binding ◽  
Maximum Plasma ◽  
Sprague Dawley ◽  
Bacterial Strains ◽  
Time Curve ◽  
Fed State ◽  
Sd Rats ◽  
The Mean ◽  
Oral Doses

ABSTRACT KBP-7072 is a semisynthetic aminomethylcycline with broad-spectrum activity against Gram-positive and Gram-negative pathogens, including multidrug-resistant bacterial strains. The pharmacokinetics (PK) of KBP-7072 after oral and intravenous (i.v.) administrations of single and multiple doses were investigated in animal models, including during fed and fasted states, and the protein binding and excretion characteristics were also evaluated. In Sprague-Dawley (SD) rats, beagle dogs, and CD-1 mice, KBP-7072 demonstrated a linear PK profile after the administration of single oral and i.v. and multiple oral doses. The oral bioavailability ranged from 12% to 32%. The mean time to maximum concentration (Tmax) ranged from 0.5 to 4 h, and the mean half-life ranged from approximately 6 to 11 h. The administration of oral doses in the fed state resulted in marked reductions in the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) compared with dosing in fasted animals. The mean bound fractions of KBP-7072 were 77.5%, 69.8%, 64.5%, 69.3%, and 69.2% in mouse, rat, dog, monkey, and human plasma, respectively. Following a single 22.5-mg/kg oral dose of KBP-7072 in SD rats, the cumulative excretion in feces was 64% and that in urine was 2.5% of the administered dose. The PK results in animal models are consistent with single- and multiple-ascending-dose studies in healthy volunteers and confirm the suitability of KBP-7072 for once-daily oral and i.v. administration in clinical studies.

Abstract P410: A Novel Curcumin Formulation, ASD-cur Suppressed Heart Failure After Myocardial Infarction In Rats

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Hidemichi Takai ◽  
Tatsuya Morimoto
Keyword(s):  
Heart Failure ◽  
Plasma Concentration ◽  
Cardiac Fibrosis ◽  
Myocardial Cell ◽  
Left Ventricular ◽  
Cell Diameter ◽  
Maximum Plasma ◽  
Mrna Levels ◽  
Time Curve ◽  
Sd Rats

Introduction: Curcumin prevents the development of heart failure and is a potential treatment for heart failure. Although curcumin is known to be safe, its therapeutic efficiency is limited due to its low bioavailability. To overcome this problem, we developed ASD-Cur, an amorphous formulation of curcumin. In this study, we investigated the effect of ASD-Cur and compared it with Theracurmin ® , a colloidal submicron dispersion of curcumin. Methods: Male SD rats were orally administrated with ASD-Cur or Theracurmin ® (10 mg/kg curcumin). The plasma levels of curcumin were measured at 0.25, 0.5, 1, 2, 4 and 6 hours after administration. Twelve healthy volunteers, who had provided written informed consent, were administrated with ASD-Cur and Theracurmin ® containing 30 mg curcumin, and plasma curcumin concentrations were determined at 0.5, 1, 2, 4, and 8 hours. Next, male SD rats were subjected to MI or sham surgery. One week after surgery, the MI rats were randomly assigned to 4 groups: vehicle, ASD-Cur (0.2 mg/kg curcumin) or Theracurmin ® (0.2 or 0.5 mg/kg curcumin). Oral administration of these compounds was repeated for 6 weeks. After echocardiographic examinations, myocardial cell diameter, perivascular fibrosis, mRNA levels, and the acetylation of histone H3K9 were measured. Results: After administration in rats, the area under the plasma concentration-time curve ( AUC 0-6h ) and the maximum plasma concentration ( C max ) of ASD-Cur were 3.7-fold and 9.6-fold higher than those of Theracurmin ® , respectively. The AUC 0-8h and C max of ASD-Cur in humans were 3.4-fold and 5.4-fold higher than those of Theracurmin ® , respectively. Echocardiographic analysis showed that 0.2 mg/kg ASD-Cur and 0.5 mg/kg Theracurmin ® significantly improved the MI-induced deterioration of FS and left ventricular hypertrophy to the same extent. Both treatments significantly suppressed MI-induced increases in myocardial cell diameter, perivascular fibrosis, mRNA levels of hypertrophic markers and cardiac fibrosis, and acetylation of histone H3K9 to the same extent. Conclusion: These findings indicated that ASD-Cur has greater bioavailability than Theracurmin ® , and could exhibit greater therapeutic potency towards for MI-induced heart failure at a lower dose.

