Pharmacokinetics of Intravenous and Oral Linezolid in Adults with Cystic Fibrosis

ABSTRACTLinezolid is a treatment option for methicillin-resistantStaphylococcus aureus(MRSA) infections in cystic fibrosis (CF) patients. Little is known, however, about its pharmacokinetics in this population. Eight adults with CF were randomized to receive intravenous (i.v.) and oral linezolid at 600 mg twice daily for 9 doses in a crossover design with a 9-day washout. Plasma samples were collected after the first and ninth doses of each phase. Population pharmacokinetic analyses were performed by nonlinear mixed-effects modeling using a previously described 2-compartment model with time-dependent clearance inhibition. Monte Carlo simulation was performed to assess the activities of the linezolid dosing regimens against 42 contemporary MRSA isolates recovered from CF patients. The following pharmacokinetic parameter estimates were observed for the population: absorption rate constant, 1.91 h−1; clearance, 9.54 liters/h; volume of central compartment, 26.8 liters; volume of peripheral compartment, 17.3 liters; and intercompartmental clearance, 104 liters/h. Linezolid demonstrated nonlinear clearance after 9 doses, which was reduced by a mean of 38.9% (range, 28.8 to 59.9%). Mean bioavailability was 85% (range, 47 to 131%). At steady state, 600 mg given twice daily produced 93.0% and 87.2% probabilities of obtaining the target pharmacodynamic exposure against the MRSA isolates for the i.v. and oral formulations, respectively. Thrice-daily dosing increased the probabilities to 97.0% and 95.6%, respectively. Linezolid pharmacokinetics in these adults with CF were well described by a 2-compartment model with time-dependent clearance inhibition. Standard i.v. and oral dosing regimens should be sufficient to reliably attain pharmacodynamic targets against most MRSA isolates; however, more frequent dosing may be required for isolates with MICs of ≥2 μg/ml.

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Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01914-19 ◽

2019 ◽

Vol 64 (1) ◽

Author(s):

James M. Kidd ◽

Colleen M. Sakon ◽

Louise-Marie Oleksiuk ◽

Jeffrey J. Cies ◽

Rebecca S. Pettit ◽

...

Keyword(s):

Cystic Fibrosis ◽

Body Weight ◽

Total Body Weight ◽

Central Compartment ◽

Volume Of Distribution ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Minimal Risk ◽

Content Type ◽

Total Body

ABSTRACT Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus. Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (n = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment (Vc) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight (Vθ) normalized by the median observed value (Vc = Vθ × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CLNR + CLθ × CRCL), where CLNR represents nonrenal clearance and CLθ represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: Vθ, 4.92 ± 0.76 liters · kg−1; CLNR, 0.59 ± 0.30 liters · h−1; CLθ, 5.97 × 10−3 ± 1.24 × 10−3; Vp (volume of the peripheral compartment), 3.77 ± 1.41 liters; Q (intercompartmental clearance), 4.08 ± 2.17 liters · h−1. The free area under the concentration-time curve (fAUC) values for 7.5 and 10 mg/kg were 30 ± 4.6 and 52 ± 12 mg · h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a fAUC/MIC threshold of >215, respectively, for MIC of ≤0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg · h · liter−1) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.)

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Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?

Pharmaceutics ◽

10.3390/pharmaceutics12040380 ◽

2020 ◽

Vol 12 (4) ◽

pp. 380 ◽

Cited By ~ 2

Author(s):

Quentin Allard ◽

Zoubir Djerada ◽

Claire Pouplard ◽

Yohann Repessé ◽

Dominique Desprez ◽

...

Keyword(s):

Half Life ◽

Random Effect ◽

Real Life ◽

Compartment Model ◽

Central Compartment ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Severe Haemophilia ◽

Fviii Activity ◽

Data Files

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.

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Nemonoxacin Dosage Adjustment in Patients with Severe Renal Impairment Based on Population Pharmacokinetic and Pharmacodynamic Analysis

10.22541/au.161167889.97008719/v1 ◽

2021 ◽

Author(s):

Yi Li ◽

Jianda Lu ◽

Yue Kang ◽

Xiaoyong Xu ◽

Xin Li ◽

...

