scholarly journals Use of an In Vitro Pharmacodynamic Model To Derive a Linezolid Regimen That Optimizes Bacterial Kill and Prevents Emergence of Resistance in Bacillus anthracis

2008 ◽  
Vol 52 (7) ◽  
pp. 2486-2496 ◽  
Author(s):  
A. Louie ◽  
H. S. Heine ◽  
K. Kim ◽  
D. L. Brown ◽  
B. VanScoy ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Drug Concentration ◽  
Human Subjects ◽  
Time Profile ◽  
Pharmacodynamic Model ◽  
Dose Fractionation ◽  
Serum Drug Concentration ◽  
Maximum Serum ◽  
Concentration Time

ABSTRACT Simulating the average non-protein-bound (free) human serum drug concentration-time profiles for linezolid in an in vitro pharmacodynamic model, we characterized the pharmacodynamic parameter(s) of linezolid predictive of kill and for prevention of resistance in Bacillus anthracis. In 10-day dose-ranging studies, the average exposure for ≥700 mg of linezolid given once daily (QD) resulted in >3-log CFU/ml declines in B. anthracis without resistance selection. Linezolid at ≤600 mg QD amplified for resistance. With twice-daily (q12h) dosing, linezolid at ≥500 mg q12 h was required for resistance prevention. In dose fractionation studies, killing of B. anthracis was predicted by the area under the time-concentration curve (AUC)/MIC ratio. However, resistance prevention was linked to the maximum serum drug concentration (C max)/MIC ratio. Monte Carlo simulations predicted that linezolid at 1,100 mg QD would produce in 96.7% of human subjects a free 24-h AUC that would match or exceed the average 24-h AUC of 78.5 mg·h/liter generated by linezolid at 700 mg QD while reproducing the shape of the concentration-time profile for this pharmacodynamically optimized regimen. However, linezolid at 700 mg q12h (cumulative daily dose of 1,400 mg) would produce an exposure that would equal or exceed the average free 24-h AUC of 90 mg·h/liter generated by linezolid at 500 mg q12h in 93.8% of human subjects. In conclusion, in our in vitro studies, the QD-administered, pharmacodynamically optimized regimen for linezolid killed drug-susceptible B. anthracis and prevented resistance emergence at lower dosages than q12h regimens. The lower dosage for the pharmacodynamically optimized regimen may decrease drug toxicity. Also, the QD administration schedule may improve patient compliance.

scholarly journals Development of a Physiologically Based Pharmacokinetic Model for Prediction of Ethanol Concentration-Time Profile in Different Organs

2020 ◽  
Author(s):  
Armin Sadighi ◽  
Lorenzo Leggio ◽  
Fatemeh Akhlaghi
Keyword(s):  
Pbpk Model ◽  
Organ Damage ◽  
Time Profile ◽  
Sensitivity Analyses ◽  
Pbpk Modeling ◽  
Time Curve ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Physiologically Based

Abstract Aims A physiologically based pharmacokinetic (PBPK) modeling approach was used to simulate the concentration-time profile of ethanol (EtOH) in stomach, duodenum, plasma and other tissues upon consumption of beer and whiskey under fasted and fed conditions. Methods A full PBPK model was developed for EtOH using the advanced dissolution, absorption and metabolism (ADAM) model fully integrated into the Simcyp Simulator® 15 (Simcyp Ltd., Sheffield, UK). The prediction performance of the developed model was verified and the EtOH concentration-time profile in different organs was predicted. Results Simcyp simulation showed ≤ 2-fold difference in values of EtOH area under the concentration-time curve (AUC) in stomach and duodenum as compared to the observed values. Moreover, the simulated EtOH maximum concentration (Cmax), time to reach Cmax (Tmax) and AUC in plasma were comparable to the observed values. We showed that liver is exposed to the highest EtOH concentration, faster than other organs (Cmax = 839.50 mg/L and Tmax = 0.53 h), while brain exposure of EtOH (AUC = 1139.43 mg·h/L) is the highest among all other organs. Sensitivity analyses (SAs) showed direct proportion of EtOH rate and extent of absorption with administered EtOH dose and inverse relationship with gastric emptying time (GE) and steady-state volume of distribution (Vss). Conclusions The current PBPK model approach might help with designing in vitro experiments in the area of alcohol organ damage or alcohol-drug interaction studies.

