scholarly journals Comparable Bioavailability and Disposition of Pefloxacin in Patients with Cystic Fibrosis and Healthy Volunteers Assessed via Population Pharmacokinetics

Pharmaceutics ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 323 ◽  
Author(s):  
Jürgen B. Bulitta ◽  
Yuanyuan Jiao ◽  
Cornelia B. Landersdorfer ◽  
Dhruvitkumar S. Sutaria ◽  
Xun Tao ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Healthy Volunteers ◽  
Allometric Scaling ◽  
Oral Treatment ◽  
Volume Of Distribution ◽  
Fat Free Mass ◽  
Parameter Estimates ◽  
Total Clearance ◽  
Quinolone Antibiotics ◽  
Volumes Of Distribution

Quinolone antibiotics present an attractive oral treatment option in patients with cystic fibrosis (CF). Prior studies have reported comparable clearances and volumes of distribution in patients with CF and healthy volunteers for primarily renally cleared quinolones. We aimed to provide the first pharmacokinetic comparison for pefloxacin as a predominantly nonrenally cleared quinolone and its two metabolites between both subject groups. Eight patients with CF (fat-free mass [FFM]: 36.3 ± 6.9 kg, average ± SD) and ten healthy volunteers (FFM: 51.7 ± 9.9 kg) received 400 mg pefloxacin as a 30 min intravenous infusion and orally in a randomized, two-way crossover study. All plasma and urine data were simultaneously modelled. Bioavailability was complete in both subject groups. Pefloxacin excretion into urine was approximately 74% higher in patients with CF compared to that in healthy volunteers, whereas the urinary excretion of metabolites was only slightly higher in patients with CF. After accounting for body size and composition via allometric scaling by FFM, pharmacokinetic parameter estimates in patients with CF divided by those in healthy volunteers were 0.912 for total clearance, 0.861 for nonrenal clearance, 1.53 for renal clearance, and 0.916 for volume of distribution. Nonrenal clearance accounted for approximately 90% of total pefloxacin clearance. Overall, bioavailability and disposition were comparable between both subject groups.

scholarly journals Population Pharmacokinetic Comparison and Pharmacodynamic Breakpoints of Ceftazidime in Cystic Fibrosis Patients and Healthy Volunteers

2010 ◽  
Vol 54 (3) ◽  
pp. 1275-1282 ◽  
Author(s):  
J. B. Bulitta ◽  
C. B. Landersdorfer ◽  
S. J. Hüttner ◽  
G. L. Drusano ◽  
M. Kinzig ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Healthy Volunteers ◽  
Burkholderia Cepacia ◽  
Total Body Weight ◽  
Volume Of Distribution ◽  
Fat Free Mass ◽  
Population Pharmacokinetic ◽  
Total Clearance ◽  
Target Time ◽  
Population Pk

ABSTRACT Despite the promising activity of ceftazidime against Pseudomonas aeruginosa and Burkholderia cepacia, there has not yet been a study that directly compared the pharmacokinetics (PK) of ceftazidime in cystic fibrosis (CF) patients and healthy volunteers by population PK methodology. We assessed the population PK and PK/pharmacodynamic (PD) breakpoints of ceftazidime in CF patients and healthy volunteers. Eight CF patients (total body weight [WT] [average ± standard deviation] = 42.9 ± 18.4 kg) and seven healthy volunteers (WT = 66.2 ± 4.9 kg) received 2 g ceftazidime as a 5-min intravenous infusion. High-performance liquid chromatography (HPLC) was used for drug analysis, and NONMEM (results reported), S-ADAPT, and NPAG were used for parametric and nonparametric population PK modeling. We considered linear and allometric body size models to scale clearance and volume of distribution. Monte Carlo simulations were based on a target time of non-protein-bound plasma concentration of ceftazidime above MIC of ≥65%, which represents near-maximal killing. Unscaled total clearance was 19% lower in CF patients, and volume of distribution was 36% lower. Total clearance was 7.82 liters/h for CF patients and 6.68 liters/h for healthy volunteers with 53 kg fat-free mass. Allometric scaling by fat-free mass reduced the between-subject variability by 32% for clearance and by 18 to 26% for volume of both peripheral compartments compared to linear scaling by WT. A 30-min ceftazidime infusion of 2 g/70 kg WT every 8 h (q8h) achieved robust (≥90%) probabilities of target attainment (PTAs) for MICs of ≤1 mg/liter in CF patients and ≤3 mg/liter in healthy volunteers. Alternative modes of administration achieved robust PTAs up to markedly higher MICs of ≤8 to 12 mg/liter in CF patients for 5-h infusions of 2 g/70 kg WT q8h and ≤12 mg/liter for continuous infusion of 6 g/70 kg WT daily.