Keyword(s):

Renal Impairment ◽

Severe Renal Impairment ◽

Compartment Model ◽

Central Compartment ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Healthy Controls ◽

Dosing Regimen ◽

Open Label ◽

Optimal Dosing

Aims: To optimize the dosing regimen in patients with severe renal impairment based on population pharmacokinetic/pharmacodynamic (PPK/PD) analysis. Methods: The pharmacokinetics and safety of nemonoxacin was evaluated in a single-dose, open-label, nonrandomized, parallel-group study after single oral dose of 0.5 g nemonoxacin capsule in 10 patients with severe renal impairment and 10 healthy controls. Both blood and urine samples were collected within 48 hours after admission and determined the concentrations. A PPK model was built using nonlinear mixed effects modelling. The probability of target attainment (PTA) and the cumulative fraction of response (CFR) against S. Pneumoniae and S. aureus was calculated by Monte Carlo simulation. Results: The data best fitted to a two-compartment model, from which the PPK parameters were estimated, including clearance (8.55 L/h), central compartment volume (80.8 L), and peripheral compartment volume (50.6 L). The accumulative urinary excretion was 23.4±6.5% in severe renal impairment patients and 66.1±16.8% in healthy controls. PPK/PD modeling and simulation of 4 dosage regimens found that nemonoxacin 0.5 g q48h was the optimal dosing regimen in severe renal impairment patients, evidenced by higher PTA (92.7%) and CFR (>99%) at nemonoxacin MIC ≤ 1 mg/L against S. pneumoniae and S. aureus. The alternative regimens (0.25 g q24h; loading dose 0.5 g on Day 1 followed by 0.25 g q24h) were insufficient to cover the pathogens even if MIC ≤ 0.5 mg/L. Conclusion: An extended dosing interval (0.5 g q48h) may be appropriate for optimal efficacy of nemonoxacin in case of severe renal impairment.

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Population Pharmacokinetic Model for Vancomycin Used in Open Heart Surgery: Model-Based Evaluation of Standard Dosing Regimens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00088-18 ◽

2018 ◽

Vol 62 (7) ◽

Cited By ~ 1

Author(s):

Saeed A. Alqahtani ◽

Abdullah S. Alsultan ◽

Hussain M. Alqattan ◽

Ahmed Eldemerdash ◽

Turki B. Albacker

Keyword(s):

Heart Surgery ◽

Open Heart Surgery ◽

Central Compartment ◽

Volume Of Distribution ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Albumin Concentration ◽

Open Heart ◽

Blood Samples ◽

Dosing Regimens

ABSTRACTThe purpose of this study was to investigate the population pharmacokinetics of vancomycin in patients undergoing open heart surgery. In this observational pharmacokinetic study, multiple blood samples were drawn over a 48-h period of intravenous vancomycin in patients who were undergoing open heart surgery. Blood samples were analyzed using an Architect i4000SR immunoassay analyzer. Population pharmacokinetic models were developed using Monolix 4.4 software. Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. A total of 168 blood samples were analyzed from 28 patients. The pharmacokinetics of vancomycin are best described by a two-compartment model with between-subject variability in clearance (CL), the volume of distribution of the central compartment (V1), and volume of distribution of the peripheral compartment (V2). The CL and theV1of vancomycin were related to creatinine CL (CLCR), body weight, and albumin concentration. Dosing simulations showed that standard dosing regimens of 1 and 1.5 g failed to achieve the PK-PD target of AUC0–24/MIC > 400 for an MIC of 1 mg/liter, while high weight-based dosing regimens were able to achieve the PK-PD target. In summary, the administration of standard doses of 1 and 1.5 g of vancomycin two times daily provided inadequate antibiotic prophylaxis in patients undergoing open heart surgery. The same findings were obtained when 15- and 20-mg/kg doses of vancomycin were administered. Achieving the PK-PD target required higher doses (25 and 30 mg/kg) of vancomycin.

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Pharmacokinetics of Tedizolid in Plasma and Sputum of Adults with Cystic Fibrosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00550-18 ◽

2018 ◽

Vol 62 (9) ◽

Cited By ~ 2

Author(s):

A young J. Park ◽

Joshua Wang ◽

Jordanna Jayne ◽

Lynn Fukushima ◽

Adupa P. Rao ◽

...