scholarly journals Differential Effects of Linezolid and Ciprofloxacin on Toxin Production by Bacillus anthracis in anIn VitroPharmacodynamic System

2011 ◽  
Vol 56 (1) ◽  
pp. 513-517 ◽  
Author(s):  
Arnold Louie ◽  
Brian D. VanScoy ◽  
Henry S. Heine ◽  
Weiguo Liu ◽  
Terry Abshire ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Bacterial Population ◽  
Total Population ◽  
Toxin Production ◽  
Pharmacodynamic Model ◽  
Protein Synthesis Inhibitor ◽  
Synthesis Inhibitor ◽  
Content Type ◽  
Linezolid Therapy

ABSTRACTBacillus anthraciscauses anthrax. Ciprofloxacin is a gold standard for the treatment of anthrax. Previously, using the non-toxin-producing ΔSterne strain ofB. anthracis, we demonstrated that linezolid was equivalent to ciprofloxacin for reducing the total (vegetative and spore) bacterial population. With ciprofloxacin therapy, the total population consisted of spores. With linezolid therapy, the population consisted primarily of vegetative bacteria. Linezolid is a protein synthesis inhibitor, while ciprofloxacin is not. Since toxins are produced only by vegetativeB. anthracis, the effect of linezolid and ciprofloxacin on toxin production is of interest. The effect of simulated clinical regimens of ciprofloxacin and linezolid on the vegetative and spore populations and on toxin production was examined in anin vitropharmacodynamic model over 15 days by using the toxin-producing Sterne strain ofB. anthracis. Ciprofloxacin and linezolid reduced the total Sterne population at similar rates. With ciprofloxacin therapy, the total Sterne population consisted of spores. With linezolid therapy, >90% of the population was vegetativeB. anthracis. With ciprofloxacin therapy, toxin was first detectable at 3 h and remained detectable for at least 5 h. Toxin was never detected with linezolid therapy. Ciprofloxacin and linezolid reduced the total Sterne population at similar rates. However, theB. anthracispopulation was primarily spores with ciprofloxacin therapy and was primarily vegetative bacteria with linezolid therapy. Toxin production was detected for at least 5 h with ciprofloxacin therapy but was never detected with linezolid treatment. Linezolid may have an advantage over ciprofloxacin for the treatment ofB. anthracisinfections.

scholarly journals Pharmacodynamics of Isavuconazole in a DynamicIn VitroModel of Invasive Pulmonary Aspergillosis

2015 ◽  
Vol 60 (1) ◽  
pp. 278-287 ◽  
Author(s):  
Helen Box ◽  
Joanne Livermore ◽  
Adam Johnson ◽  
Laura McEntee ◽  
Timothy W. Felton ◽  
...  
Keyword(s):  
Invasive Pulmonary Aspergillosis ◽  
Pathogenic Fungi ◽  
Time Profile ◽  
Wild Type ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Target Values ◽  
Maximal Suppression

ABSTRACTIsavuconazonium sulfate is a novel triazole prodrug that has been recently approved for the treatment of invasive aspergillosis by the FDA. The active moiety (isavuconazole) has a broad spectrum of activity against many pathogenic fungi. This study utilized a dynamicin vitromodel of the human alveolus to describe the pharmacodynamics of isavuconazole against two wild-type and two previously defined azole-resistant isolates ofAspergillus fumigatus. A human-like concentration-time profile for isavuconazole was generated. MICs were determined using CLSI and EUCAST methodologies. Galactomannan was used as a measure of fungal burden. Target values for the area under the concentration-time curve (AUC)/MIC were calculated using a population pharmacokinetics-pharmacodynamics (PK-PD) mathematical model. Isolates with higher MICs required higher AUCs in order to achieve maximal suppression of galactomannan. The AUC/MIC targets necessary to achieve 90% probability of galactomannan suppression of <1 were 11.40 and 11.20 for EUCAST and CLSI, respectively.