scholarly journals Pharmacokinetic Profile of μSMIN Plus™, a new Micronized Diosmin Formulation, after Oral Administration in Rats

2015 ◽  
Vol 10 (9) ◽  
pp. 1934578X1501000 ◽  
Author(s):  
Rosario Russo ◽  
Angelo Mancinelli ◽  
Michele Ciccone ◽  
Fabio Terruzzi ◽  
Claudio Pisano ◽  
...  
Keyword(s):  
Oral Administration ◽  
Plasma Concentrations ◽  
Compartmental Analysis ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Sprague Dawley ◽  
Time Curve ◽  
Maximum Plasma Drug Concentration

Diosmin is a naturally occurring flavonoid present in citrus fruits and other plants belonging to the Rutaceae family. It is used for the treatment of chronic venous insufficiency (CVI) for its pheblotonic and vaso-active properties, safety and tolerability as well. The aim of the current in vivo study was to investigate the pharmacokinetic profile of a branded micronized diosmin (μSMIN Plus™) compared with plain micronized diosmin in male Sprague-Dawley rats. After oral administration by gastric gavage, blood samples were collected via jugular vein catheters at regular time intervals from baseline up to 24 hours. Plasma concentrations were assessed by LC/MS. For each animal, the following pharmacokinetic parameters were calculated using a non-compartmental analysis: maximum plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-last), elimination half-life (t1/2), and relative oral bioavailability (%F). The results of the current study clearly showed an improvement in the pharmacokinetic parameters in animals treated with μSMIN Plus™ compared with animals treated with micronized diosmin. In particular, μSMIN Plus™ showed a 4-fold increased bioavailability compared with micronized diosmin. In conclusion, the results from the current study provided a preliminary pharmacokinetic profile for μSMIN Plus™, which may represent a new tool for CVI management.

scholarly journals Population Pharmacokinetics of Pyrazinamide in Patients with Tuberculosis

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Abdullah Alsultan ◽  
Rada Savic ◽  
Kelly E. Dooley ◽  
Marc Weiner ◽  
William Whitworth ◽  
...  
Keyword(s):  
Body Weight ◽  
Therapeutic Target ◽  
Volume Of Distribution ◽  
Current Treatment ◽  
Population Pharmacokinetic ◽  
Maximum Plasma ◽  
Target Attainment ◽  
Time Curve ◽  
The Mean ◽  
Higher Doses

ABSTRACT The current treatment used for tuberculosis (TB) is lengthy and needs to be shortened and improved. Pyrazinamide (PZA) has potent sterilizing activity and has the potential to shorten the TB treatment duration, if treatment is optimized. The goals of this study were (i) to develop a population pharmacokinetic (PK) model for PZA among patients enrolled in PK substudies of Tuberculosis Trial Consortium (TBTC) trials 27 and 28 and (ii) to determine covariates that affect PZA PK. (iii) We also performed simulations and target attainment analysis using the proposed targets of a maximum plasma concentration (C max) of >35 μg/ml or an area under the concentration-versus-time curve (AUC) of >363 μg · h/ml to see if higher weight-based dosing could improve PZA efficacy. Seventy-two patients participated in the substudies. The mean (standard deviation [SD]) C max was 30.8 (7.4) μg/ml, and the mean (SD) AUC from time zero to 24 h (AUC0–24) was 307 (83) μg · h/ml. A one-compartment open model best described PZA PK. Only body weight was a significant covariate for PZA clearance. Women had a lower volume of distribution (V/F) than men, and both clearance (CL/F) and V/F increased with body weight. Our simulations show that higher doses of PZA (>50 mg/kg of body weight) are needed to achieve the therapeutic target of an AUC/MIC of >11.3 in >80% of patients, while doses of >80 mg/kg are needed for target attainment in 90% of patients, given specific assumptions about MIC determinations. For the therapeutic targets of a C max of >35 μg/ml and/or an AUC of >363 μg · h/ml, doses in the range of 30 to 40 mg/kg are needed to achieve the therapeutic target in >90% of the patients. Further clinical trials are needed to evaluate the safety and efficacy of higher doses of PZA.