Keyword(s):

Cystic Fibrosis ◽

Dosage Form ◽

Plasma Concentrations ◽

Compartment Model ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Published Data ◽

Total Clearance ◽

Content Type ◽

Complicated Skin

ABSTRACT Over the past decade, the prevalence of infections involving methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) has increased significantly. Tedizolid (TZD) demonstrates excellent activity against MRSA and a favorable safety profile. The pharmacokinetics of several antibiotics have been shown to be altered in CF patients. The purpose of this study was to characterize the pharmacokinetics of tedizolid in this population. Eleven patients with CF were randomized to receive tedizolid phosphate at 200 mg orally or intravenously once daily for 3 doses with a minimum 2-day washout, followed by crossover to the remaining dosage form. Plasma and expectorated sputum were collected following the third dose of each dosage form for analysis. Population pharmacokinetic analysis was performed using the maximum likelihood expectation maximization method, and the disposition of TZD was described by a two-compartment model. The sputum concentrations exceeded the unbound plasma concentrations with an estimated mean sputum-to-unbound plasma penetration ratio of 2.88 (coefficient of variation, 50.3%). The estimated population mean ± standard deviation of total clearance, central volume of distribution, and bioavailability were 9.72 ± 1.62 liters/h, 61.6 ± 6.94 liters, and 1.04 ± 0.232, respectively. The total clearance was higher in CF patients than in healthy volunteers; however, it was similar to published data for patients with complicated skin and skin structure infections (cSSSIs). This study demonstrates that the oral bioavailability of tedizolid is excellent in patients with CF and that the plasma pharmacokinetics are similar to those reported for patients with cSSSIs.

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Population Pharmacokinetics of Piperacillin in the Early Phase of Septic Shock: Does Standard Dosing Result in Therapeutic Plasma Concentrations?

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01347-15 ◽

2015 ◽

Vol 59 (11) ◽

pp. 7018-7026 ◽

Cited By ~ 14

Author(s):

Kristina Öbrink-Hansen ◽

Rasmus Vestergaard Juul ◽

Merete Storgaard ◽

Marianne Kragh Thomsen ◽

Tore Forsingdal Hardlei ◽

...

Keyword(s):

Septic Shock ◽

Renal Function ◽

Plasma Concentrations ◽

Compartment Model ◽

Pharmacokinetic Profile ◽

Population Pharmacokinetic ◽

Relative Standard Error ◽

Content Type ◽

Relative Standard ◽

Dosing Regimens

ABSTRACTAntibiotic dosing in septic shock patients poses a challenge for clinicians due to the pharmacokinetic (PK) variability seen in this patient population. Piperacillin-tazobactam is often used for empirical treatment, and initial appropriate dosing is crucial for reducing mortality. Accordingly, we determined the pharmacokinetic profile of piperacillin (4 g) every 8 h, during the third consecutive dosing interval, in 15 patients treated empirically for septic shock. We developed a population pharmacokinetic model to assess empirical dosing and to simulate alternative dosing regimens and modes of administration. Time above the MIC (T>MIC) predicted for each patient was evaluated against clinical breakpoint MIC forPseudomonas aeruginosa(16 mg/liter). Pharmacokinetic-pharmacodynamic (PK/PD) targets evaluated were 50%fT>4×MIC and 100%fT>MIC. A population PK model was developed using NONMEM, and data were best described by a two-compartment model. Central and intercompartmental clearances were 3.6 liters/h (relative standard error [RSE], 15.7%) and 6.58 liters/h (RSE, 16.4%), respectively, and central and peripheral volumes were 7.3 liters (RSE, 11.8%) and 3.9 liters (RSE, 9.7%), respectively. Piperacillin plasma concentrations varied considerably between patients and were associated with levels of plasma creatinine. Patients with impaired renal function were more likely to achieve predefined PK/PD targets than were patients with preserved or augmented renal function. Simulations of alternative dosing regimens showed that frequent intermittent bolus dosing as well as dosing by extended and continuous infusion increases the probability of attaining therapeutic plasma concentrations. For septic shock patients with preserved or augmented renal function, dose increment or prolonged infusion of the drug needs to be considered. (This study has been registered at ClinicalTrials.gov under registration no. NCT02306928.)

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Population Pharmacokinetics of Teicoplanin in Preterm and Term Neonates: Is It Time for a New Dosing Regimen?

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01971-19 ◽

2020 ◽

Vol 64 (4) ◽

Cited By ~ 1

Author(s):

A. Kontou ◽

K. Sarafidis ◽

O. Begou ◽

H. G. Gika ◽

A. Tsiligiannis ◽

...