scholarly journals Ampicillin in Combination with Ceftaroline, Cefepime, or Ceftriaxone Demonstrates Equivalent Activities in a High-Inoculum Enterococcus faecalis Infection Model

2016 ◽  
Vol 60 (5) ◽  
pp. 3178-3182 ◽  
Author(s):  
Megan K. Luther ◽  
Louis B. Rice ◽  
Kerry L. LaPlante
Keyword(s):  
Combination Therapy ◽  
Enterococcus Faecalis ◽  
Pharmacodynamic Model ◽  
Infection Model ◽  
Vancomycin Resistant Enterococcus ◽  
Content Type ◽  
Time Profiles ◽  
Concentration Time ◽  
Vancomycin Resistant

ABSTRACTAmpicillin-ceftriaxone combination therapy has become a predominant treatment for seriousEnterococcus faecalisinfections, such as endocarditis. Unfortunately, ceftriaxone use is associated with future vancomycin-resistant enterococcus colonization. We evaluatedE. faecalisin anin vitropharmacodynamic model against simulated human concentration-time profiles of ampicillin plus ceftaroline, cefepime, ceftriaxone, or gentamicin. Ampicillin-cefepime and ampicillin-ceftaroline demonstrated activities similar to those of ampicillin-ceftriaxone againstE. faecalis.

scholarly journals Intrapulmonary Distribution of Intravenous Telavancin in Healthy Subjects and Effect of Pulmonary Surfactant on In Vitro Activities of Telavancin and Other Antibiotics

2007 ◽  
Vol 52 (1) ◽  
pp. 92-97 ◽  
Author(s):  
Mark H. Gotfried ◽  
Jeng-Pyng Shaw ◽  
Bret M. Benton ◽  
Kevin M. Krause ◽  
Michael R. Goldberg ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Pulmonary Surfactant ◽  
Respiratory Infections ◽  
Time Profile ◽  
Epithelial Lining Fluid ◽  
Plasma Ratio ◽  
The Third ◽  
Concentration Time ◽  
In Vitro Antibacterial Activity

ABSTRACT Steady-state concentrations of telavancin, a novel, bactericidal lipoglycopeptide, were determined in the plasma, pulmonary epithelial lining fluid (ELF), and alveolar macrophages (AMs) of 20 healthy subjects. Telavancin at 10 mg of drug/kg of body weight/day was administered as a 1-h intravenous infusion on three successive days, with bronchoalveolar lavage performed on five subjects, each at 4, 8, 12, and 24 h after the last dose. Plasma samples were collected before the first and third infusions and at 1, 2, 3, 4, 8, 12, and 24 h after the third infusion. The plasma telavancin concentration-time profile was as reported previously. Telavancin (mean ± standard deviation) penetrated well into ELF (3.73 ± 1.28 μg/ml at 8 h and 0.89 ± 1.03 μg/ml at 24 h) and extensively into AMs (19.0 ± 16.8 μg/ml at 8 h, 45.0 ± 22.4 μg/ml at 12 h, and 42.0 ± 31.4 μg/ml at 24 h). Mean concentrations in AMs and plasma at 12 h were 45.0 μg/ml and 22.9 μg/ml (mean AM/plasma ratio, 1.93), respectively, and at 24 h were 42.0 μg/ml and 7.28 μg/ml (mean AM/plasma ratio, 6.67), respectively. Over the entire dosing interval, telavancin was present in ELF and AMs at concentrations up to 8-fold and 85-fold, respectively, above its MIC90 for methicillin-resistant Staphylococcus aureus (0.5 μg/ml). Pulmonary surfactant did not affect telavancin's in vitro antibacterial activity. Telavancin was well tolerated. These results support the proposal for further clinical evaluation of telavancin for treating gram-positive respiratory infections.

scholarly journals Absolute Bioavailability and Intracellular Pharmacokinetics of Azithromycin in Patients with Cystic Fibrosis