scholarly journals Comparable Population Pharmacokinetics and Pharmacodynamic Breakpoints of Cefpirome in Cystic Fibrosis Patients and Healthy Volunteers

2011 ◽  
Vol 55 (6) ◽  
pp. 2927-2936 ◽  
Author(s):  
J. B. Bulitta ◽  
M. Kinzig ◽  
C. B. Landersdorfer ◽  
U. Holzgrabe ◽  
U. Stephan ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Healthy Volunteers ◽  
High Performance ◽  
Standard Dose ◽  
Total Body Weight ◽  
Volume Of Distribution ◽  
Nonparametric Bootstrap ◽  
Population Pk ◽  
Total Body ◽  
Similar Body

ABSTRACTCystic fibrosis (CF) patients are often reported to have higher clearances and larger volumes of distribution per kilogram of total body weight (WT) for beta-lactams than healthy volunteers. As pharmacokinetic (PK) data on cefpirome from studies of CF patients are lacking, we systematically compared its population PK and pharmacodynamic breakpoints for CF patients and healthy volunteers of similar body size. Twelve adult CF patients (median lean body mass [LBM] = 45.7 kg) and 12 healthy volunteers (LBM = 50.0 kg) received a single 10-min intravenous infusion of 2 g cefpirome. Plasma and urine concentrations were determined by high-performance liquid chromatography (HPLC). Population PK and Monte Carlo simulations were performed using NONMEM and S-ADAPT and a duration of an unbound plasma concentration above the MIC ≥ 65% of the dosing interval as a pharmacodynamic target. Unscaled clearances for CF patients were similar to those seen with healthy volunteers, and the volume of distribution was 6% lower for CF patients. Linear scaling of total clearance by WT resulted in clearance that was 20% higher (P≤ 0.001 [nonparametric bootstrap]) in CF patients. Allometric scaling by LBM explained the differences between the two subject groups with respect to average clearance and volume of distribution and reduced the unexplained between-subject variability of renal and nonrenal clearance by 10 to 14%. For the CF patients, robust (>90%) probabilities of target attainment (PTA) were achieved by the administration of a standard dose of 2 g/70 kg WT every 12 h (Q12h) given as 30-min infusions for MICs ≤ 1.5 mg/liter. As alternative dosage regimens, a 5-h infusion of 1.33 g/70 kg WT Q8h achieved robust PTAs for MICs ≤ 8 to 12 mg/liter and a continuous infusion of 4 g/day for MICs ≤ 12 mg/liter. Prolonged infusion of cefpirome is expected to be superior to short-term infusions for MICs between 2 and 12 mg/liter.

scholarly journals Novel Population Pharmacokinetic Approach to Explain the Differences between Cystic Fibrosis Patients and Healthy Volunteers via Protein Binding

Pharmaceutics ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 286 ◽  
Author(s):  
Nirav Shah ◽  
Jürgen Bulitta ◽  
Martina Kinzig ◽  
Cornelia Landersdorfer ◽  
Yuanyuan Jiao ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Protein Binding ◽  
Healthy Volunteers ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Unbound Fraction ◽  
Low Protein ◽  
Novel Approach ◽  
Special Patient

The pharmacokinetics in patients with cystic fibrosis (CF) has long been thought to differ considerably from that in healthy volunteers. For highly protein bound β-lactams, profound pharmacokinetic differences were observed between comparatively morbid patients with CF and healthy volunteers. These differences could be explained by body weight and body composition for β-lactams with low protein binding. This study aimed to develop a novel population modeling approach to describe the pharmacokinetic differences between both subject groups by estimating protein binding. Eight patients with CF (lean body mass [LBM]: 39.8 ± 5.4kg) and six healthy volunteers (LBM: 53.1 ± 9.5kg) received 1027.5 mg cefotiam intravenously. Plasma concentrations and amounts in urine were simultaneously modelled. Unscaled total clearance and volume of distribution were 3% smaller in patients with CF compared to those in healthy volunteers. After allometric scaling by LBM to account for body size and composition, the remaining pharmacokinetic differences were explained by estimating the unbound fraction of cefotiam in plasma. The latter was fixed to 50% in male and estimated as 54.5% in female healthy volunteers as well as 56.3% in male and 74.4% in female patients with CF. This novel approach holds promise for characterizing the pharmacokinetics in special patient populations with altered protein binding.

scholarly journals Population pharmacokinetics of ceftazidime in cystic fibrosis patients analyzed by using a nonparametric algorithm and optimal sampling strategy.