scholarly journals Comparison of Plasma and Intrapulmonary Concentrations of Nafithromycin (WCK 4873) in Healthy Adult Subjects

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Keith A. Rodvold ◽  
Mark H. Gotfried ◽  
Rakesh Chugh ◽  
Mugdha Gupta ◽  
H. David Friedland ◽  
...  
Keyword(s):  
Healthy Adult ◽  
Plasma Concentrations ◽  
Maximum Plasma ◽  
Total Plasma ◽  
Time Curve ◽  
The Third ◽  
Elimination Half ◽  
The Mean ◽  
Repeated Dosing ◽  
Tract Infections

ABSTRACT The nafithromycin concentrations in the plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) of 37 healthy adult subjects were measured following repeated dosing of oral nafithromycin at 800 mg once daily for 3 days. The values of noncompartmental pharmacokinetic (PK) parameters were determined from serial plasma samples collected over a 24-h interval following the first and third oral doses. Each subject underwent one standardized bronchoscopy with bronchoalveolar lavage (BAL) at 3, 6, 9, 12, 24, or 48 h after the third dose of nafithromycin. The mean ± standard deviation values of the plasma PK parameters after the first and third doses included maximum plasma concentrations (C max) of 1.02 ± 0.31 μg/ml and 1.39 ± 0.36 μg/ml, respectively; times to C max of 3.97 ± 1.30 h and 3.69 ± 1.28 h, respectively; clearances of 67.3 ± 21.3 liters/h and 52.4 ± 18.5 liters/h, respectively, and elimination half-lives of 7.7 ± 1.1 h and 9.1 ± 1.7 h, respectively. The values of the area under the plasma concentration-time curve (AUC) from time zero to 24 h postdosing (AUC0–24) for nafithromycin based on the mean or median total plasma concentrations at BAL fluid sampling times were 16.2 μg · h/ml. For ELF, the respective AUC0–24 values based on the mean and median concentrations were 224.1 and 176.3 μg · h/ml, whereas for AM, the respective AUC0–24 values were 8,538 and 5,894 μg · h/ml. Penetration ratios based on ELF and total plasma AUC0–24 values based on the mean and median concentrations were 13.8 and 10.9, respectively, whereas the ratios of the AM to total plasma concentrations based on the mean and median concentrations were 527 and 364, respectively. The sustained ELF and AM concentrations for 48 h after the third dose suggest that nafithromycin has the potential to be a useful agent for the treatment of lower respiratory tract infections. (This study has been registered at ClinicalTrials.gov under registration no. NCT02453529.)

scholarly journals Diabetic Retinal and Choroidal Edema in SDT Rats

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Fumihiko Toyoda ◽  
Yoshiaki Tanaka ◽  
Machiko Shimmura ◽  
Nozomi Kinoshita ◽  
Hiroko Takano ◽  
...  
Keyword(s):  
Animal Model ◽  
Diabetic Retinopathy ◽  
Choroidal Thickness ◽  
Retinal Thickness ◽  
Sprague Dawley ◽  
Rat Models ◽  
Sd Rats ◽  
Diabetic Choroidopathy ◽  
The Mean

