scholarly journals Pharmacokinetics of Tedizolid in Adults with Cystic Fibrosis

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S293-S293
Author(s):  
Joshua Wang ◽  
Jenny Park ◽  
Jordanna Jayne ◽  
Timothy Bensman ◽  
David D’Argenio ◽  
...  
Keyword(s):  
Rate Constant ◽  
Clinical Care ◽  
Elimination Rate ◽  
Study Drug ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Lung Function Decline ◽  
Once Daily ◽  
Linear Trapezoidal Rule ◽  
Laboratory Changes

Abstract Background The presence of MRSA in the airways of patients with CF is associated with more rapid lung function decline and a higher mortality. Tedizolid (TDZ) is an oxazolidinone antibiotic with potent activity against MRSA; however, the pharmacokinetics (PK) in CF have not been described. The purpose of this study was to determine the PK of IV/PO tedizolid in plasma in patients being treated for acute pulmonary exacerbations. Methods We conducted a prospective, multiple dose, randomized, crossover study. TDZ phosphate was administered as 200 mg IV over 1h or PO once daily x 3 under fed conditions, with a 2-day washout, followed by crossover. Laboratory studies were performed throughout the study as routine clinical care. Blood samples were obtained prior to the Third dose of IV and PO and at 8 additional timepoints over 48 hours. TDZ concentrations in plasma were determined by LC-MS/MS. The maximum concentration (Cmax) and time to maximum (Tmax) were obtained from the measured data. Area-under-the concentration curve (AUC24) was determined using the linear trapezoidal rule. Compartmental PK was performed using ADAPT 5 software. Data are described by mean ± SD. Results The patients (4M, 2F) had a mean age of 27 years (22–32), BMI 22.0 ± 4.2 kg/m2, and predicted creatinine clearance of 128 ± 44 mL/minute. There was one report of diarrhea and hoarseness of voice that was unlikely related to the study drug. There were no clinically relevant laboratory changes. The Cmax, Tmax, and AUC24 following IV and PO administration were 2.87 ± 0.64 mg/L / 2.26 ± 0.70 mg/L, 1.32 ± 0.49 hours /2.06 ± 1.29 hours, and 27.1 ± 4.74 mg/L x hours / 25.8 ± 6.03 mg/L x hours respectively. The PK parameters for TDZ were described by a 1-compartment model: Elimination rate constant (Kel) = 0.088 ± 0.014 hour-1, Volume of distribution (V) = 96.4 ± 27.4 L, absorption rate constant (Ka) = 0.869 ± 0.978 hours−1, and bioavailability (F) = 1.00 ± 0.101. Conclusion The oral bioavailability of TDZ in patients with CF is complete and the pharmacokinetics are similar to that reported for healthy volunteers indicating no dose adjustments are needed in future studies evaluating the efficacy and safety in patients with CF. Disclosures All authors: No reported disclosures.

scholarly journals Population Pharmacokinetics of Linezolid in Adults with Pulmonary Tuberculosis

2009 ◽  
Vol 53 (9) ◽  
pp. 3981-3984 ◽  
Author(s):  
Bryan McGee ◽  
Reynaldo Dietze ◽  
David Jamil Hadad ◽  
Lucilia Pereira Dutra Molino ◽  
Ethel Leonor Noia Maciel ◽  
...  
Keyword(s):  
Pulmonary Tuberculosis ◽  
Rate Constant ◽  
Population Model ◽  
Absorption Rate ◽  
Elimination Rate ◽  
Volume Of Distribution ◽  
Free Drug ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time

ABSTRACT Nineteen adults with pulmonary tuberculosis received linezolid (600 mg) once or twice daily in an early bactericidal activity trial. A one-compartment population model produced median values for the absorption rate constant, volume of distribution, and elimination rate constant of 1.5 h−1, 29.6 liters, and 0.25 h−1 (once daily) and 2.7 h−1, 32.1 liters, and 0.15 h−1 (twice daily). Linezolid administered twice daily produced higher values for free drug area under the concentration-time curve (AUC)/MIC and time above MIC. Both regimens achieved free AUC/MIC ratios > 100. Median times above the MIC for free drug were 100% (twice daily) and 63% (once daily).