1996 ◽  
Vol 40 (5) ◽  
pp. 1091-1097 ◽  
Author(s):  
A A Vinks ◽  
J W Mouton ◽  
D J Touw ◽  
H G Heijerman ◽  
M Danhof ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Population Modeling ◽  
Sampling Strategy ◽  
Volume Of Distribution ◽  
Population Models ◽  
Posteriori Probability ◽  
Parameter Estimates ◽  
Data Sets ◽  
Optimal Sampling ◽  
Two Stage

Postinfusion data obtained from 17 patients with cystic fibrosis participating in two clinical trials were used to develop population models for ceftazidime pharmacokinetics during continuous infusion. Determinant (D)-optimal sampling strategy (OSS) was used to evaluate the benefits of merging four maximally informative sampling times with population modeling. Full and sparse D-optimal sampling data sets were analyzed with the nonparametric expectation maximization (NPEM) algorithm and compared with the model obtained by the traditional standard two-stage approach. Individual pharmacokinetic parameter estimates were calculated by weighted nonlinear least-squares regression and by maximum a posteriori probability Bayesian estimator. Individual parameter estimates obtained with four D-optimally timed serum samples (OSS4) showed excellent correlation with parameter estimates obtained by using full data sets. The parameters of interest, clearance and volume of distribution, showed excellent agreement (R2 = 0.89 and R2 = 0.86). The ceftazidime population models were described as two-compartment kslope models, relating elimination constants to renal function. The NPEM-OSS4 model was described by the equations kel = 0.06516+ (0.00708.CLCR) and V1 = 0.1773 +/- 0.0406 liter/kg where CLCR is creatinine clearance in milliliters per minute per 1.73 m2, V1 is the volume of distribution of the central compartment, and kel is the elimination rate constant. Predictive performance evaluation for 31 patients with data which were not part of the model data sets showed that the NPEM-ALL model performed best, with significantly better precision than that of the standard two-stage model (P < 0.001). Predictions with the NPEM-OSS4 model were as precise as those with the NPEM-ALL model but slightly biased (-2.2 mg/liter; P < 0.01). D-optimal monitoring strategies coupled with population modeling results in useful and cost-effective population models and will be of advantage in clinical practice, as it allows pharmacokinetic-pharmacodynamic modeling with sparse data, thus describing the relationship between ceftazidime exposure and response in the treatment of acute exacerbations in patients with cystic fibrosis.

scholarly journals Pharmacokinetics of CS-023 (RO4908463), a Novel Parenteral Carbapenem, in Healthy Male Caucasian Volunteers

2006 ◽  
Vol 50 (12) ◽  
pp. 4186-4188 ◽  
Author(s):  
Takahiro Shibayama ◽  
Yoko Matsushita ◽  
Takashi Hirota ◽  
Toshihiko Ikeda ◽  
Shogo Kuwahara
Keyword(s):  
Urinary Excretion ◽  
Healthy Volunteers ◽  
Renal Clearance ◽  
Half Life ◽  
Volume Of Distribution ◽  
Total Clearance ◽  
Healthy Male ◽  
Cumulative Urinary Excretion

ABSTRACT The CS-023 concentration in plasma after administration by infusion to healthy volunteers at a dose of 700 mg was decreased, with a half-life of 1.7 h, and the cumulative urinary excretion was 59.4% of the dose. The total clearance, renal clearance, and volume of distribution were 8.12 liters/h, 4.14 liters/h, and 17.2 liters, respectively.

scholarly journals Pharmacokinetic Evaluation of Single-Dose Intravenous Daptomycin in Patients with Thermal Burn Injury

2008 ◽  
Vol 52 (5) ◽  
pp. 1891-1893 ◽  
Author(s):  
John F. Mohr ◽  
Luis Ostrosky-Zeichner ◽  
David J. Wainright ◽  
Donald H. Parks ◽  
Timothy C. Hollenbeck ◽  
...  
Keyword(s):  
Body Weight ◽  
Healthy Volunteers ◽  
Burn Injury ◽  
Volume Of Distribution ◽  
Burn Patients ◽  
Total Clearance ◽  
Time Curve ◽  
Thermal Burn ◽  
Concentration Time ◽  
Pharmacokinetic Evaluation

ABSTRACT Daptomycin pharmacokinetics were evaluated for burn patients. Burn patients had decreases in the maximum concentration of the drug in serum (44%) and the area under the concentration-time curve (47%) and increases in the volume of distribution (64%) and total clearance (77%) compared to healthy volunteers. In burn patients, daptomycin at 10 to 12 mg/kg of body weight/day would be required to achieve drug exposures similar to those for healthy volunteers receiving 6 mg/kg.