We evaluated the features of diabetic retinal and choroidal edema in Spontaneously Diabetic Torii (SDT) rats. We measured the retinal and choroidal thicknesses in normal Sprague-Dawley (SD) rats(n=9)and SDT rats(n=8). The eyes were enucleated 40 weeks later after they were diagnosed with diabetes, and 4-micron sections were cut for conventional histopathologic studies. The mean retinal and choroidal thicknesses were significantly thicker in the SDT rats than in the normal SD rats. The choroidal thickness was correlated strongly with the retinal thickness in both rat models. Diabetic retinopathy (DR) and diabetic choroidopathy appeared as edema in the SDT rats. The retinal thickness was correlated strongly with the choroidal thickness in the SDT rats, which is an ideal animal model of both DR and choroidopathy.

scholarly journals Novel Lipid-Free Nanoformulation for Improving Oral Bioavailability of Coenzyme Q10

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Huafeng Zhou ◽  
Guoqing Liu ◽  
Jing Zhang ◽  
Ning Sun ◽  
Mingxing Duan ◽  
...  
Keyword(s):  
Particle Size ◽  
Plasma Concentration ◽  
Zeta Potential ◽  
Coenzyme Q10 ◽  
Oral Bioavailability ◽  
Maximum Plasma ◽  
Sprague Dawley ◽  
Scanning Calorimetry ◽  
Time Curve ◽  
Free System

To improve the bioavailability of orally administered lipophilic coenzyme Q10 (CoQ10), we formulated a novel lipid-free nano-CoQ10 system stabilized by various surfactants. Nano-CoQ10s, composed of 2.5% (w/w) CoQ10, 1.67% (w/w) surfactant, and 41.67% (w/w) glycerol, were prepared by hot high-pressure homogenization. The resulting formulations were characterized by particle size, zeta potential, differential scanning calorimetry, and cryogenic transmission electron microscopy. We found that the mean particle size of all nano-CoQ10s ranged from66.3±1.5 nm to92.7±1.5 nm and the zeta potential ranged from-12.8±1.4 mV to-41.6±1.4 mV. The CoQ10 in nano-CoQ10s likely existed in a supercooled state, and nano-CoQ10s stored in a brown sealed bottle were stable for 180 days at 25°C. The bioavailability of CoQ10 was evaluated following oral administration of CoQ10 formulations in Sprague-Dawley rats. Compared to the values observed following administration of CoQ10-Suspension, nano-CoQ10 modified with various surfactants significantly increased the maximum plasma concentration and the area under the plasma concentration-time curve. Thus, the lipid-free system of a nano-CoQ10 stabilized with a surfactant may be an effective vehicle for improving oral bioavailability of CoQ10.

scholarly journals Pharmacokinetics of Solithromycin (CEM-101) after Single or Multiple Oral Doses and Effects of Food on Single-Dose Bioavailability in Healthy Adult Subjects

2011 ◽  
Vol 55 (5) ◽  
pp. 1997-2003 ◽  
Author(s):  
J. Gordon Still ◽  
Jennifer Schranz ◽  
Thorsten P. Degenhardt ◽  
Drusilla Scott ◽  
Prabhavathi Fernandes ◽  
...  
Keyword(s):  
Phase 1 ◽  
Pharmacokinetic Profile ◽  
Time Curve ◽  
Time To Peak ◽  
Dose Study ◽  
Human Pharmacokinetic ◽  
The Mean ◽  
Double Blinded ◽  
Oral Doses