2005 ◽  
Vol 49 (12) ◽  
pp. 5013-5017 ◽  
Author(s):  
Paul Beringer ◽  
Kitty My Tu Huynh ◽  
Jane Kriengkauykiat ◽  
Luke Bi ◽  
Nils Hoem ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Healthy Volunteers ◽  
Drug Concentration ◽  
Elimination Rate ◽  
Pancreatic Enzymes ◽  
Absolute Bioavailability ◽  
Peripheral Compartment ◽  
Serum Drug Concentration ◽  
Open Label ◽  
Maximum Serum

ABSTRACT Chronic pulmonary infections with Pseudomonas aeruginosa are the primary cause of morbidity and mortality in patients with cystic fibrosis (CF). The macrolide antibiotics exhibit immunomodulatory and antivirulence activity. Clinical trials with azithromycin in CF have demonstrated significant improvements in pulmonary function and decreased hospitalizations. The purpose of this study was to compare the pharmacokinetics (PK) of azithromycin in patients with CF and controls. The study was conducted as an open-label, parallel, two-period crossover study involving 12 healthy volunteers and 12 patients with CF. Period 1 examined the serum PK following a single oral and intravenous dose, while period 2 examined the intracellular PK following multiple-dose oral administration. CF subjects differed significantly from controls based on weight (53.1 versus 71.0 kg; P < 0.01) and body mass index (19.7 versus 23.2; P < 0.01), respectively. Ninety-two percent of CF patients were pancreatic insufficient and were receiving pancreatic enzymes. The rate (time to reach maximum serum drug concentration, 3.0 versus 3.0 h; P = 0.78) and extent of absorption (absolute bioavailability, 34.2 versus 42.8%; P = 0.37) were similar in patients with CF and controls, respectively. Distribution to the tissues (rate of drug transfer from the central to the peripheral compartment, 1.22 versus 0.759 h−1; P = 0.03) and elimination (rate of elimination from the central compartment, 0.693 versus 0.492 h−1; P < 0.01) were more rapid in the healthy volunteers than in the CF subjects, respectively. Mononuclear cell concentrations (15.2 ± 6.0 mg/liter) far exceeded the maximum serum drug concentration (∼50-fold), demonstrating significant intracellular accumulation. These results indicate no alteration in dosage of azithromycin is necessary in patients with CF taking pancreatic enzymes.

scholarly journals Preclinical Pharmacokinetics of MI-219, a Novel Human Double Minute 2 (HDM2) Inhibitor and Prediction of Human Pharmacokinetics

2012 ◽  
Vol 15 (2) ◽  
pp. 265 ◽  
Author(s):  
Peng Zou ◽  
Nan Zheng ◽  
Yanke Yu ◽  
Shanghai Yu ◽  
Wei Sun ◽  
...  
Keyword(s):  
Allometric Scaling ◽  
Human Study ◽  
Volume Of Distribution ◽  
Time Profile ◽  
In Vitro Assays ◽  
Pharmacokinetic Studies ◽  
Human Pharmacokinetics ◽  
Preclinical Pharmacokinetics ◽  
Concentration Time

Purpose. The two purposes of this study were evaluating preclinical pharmacokinetics of MI-219 and predicting clearance (CL) and volume of distribution at steady-state (Vdss) of MI-219 in humans. Methods. Pharmacokinetic studies were conducted on mice, rats, dogs, and monkeys. Human CL of MI-219 was predicted using allometric scaling (SA), multi-exponential allometric scaling (ME), rule of exponents (RoE), single species scaling, two-term power equation (TTPE), physiologically based in vitro-in vivo extrapolation (IVIVE), and fu corrected intercept method (FCIM). In vitro assays were conducted to determine in vitro intrinsic CL, protein binding, and blood-plasma partition coefficients. To estimate half-life of MI-219, plasma concentration–time profile in humans was predicted using kallynochron and apolysichron time transformation (Dedrick plots) and normalization with MRT and Vdss (Wajima’s method). In addition, simultaneous interspecies scaling of CL, Vdss and concentration–time profile were performed by using Nonlinear Mixed Effects Modeling (NONMEM). Results. Preclinical studies showed that the elimination of MI-219 was mainly through metabolism. The validation using observed monkey CL and Vdss showed that MA, IVIVE and Oie-Tozer methods were accurately than the other methods. Human CL of MI-219 predicted by ME and IVIVE was between 0.237-0.342 L*h-1*kg-1. Human Vdss predicted by Oie-Tozer method and allometric scaling of unbound volume of distribution of tissues (VT/fuT) method was between 0.93-1.40 L*kg-1. Superimposition of rat, monkey and dog data was observed in Dedrick plots and Wajima’s transformations. Conclusions. The predicted human pharmacokinetics is useful for the design of first-in-human study. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Activities of Mutant Prevention Concentration-Targeted Moxifloxacin and Levofloxacin against Streptococcus pneumoniae in an In Vitro Pharmacodynamic Model