Letters to the Editor

PEDIATRICS ◽  
1981 ◽  
Vol 68 (4) ◽  
pp. 602-603
Author(s):  
Charles H. Feldman ◽  
Vincent E. Hutchinson ◽  
Charles E. Pippenger ◽  
Thomas A. Blumenfeld ◽  
Bernard R. Feldman ◽  
...  
Keyword(s):  
Elimination Rate ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Apparent Volume ◽  
Systemic Circulation ◽  
Volume Of Distribution ◽  
Letters To The Editor ◽  
Correct Formula ◽  
Original Report ◽  
Apparent Volume Of Distribution

We appreciate the comments of Weinberger et al and Spino et al. The equation utilized in our original report to calculate the apparent volume of distribution (V) was in error, as it was based on determinations for drugs that exhibit monoexponential elimination following a single intravenous dose. The correct formula for oral dosing at steady state with a drug obeying one-compartment model kinetics is: V = F.X0/AUCτ. K, where F is the total fraction of dose reaching systemic circulation, X0, is the dose, AUCτ is the area under the curve during a dosing interval; K is the elimination rate constant.1

scholarly journals 1573. Population Pharmacokinetic Analyses for Cefepime in Adult and Pediatric Patients

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S574-S575
Author(s):  
Jiajun Liu ◽  
Michael Neely ◽  
Jeffrey Lipman ◽  
Fekade B Sime ◽  
Jason Roberts ◽  
...  
Keyword(s):  
Rate Constant ◽  
Pediatric Patients ◽  
Validation Cohort ◽  
External Validation ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Information Criteria ◽  
Population Pharmacokinetic ◽  
Final Model ◽  
Two Compartment Model

Abstract Background Cefepime (CEF) is commonly used for adult and pediatric infections. Several studies have examined CEF’s pharmacokinetics (PK) in various populations; however, a unifying PK model for adult and pediatric subjects does not yet exist. We developed a combined population model for adult and pediatric patients and validated the model. Methods The initial model includes adult and pediatric patients with a rich cefepime sampling design. All adults received 2 g CEF while pediatric subjects received a mean of 49 (SD 5) mg/kg. One- and two-compartment models were considered as base models and were fit using a non-parametric adaptive grid algorithm within the Pmetrics package 1.5.2 (Los Angeles, CA) for R 3.5.1. Compartmental model selection was based on Akaike information criteria (AIC). Covariate relationships with PK parameters were visually inspected and mathematically assessed. Predictive performance was evaluated using bias and imprecision of the population and individual prediction models. External validation was conducted using a separate adult cohort. Results A total of 45 subjects (n = 9 adults; n = 36 pediatrics) were included in the initial PK model build and 12 subjects in the external validation cohort. Overall, the data were best described using a two-compartment model with volume of distribution (V) normalized to total body weight (TBW/70 kg) and an allometric scaled elimination rate constant (Ke) for pediatric subjects (AIC = 4,138.36). Final model observed vs. predicted plots demonstrated good fit (population R2 = 0.87, individual R2 = 0.97, Figure 1a and b). For the final model, the population median parameter values (95% credibility interval) were V0 (total volume of distribution), 11.7 L (10.2–14.6); Ke for adult, 0.66 hour−1 (0.38–0.78), Ke for pediatrics, 0.82 hour−1 (0.64–0.85), KCP (rate constant from central to peripheral compartment), 1.4 hour−1 (1.3–1.8), KPC (rate constant from peripheral to central compartment), 1.6 hour−1 (1.2–1.8). The validation cohort has 12 subjects, and the final model fit the data well (individual R2 = 0.75). Conclusion In this diverse group of adult and pediatrics, a two-compartment model described CEF PK well and was externally validated with a unique cohort. This model can serve as a population prior for real-time PK software algorithms. Disclosures All authors: No reported disclosures.

scholarly journals Pregnancy-Related Effects on Lamivudine Pharmacokinetics in a Population Study with 228 Women