Keyword(s):

Creatinine Clearance ◽

Maintenance Dose ◽

Plasma Concentrations ◽

Central Compartment ◽

Preterm Neonates ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Dosing Regimen ◽

Time Curve ◽

Content Type

ABSTRACT Our objective was to develop a population pharmacokinetic (PK) model in order to evaluate the currently recommended dosing regimen in term and preterm neonates. By using an optimal design approach, a prospective PK study was designed and implemented in 60 neonates with postmenstrual ages (PMA) of 26 to 43 weeks. A loading dose of 16 mg/kg was administered at day 1, followed by a maintenance dose of 8 mg/kg daily. Plasma concentrations were quantified by high-pressure liquid chromatography–mass spectrometry. Population PK (popPK) analysis was performed using NONMEM software. Monte-Carlo (MC) simulations were performed to evaluate currently recommended dosing based on a pharmacodynamic index of area under the concentration-time curve (AUC)/MIC ratio of ≥400. A two-compartment model with linear elimination best described the data by the following equations: clearance (CL) = 0.0227 × (weight [wt]/1,765)0.75 × (estimated creatinine clearance [eCRCL]/22)0.672, central compartment volume of distribution (V1) = 0.283 (wt/1,765), intercompartmental clearance (Q) = 0.151 (wt/1,765)0.75, and peripheral compartment volume (V2) = 0.541 (wt/1,765). The interindividual variability estimates for CL, V1, and V2 were 36.5%, 45.7%, and 51.4%, respectively. Current weight (wt) and estimated creatinine clearance (eCRCL) significantly explained the observed variability. MC simulation demonstrated that, with the current dosing regimen, an AUC/MIC ratio of ≥400 was reached by only 68.5% of neonates with wt of <1 kg when the MIC was equal to 1 mg/kg, versus 82.2%, 89.7%, and 92.7% of neonates with wt of 1 to <2, 2 to <3, or ≥3 kg, respectively. Augmentation of a maintenance dose up to 10 or 11 mg/kg for preterm neonates with wt of 1 to <2 or <1 kg, respectively, increases the probability of reaching the therapeutic target; the recommended doses seem to be adequate for neonates with wt of ≥2 kg. Teicoplanin PK are variable in neonates, with wt and eCRCL having the most significant impact. Neonates with wt of <2 kg need higher doses, especially for Staphylococcus spp. with an MIC value of ≥1 mg/liter.

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Integrated Population Pharmacokinetic Analysis of Voriconazole in Children, Adolescents, and Adults

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05761-11 ◽

2012 ◽

Vol 56 (6) ◽

pp. 3032-3042 ◽

Cited By ~ 80

Author(s):

Lena E. Friberg ◽

Patanjali Ravva ◽

Mats O. Karlsson ◽

Ping Liu

Keyword(s):

Pediatric Population ◽

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Loading Dose ◽

Time Curve ◽

Individual Parameter ◽

Dosing Regimens

ABSTRACTTo further optimize the voriconazole dosing in the pediatric population, a population pharmacokinetic analysis was conducted on pooled data from 112 immunocompromised children (2 to <12 years), 26 immunocompromised adolescents (12 to <17 years), and 35 healthy adults. Different maintenance doses (i.e., 3, 4, 6, 7, and 8 mg/kg of body weight intravenously [i.v.] every 12 h [q12h]; 4 mg/kg, 6 mg/kg, and 200 mg orally q12h) were evaluated in these children. The adult dosing regimens (6 mg/kg i.v. q12h on day 1, followed by 4 mg/kg i.v. q12h, and 300 mg orally q12h) were evaluated in the adolescents. A two-compartment model with first-order absorption and mixed linear and nonlinear (Michaelis-Menten) elimination adequately described the voriconazole data. Larger interindividual variability was observed in pediatric subjects than in adults. Deterministic simulations based on individual parameter estimates from the final model revealed the following. The predicted total exposure (area under the concentration-time curve from 0 to 12 h [AUC0-12]) in children following a 9-mg/kg i.v. loading dose was comparable to that in adults following a 6-mg/kg i.v. loading dose. The predicted AUC0-12s in children following 4 and 8 mg/kg i.v. q12h were comparable to those in adults following 3 and 4 mg/kg i.v. q12h, respectively. The predicted AUC0-12in children following 9 mg/kg (maximum, 350 mg) orally q12h was comparable to that in adults following 200 mg orally q12h. To achieve voriconazole exposures comparable to those of adults, dosing in 12- to 14-year-old adolescents depends on their weight: they should be dosed like children if their weight is <50 kg and dosed like adults if their weight is ≥50 kg. Other adolescents should be dosed like adults.