ABSTRACTThe pharmacokinetics of orally administered solithromycin (CEM-101), a novel fluoroketolide, were evaluated in healthy subjects in three phase 1 studies. In two randomized, double-blinded, placebo-controlled studies, escalating single oral doses of solithromycin (50 to 1,600 mg) or seven oral daily doses (200 to 600 mg) of solithromycin were administered. A third study evaluated the effects of food on the bioavailability of single oral doses (400 mg) of solithromycin. Following single doses, the median time to peak concentration (Tmax) ranged from 1.5 h to 6 h. The mean maximum measured plasma concentration (Cmax) ranged from 0.0223 μg/ml to 19.647 μg/ml, and the area under the concentration-versus-time curve from time zero to timet(AUC0–t) ranged from 0.0402 μg · h/ml to 28.599 μg · h/ml. There was no effect of high-fat food on the oral bioavailability of solithromycin. In the multiple-dose study, after 7 days, the mean maximum measured plasma solithromycin concentration at steady-state (Cmax,ss) ranged from 0.248 to 1.50 μg/ml, and the area under the concentration-versus-time curve over the final dosing interval (AUCτ) ranged from 2.310 to 18.41 μg · h/ml. These values indicate a greater than proportional increase in exposure at 200 and 400 mg but a proportional exposure at 600 mg. MedianTmaxvalues remained constant between day 1 and day 7. Moderate accumulation ratios of solithromycin were observed after 7 days of dosing. All dose regimens of solithromycin were well tolerated, and no discontinuations due to an adverse event occurred. The human pharmacokinetic profile and tolerability of solithromycin, combined with itsin vitropotency and efficacy in animal models against a broad spectrum of pathogens, support further development of solithromycin.

The pharmacokinetics of oxycodone and its metabolites following single oral doses of Remoxy®, an abuse-deterrent formulation of extended-release oxycodone, in patients with hepatic or renal impairment

2015 ◽  
Vol 11 (2) ◽  
pp. 157 ◽  
Author(s):  
Bimal K. Malhotra, PhD ◽  
Grant L. Schoenhard, PhD ◽  
Annelies W. De Kater, PhD ◽  
Nadav Friedmann, PhD, MD
Keyword(s):  
Renal Function ◽  
Hepatic Impairment ◽  
Impaired Renal Function ◽  
Extended Release ◽  
Phase 1 ◽  
Hepatic Function ◽  
Maximum Plasma ◽  
Time Curve ◽  
Impaired Hepatic Function ◽  
Oral Doses

Objective: Remoxy® (Pain Therapeutics, Inc., Austin, TX) is an abuse-deterrent formulation of extended-release oxycodone. The effects of renal or hepatic impairment on the pharmacokinetics (PK) of single, oral doses of Remoxy 20 or 10 mg, respectively, were assessed in two phase 1 studies in subjects aged 18-80 years.Methods: PK parameters included maximum plasma concentration (Cmax) and area under the concentration-time curve from time 0 to the last quantifiable concentration (AUC0-t), and extrapolated to infinity (AUCinf). Adverse events (AEs) were monitored.Results: Mean (SD) oxycodone Cmax values following Remoxy 20-mg administration were 17.6 (9.1), 21.9 (11.2), 25.9 (18.2), and 31.6 (14.5) ng/mL and AUC0-t values were 210.7 (82.1), 271.6 (83.3), 299.5 (76.3), and 493.5 (175.9) ng·h/mL in subjects with normal or mild (n = 6 each), moderate (n = 5), and severely impaired renal function (n = 6), respectively. Mean (SD) oxycodone Cmax following Remoxy 10-mg administration was 7.6 (3.3), 7.8 (2.3), and 13.1 (5.3) ng/mL and AUC0-t was 105.7 (49.5), 134.7 (38.3), and 218.0 (74.1) ng·h/mL in subjects with normal, mild, and moderately impaired hepatic function (n = 6 each), respectively. Differences in exposure values between the different renal and hepatic groups were significant. Treatment-emergent AEs were reported by 14.3, 66.7, 66.7, and 50.0 percent of subjects with normal, mild, moderate, and severely impaired renal function, respectively, and by 50.0, 33.3, and 66.7 percent of subjects with normal, mild, and moderately impaired hepatic function, respectively.Conclusions: As renal or hepatic function decreased, oxycodone Cmax and AUC0-t were up to approximately twofold higher following single, oral doses of extended-release Remoxy. AEs were those typically reported for opioids. Lower doses of Remoxy may thus be safely prescribed to subjects with renal or hepatic impairment.