2011 ◽  
Vol 56 (2) ◽  
pp. 776-782 ◽  
Author(s):  
Sihem Benaboud ◽  
Jean Marc Tréluyer ◽  
Saik Urien ◽  
Stéphane Blanche ◽  
Naim Bouazza ◽  
...  
Keyword(s):  
Amniotic Fluid ◽  
Pregnant Women ◽  
Rate Constant ◽  
Clearance Rate ◽  
Placental Transfer ◽  
Elimination Rate ◽  
Volume Of Distribution ◽  
Therapeutic Drug ◽  
Parameter Estimates ◽  
Population Parameter

ABSTRACTThe aim of this study was to describe lamivudine (3TC) pharmacokinetics (PK) in HIV-infected nonpregnant and pregnant women and their fetuses. Samples were collected according to therapeutic drug monitoring from 228 women treated with lamivudine and retrospectively analyzed by a population approach. The samples were also collected from cord blood and amniotic fluid at birth. Lamivudine pharmacokinetics were ascribed to an open two-compartment model with linear absorption and elimination. Mean population parameter estimates (intersubject variability) for women were an absorption rate constant of 1.04 h−1, an elimination clearance rate of 23.6 (0.266) liters · h−1, a central volume of distribution of 109 (0.897) liters, an intercompartmental clearance rate of 6.7 liters/h, and a peripheral volume of distribution of 129 liters. A fetal compartment was linked to maternal circulation by mother-to-cord (or fetus) and cord-to-mother rate constants of 0.463 h−1and 0.538 h−1, respectively. The amniotic fluid compartment was connected to the fetal compartment with an elimination rate constant of 0.163 h−1and a fixed-constant swallowing flow. The placental transfer expressed as fetal-to-maternal area under the concentration-time curve (AUC) ratio was 0.86, and the lamivudine amniotic fluid accumulation, expressed as the amniotic fluid-to-fetal AUC ratio, was 2.9. Pregnant women had a 22% higher apparent clearance than nonpregnant and parturient women; however, this increase did not lead to subexposure and should not require a dosage adjustment.

scholarly journals Absence of Effect of Rufloxacin on Theophylline Pharmacokinetics in Steady State

1998 ◽  
Vol 42 (9) ◽  
pp. 2359-2364 ◽  
Author(s):  
Martina Kinzig-Schippers ◽  
Uwe Fuhr ◽  
Marina Cesana ◽  
Carola Müller ◽  
A. Horst Staib ◽  
...  
Keyword(s):  
Steady State ◽  
Adverse Events ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Reversed Phase ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Elimination Phase ◽  
Once Daily ◽  
Model Independent

ABSTRACT Several quinolone antibacterial agents are known to inhibit the metabolism of theophylline, with the potential to cause adverse events due to raised theophylline concentrations during coadministration. A randomized crossover study was therefore conducted with 12 healthy male volunteers (ages, 23 to 34 years; body weight, 64 to 101 kg) to evaluate a possible interaction between rufloxacin and theophylline. Both drugs were administered at steady state. Following the administration of an oral loading dose of 400 mg on day 1, rufloxacin was given orally at 200 mg once daily on days 2 to 7 during one period only. During both periods, 146 mg of theophylline was administered orally twice daily for 3 days (which were days 4 to 6 of the rufloxacin coadministration period) and intravenously once the next morning to test for an interaction. Theophylline and rufloxacin concentrations were measured by reversed-phase high-pressure liquid chromatography, the pharmacokinetics of theophylline at steady state following administration of the last dose were calculated by compartment-model-independent methods. To compare the treatments, analysis of variance-based point estimates and 90% confidence intervals (given in parentheses) were calculated for the mean ratios of the pharmacokinetic parameters from the test (rufloxacin coadministration) over those from the reference (theophylline without rufloxacin) period. These were as follows: maximum concentration at steady state, 1.01 (0.96 to 1.07); area under the concentration-time curve from 0 to 12 h, 0.98 (0.94 to 1.02); half-life, 0.99 (0.95 to 1.03); total clearance at steady state, 1.02 (0.99 to 1.06); and volume of distribution in the elimination phase, 1.01 (0.97 to 1.05). In conclusion, rufloxacin did not affect theophylline pharmacokinetics at steady state. Therefore, therapeutic coadministration of rufloxacin and theophylline is not expected to cause an increased incidence of theophylline-related adverse events.