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Population Pharmacokinetics of Propofol

Anesthesiology ◽

10.1097/00000542-200003000-00017 ◽

2000 ◽

Vol 92 (3) ◽

pp. 727-738 ◽

Cited By ~ 295

Author(s):

Jürgen Schüttler ◽

Harald Ihmsen

Keyword(s):

San Francisco ◽

Sampling Site ◽

Compartment Model ◽

Central Compartment ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Power Functions ◽

Target Controlled Infusion ◽

Three Compartment Model ◽

Elimination Clearance

Background Target-controlled infusion is an increasingly common type of administration for propofol. This method requires accurate knowledge of pharmacokinetics, including the effects of age and weight. The authors performed a multicenter population analysis to quantitate the effects of covariates. Methods The authors analyzed 4,112 samples of 270 individuals (150 men, 120 women, aged 2-88 yr, weighing 12-100 kg). Population pharmacokinetic modeling was performed using NONMEM (NONMEM Project Group, University of California, San Francisco, CA). Inter- and intraindividual variability was estimated for clearances and volumes. The effects of age, weight, type of administration and sampling site were investigated. Results The pharmacokinetics of propofol were best described by a three-compartment model. Weight was found to be a significant covariate for elimination clearance, the two intercompartmental clearances, and the volumes of the central compartment, the shallow peripheral compartment, and the deep peripheral compartment; power functions with exponents smaller than 1 yielded the best results. The estimates of these parameters for a 70-kg adult were 1.44 l/min, 2.25 l/min, 0.92 l/min, 9.3 l, 44.2 l, and 266 l, respectively. For patients older than 60 yr the elimination clearance decreased linearly. The volume of the central compartment decreased with age. For children, all parameters were increased when normalized to body weight. Venous data showed a decreased elimination clearance; bolus data were characterized by increases in the volumes of the central and shallow peripheral compartments and in the rapid distribution clearance (Cl2) and a decrease in the slow distribution clearance (Cl3). Conclusions Pharmacokinetics of propofol can be well described by a three-compartment model. Inclusion of age and weight as covariates significantly improved the model. Adjusting pharmacokinetics to the individual patient should improve the precision of target-controlled infusion and may help to broaden the field of application for target-controlled infusion systems.

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Population Pharmacokinetic Modeling of the Unbound Levofloxacin Concentrations in Rat Plasma and Prostate Tissue Measured by Microdialysis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01884-13 ◽

2013 ◽

Vol 58 (2) ◽

pp. 678-686 ◽

Cited By ~ 14

Author(s):

Felipe K. Hurtado ◽

Benjamin Weber ◽

Hartmut Derendorf ◽

Guenther Hochhaus ◽

Teresa Dalla Costa

Keyword(s):

Compartment Model ◽

Central Compartment ◽

Rat Plasma ◽

Population Based ◽

Prostate Tissue ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Population Pharmacokinetic Modeling ◽

Model Stability ◽

Bacterial Prostatitis

ABSTRACTLevofloxacin is a broad-spectrum fluoroquinolone used in the treatment of both acute and chronic bacterial prostatitis. Currently, the treatment of bacterial prostatitis is still difficult, especially due to the poor distribution of many antimicrobials into the prostate, thus preventing the drug to reach effective interstitial concentrations at the infection site. Newer fluoroquinolones show a greater penetration into the prostate. In the present study, we compared the unbound levofloxacin prostate concentrations measured by microdialysis to those in plasma after a 7-mg/kg intravenous bolus dose to Wistar rats. Plasma and dialysate samples were analyzed using a validated high-pressure liquid chromatography-fluorescence method. Both noncompartmental analysis (NCA) and population-based compartmental modeling (NONMEM 6) were performed. Unbound prostate tissue concentrations represented 78% of unbound plasma levels over a period of 12 h by comparing the extent of exposure (unbound AUC0–∞) of 6.4 and 4.8 h·μg/ml in plasma and tissue, respectively. A three-compartment model with simultaneous passive diffusion and saturable distribution kinetics from the prostate to the central compartment gave the best results in terms of curve fitting, precision of parameter estimates, and model stability. The following parameter values were estimated by the population model:V1(0.38 liter; whereV1represents the volume of the central compartment), CL (0.22 liter/h),k12(2.27 h−1),k21(1.44 h−1),k13(0.69 h−1),Vmax(7.19 μg/h),kM(0.35 μg/ml),V3/fuprostate(0.05 liter; where fuprostaterepresents the fraction unbound in the prostate), andk31(3.67 h−1). The interindividual variability values forV1, CL,Vmax, andkMwere 21, 37, 42, and 76%, respectively. Our results suggest that levofloxacin is likely to be substrate for efflux transporters in the prostate.

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