scholarly journals Tissue Penetration and Pharmacokinetics of Tigecycline in Diabetic Patients with Chronic Wound Infections Described by Using In Vivo Microdialysis

2010 ◽  
Vol 54 (12) ◽  
pp. 5209-5213 ◽  
Author(s):  
Catharine C. Bulik ◽  
Dora E. Wiskirchen ◽  
Ashley Shepard ◽  
Christina A. Sutherland ◽  
Joseph L. Kuti ◽  
...  
Keyword(s):  
Steady State ◽  
Protein Binding ◽  
Subcutaneous Tissue ◽  
Diabetic Patients ◽  
Tissue Penetration ◽  
Tissue Concentrations ◽  
Time Curve ◽  
The Mean

ABSTRACT Tissue penetration of systemic antibiotics is an important consideration for positive outcomes in diabetic patients. Herein we describe the exposure profile and penetration of tigecycline in the interstitial fluid of wound margins versus that of uninfected thigh tissue in 8 adult diabetic patients intravenously (IV) administered 100 mg and then 50 mg of tigecycline twice daily for 3 to 5 doses. Prior to administration of the first dose, 2 microdialysis catheters were inserted into the subcutaneous tissue, the first within 10 cm of the wound margin and the second in the thigh of the same extremity. Samples for determination of plasma and tissue concentrations were simultaneously collected over 12 h under steady-state conditions. Tissue concentrations were corrected for percent in vivo recovery by the retrodialysis technique. Plasma samples were also collected for determination of protein binding at 1, 6, and 12 h postdose for each patient. Protein binding data were corrected using a fitted polynomial equation. The mean patient weight was 95.1 kg (range, 63.6 to 149.2 kg), the mean patient age was 63.5 ± 9.4 years, and 75% of the patients were males. The mean values for the plasma, thigh, and wound free area under the concentration-time curve from 0 to 24 h (fAUC0-24) were 2.65 ± 0.33, 2.52 ± 1.15, and 2.60 ± 1.02 μg·h/ml, respectively. Protein binding was nonlinear, with the percentage of free drug increasing with decreasing serum concentrations. Exposure values for thigh tissue and wound tissue were similar (P = 0.986). Mean steady-state tissue concentrations for the thigh and wound were similar at 0.12 ± 0.02 μg/ml, and clearance from the tissues appeared similar to that from plasma. Tissue penetration ratios (tissue fAUC/plasma fAUC) were 99% in the thigh and 100% in the wound (P = 0.964). Tigecycline penetrated equally well into wound and uninfected tissue of the same extremity.

scholarly journals Solithromycin Pharmacokinetics in Plasma and Dried Blood Spots and Safety in Adolescents

2016 ◽  
Vol 60 (4) ◽  
pp. 2572-2576 ◽  
Author(s):  
Daniel Gonzalez ◽  
Debra L. Palazzi ◽  
Leena Bhattacharya-Mithal ◽  
Amira Al-Uzri ◽  
Laura P. James ◽  
...  
Keyword(s):  
Standard Deviation ◽  
Plasma Concentration ◽  
Bacterial Infections ◽  
Phase 1 ◽  
Dried Blood Spots ◽  
Maximum Plasma ◽  
Open Label ◽  
Time Curve ◽  
Small Cohort ◽  
The Mean

ABSTRACTWe assessed the pharmacokinetics and safety of solithromycin, a fluoroketolide antibiotic, in a phase 1, open-label, multicenter study of 13 adolescents with suspected or confirmed bacterial infections. On days 3 to 5, the mean (standard deviation) maximum plasma concentration and area under the concentration versus time curve from 0 to 24 h were 0.74 μg/ml (0.61 μg/ml) and 9.28 μg · h/ml (6.30 μg · h/ml), respectively. The exposure and safety in this small cohort of adolescents were comparable to those for adults. (This study has been registered at ClinicalTrials.gov under registration no. NCT01966055.)

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