Bioconcentration and Elimination Kinetics of Copper with Different Tissues of the Ascidian Styela Clava

2011 ◽  
Vol 343-344 ◽  
pp. 583-589
Author(s):  
Ai Li Jiang ◽  
Zhen Yu ◽  
Chang Hai Wang
Keyword(s):  
Rate Constant ◽  
Accumulation Rate ◽  
Elimination Rate ◽  
Equilibrium Concentration ◽  
Compartment Model ◽  
High Rate ◽  
Elimination Kinetics ◽  
Styela Clava ◽  
Marine System ◽  
Different Tissues

Based on the semi-static two compartment model, the bioconcentration and elimination of copper with tissues of Styela clava were investigated. The kinetic parameters (accumulation rate constant k1, elimination rate constant k2, bioconcentration factor BCF, biological half life t1/2 and maximum equilibrium concentration CAmax) were obtained by non-linear regression. The results showed S. clava could accumulate copper from the aquatic environment and that BCF decreased with increasing metal concentration in water. When the accumulation achieved balance, CAmax showed positive correlation to metal concentrations in water. Concentrations of copper in different tissues of S. clava were in the order of gonad > digestive gland ≈ other part >tunic, and t1/2 of copper was 12.57 to 38.18 days in elimination phase. The high rate to accumulate and eliminate copper from its body exhibited a useful potential biomonitor of short-term copper fluctuations status in marine system.

Reevaluation of Gentamicin Dosing in the Neonatal Population

1995 ◽  
Vol 11 (3) ◽  
pp. 105-109
Author(s):  
Thomas M Gray
Keyword(s):  
Rate Constant ◽  
Gestational Age ◽  
Trough Concentration ◽  
Elimination Rate ◽  
Retrospective Chart Review ◽  
Volume Of Distribution ◽  
Full Term ◽  
Pharmacokinetic Parameters ◽  
Trough Concentrations ◽  
Neonatal Population

Objective: To determine whether current recommendations for gentamicin dosing in full-term newborns yield a serum peak concentration of 6–7 μg/mL and a trough concentration less than 2 μg/mL in treating suspected neonatal sepsis. Design: Two-year retrospective chart review. Setting: Community hospital. Results: Sample consisted of 175 newborns with a gestational age ranging from 36 to 43 weeks and 188 sets of concentrations. Pharmacokinetic parameters were calculated using a one-compartment, first-order elimination model and were reported as follows: volume of distribution 0.59 kg/L, elimination rate constant (ke) 0.11 h−1 (half-life [t1/2] 6.8 h) at 36–37 weeks of age, with a significant change (p < 0.05) in rate constant occurring at 38–43 weeks of life, and ke 0.12 h−1 (t1/2 6.0 h) when using a two-tailed, two-sample t-test. Extrapolated mean peak concentrations were 5.8 ± 1.2 μg/mL and trough concentrations were 1.5 ± 0.5 μg/mL. Furthermore, 14% of newborns had an extrapolated trough concentration of 2.0 μg/mL or more. Conclusions: The current 2.5-mg/kg dosage is appropriate for the neonatal population studied. However, to decrease the number of potentially toxic trough concentrations, the initial dosing interval should be extended to every 18 hours for full-term neonates (>37 weeks gestation) with normal kidney function and for neonates with a gestational age of 36–37 weeks.

Estimation of Pharmacokinetic Parameters at Steady-State in Patients

1978 ◽  
Vol 12 (10) ◽  
pp. 612-616 ◽  
Author(s):  
James W. Crow ◽  
Milo Gibaldi
Keyword(s):  
Steady State ◽  
Rate Constant ◽  
Elimination Rate ◽  
Simulated Data ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Total Clearance ◽  
Dosing Intervals ◽  
Apparent Volume Of Distribution

A method to characterize the pharmacokinetics of a drug in a patient receiving it chronically is proposed. In principle, such characterization may be carried out by obtaining one or more drug concentration in plasma-time values from several different dosing intervals, combining the data to create a composite dosing interval representative of the steady-state situation and fitting the data to an appropriate equation. The method was evaluated using simulated data based on the average pharmacokinetic parameters of theophylline in children. Reasonable estimates of the elimination rate constant and apparent volume of distribution may be obtained, but the estimation of the absorption rate constant presents formidable problems. The method appears to be most useful for obtaining very accurate estimates of total clearance.

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