scholarly journals Pharmacokinetics of Aztreonam in Healthy Subjects and Patients with Cystic Fibrosis and Evaluation of Dose-Exposure Relationships Using Monte Carlo Simulation

2007 ◽  
Vol 51 (9) ◽  
pp. 3049-3055 ◽  
Author(s):  
Alexander A. Vinks ◽  
Ronald N. van Rossem ◽  
Ron A. A. Mathôt ◽  
Harry G. M. Heijerman ◽  
Johan W. Mouton
Keyword(s):  
Cystic Fibrosis ◽  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Pharmacokinetic Parameter ◽  
Healthy Subjects ◽  
Total Body Clearance ◽  
Volume Of Distribution ◽  
Parameter Estimates ◽  
Total Body ◽  
Body Clearance

ABSTRACT Aztreonam (AZM) is a monobactam antibiotic with a high level of activity against gram-negative micro-organisms, including Pseudomonas aeruginosa. We evaluated AZM pharmacokinetics and pharmacokinetic-pharmacodynamic relationships in patients with cystic fibrosis (CF) and healthy subjects. Pharmacokinetic data in eight CF patients and healthy subjects that were matched for age, gender, weight, and height were obtained and analyzed by using the nonparametric adaptive grid algorithm. Probabilities of target attainment using percentages of time of unbound concentration above the MIC (fT>MIC) were obtained by using a Monte Carlo simulation. AZM total body clearance was significantly higher in CF patients (100.1 ± 17.1 versus 76.2 ± 7.4 ml/min in healthy subjects; P < 0.01). The pharmacokinetic parameter estimates for terminal half-life (1.54 ± 0.17 h [mean ± the standard deviation]) and volume of distribution (0.20 ± 0.02 liters/kg in patients with CF patients were not different from those in healthy subjects. Monte Carlo simulations with a target of a fT>MIC of 50 to 60% at a dose of 1,000 mg every 8 h indicated a clinical breakpoint of 4 mg/liter and 1 to 2 mg/liter for healthy subjects and CF patients, respectively. This study using matched controls showed that AZM total body clearance and not the volume of distribution is higher in CF patients as a result of increased renal clearance. Pharmacokinetic parameter estimates in healthy subjects resulted in a clinical susceptibility breakpoint of ≤4 mg/liter for a dose of 1,000 mg every 8 h. Patients suspected of having high clearance rates, such as CF patients, should be monitored closely, with dosing regimens adjusted accordingly.

scholarly journals Cystic Fibrosis Sputum Impairs the Ability of Neutrophils to Kill Staphylococcus aureus

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 703
Author(s):  
Kayla Fantone ◽  
Samantha L. Tucker ◽  
Arthur Miller ◽  
Ruchi Yadav ◽  
Eryn E. Bernardy ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Healthy Volunteers ◽  
Airway Disease ◽  
Neutrophil Extracellular Trap ◽  
Lung Function Decline ◽  
Bacterial Killing ◽  
Cystic Fibrosis Sputum ◽  
Microbial Infections

Cystic fibrosis (CF) airway disease is characterized by chronic microbial infections and infiltration of inflammatory polymorphonuclear (PMN) granulocytes. Staphylococcus aureus (S. aureus) is a major lung pathogen in CF that persists despite the presence of PMNs and has been associated with CF lung function decline. While PMNs represent the main mechanism of the immune system to kill S. aureus, it remains largely unknown why PMNs fail to eliminate S. aureus in CF. The goal of this study was to observe how the CF airway environment affects S. aureus killing by PMNs. PMNs were isolated from the blood of healthy volunteers and CF patients. Clinical isolates of S. aureus were obtained from the airways of CF patients. The results show that PMNs from healthy volunteers were able to kill all CF isolates and laboratory strains of S. aureus tested in vitro. The extent of killing varied among strains. When PMNs were pretreated with supernatants of CF sputum, S. aureus killing was significantly inhibited suggesting that the CF airway environment compromises PMN antibacterial functions. CF blood PMNs were capable of killing S. aureus. Although bacterial killing was inhibited with CF sputum, PMN binding and phagocytosis of S. aureus was not diminished. The S. aureus-induced respiratory burst and neutrophil extracellular trap release from PMNs also remained uninhibited by CF sputum. In summary, our data demonstrate that the CF airway environment limits killing of S. aureus by PMNs and provides a new in vitro experimental model to study this phenomenon and its mechanism.

Sign in / Sign up

Export Citation Format

Share Document