2003 ◽  
Vol 47 (8) ◽  
pp. 2606-2614 ◽  
Author(s):  
George P. Allen ◽  
Glenn W. Kaatz ◽  
Michael J. Rybak
Keyword(s):  
Streptococcus Pneumoniae ◽  
Pharmacodynamic Model ◽  
The Other ◽  
Time Curve ◽  
Development Of Resistance ◽  
Concentration Time ◽  
Mutant Prevention Concentration ◽  
Resistant Mutants ◽  
Selection Of

ABSTRACT The differential effects of moxifloxacin and levofloxacin on the development of resistance in four Streptococcus pneumoniae isolates were examined by using an in vitro pharmacodynamic model. Therapeutic regimens (moxifloxacin: peak, 4.5 μg/ml; half-life [t 1/2], 12 h; and levofloxacin: peak, 6 μg/ml; t 1/2, 6 h) were tested against two fluoroquinolone-susceptible isolates (strains 79 and ATCC 49619) and KD2138 and KD2139 (parC and gyrA mutants, respectively, of ATCC 49619). Mutant prevention concentration (MPC)-targeted regimens with modified pharmacokinetics of each drug were simulated to match the area under the concentration-time curve (AUC) above the MPC for the two fluoroquinolones. Moxifloxacin MICs and MPCs (MIC/MPC) for isolates 79, ATCC 49619, KD2138, and KD2139, respectively, were 0.125 and 0.5, 0.125 and 0.5, 0.25 and 8, and 0.25 and 4 μg/ml. Levofloxacin MICs and MPCs for the same isolates were 1 and 4, 0.5 and 2, 1 and 64, and 0.5 and 32 μg/ml, respectively. Therapeutic levofloxacin concentrations led to isolation of mutants of ATCC 49619 (S79Y in ParC), KD2138 (S81Y in GyrA), and KD2139 (S79Y in ParC). Therapeutic moxifloxacin concentrations against the gyrA mutant KD2139 resulted in outgrowth of a mutant with a ParC substitution (S79Y) but caused no emergence of mutants of the other three isolates. MPC-targeted moxifloxacin (lower-than-normal peak = 0.75 to 1.5 μg/ml, administered at levofloxacin's t 1/2) caused growth of a GyrA variant (S81Y) of KD2138 and a ParC variant (S79Y) of KD2139, while no mutants of ATCC 49619 were recovered. MPC-targeted levofloxacin (higher-than-normal peak = 14.5 to 29.5 μg/ml, administered at moxifloxacin's t 1/2) against KD2138 and KD2139 did not prevent the development of the mutations observed in therapeutic regimens, but resistance in the fluoroquinolone-susceptible ATCC 49619 was no longer noted. Normalization of the respective AUC/MPC ratios of moxifloxacin and levofloxacin did not eliminate differences in resistance selectivity of the two agents in all cases. We conclude that the reduced recovery of resistant mutants of S. pneumoniae following moxifloxacin exposure compared to levofloxacin may be due to intrinsic differences between the drugs. Increasing the concentration and exposure (t 1/2) to exceed the MPC may prevent mutations from occurring in fluoroquinolone-susceptible strains. However, this strategy did not prevent the selection of secondary mutants in strains with preexisting mutations. Further study of the MPC concept to evaluate these relationships is warranted.

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