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Pharmacology

Population Pharmacokinetics of Finafloxacin in Healthy Volunteers and Patients with Complicated Urinary Tract Infections

Max Taubert, Mark Lückermann, Andreas Vente, Axel Dalhoff, Uwe Fuhr
Max Taubert
aDepartment I of Pharmacology, Clinical Pharmacology Unit, University Hospital Cologne, Cologne, Germany
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Mark Lückermann
bMerLion Pharmaceuticals GmbH, Berlin, Germany
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Andreas Vente
bMerLion Pharmaceuticals GmbH, Berlin, Germany
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Axel Dalhoff
cInstitute for Infection Medicine, Christian Albrechts University of Kiel, Kiel, Germany
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Uwe Fuhr
aDepartment I of Pharmacology, Clinical Pharmacology Unit, University Hospital Cologne, Cologne, Germany
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DOI: 10.1128/AAC.02328-17
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  • FIG 1
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    FIG 1

    Plots of individual predicted versus measured plasma concentrations stratified by trial. Plots of individual predicted versus measured plasma concentrations of finafloxacin in healthy volunteers receiving intravenous administrations (a), patients receiving intravenous administrations (b), and healthy volunteers receiving oral administrations (c), as obtained from the final model. Solid line, unity line; dashed line, line of best fit.

  • FIG 2
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    FIG 2

    Empirical Bayes estimates of elimination clearances stratified by the dose level of finafloxacin. Empirical Bayes estimates of elimination clearances are stratified by the dose (200 to 1,000 mg/day) from healthy volunteers receiving intravenous infusions of finafloxacin. Dots, medians; bars, 90% intervals. A trend toward diminished clearances can be seen at the highest dose of 1,000 mg.

  • FIG 3
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    FIG 3

    Goodness-of-fit plots of the final model incorporating the whole data set. Shown are goodness-of-fit plots of the final model incorporating plasma data from healthy volunteers receiving oral or intravenous administrations and from patients receiving intravenous administrations. The top row shows individual and population predicted versus measured plasma concentrations; the bottom row shows population predicted concentrations and the time after dose versus conditional weighted residuals. Solid lines indicate the unity line (top) or the line of zero residuals (bottom); dashed lines indicate lines of best fit.

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  • TABLE 1

    Summary statistics of demographic dataa

    TrialNo. of patientsMedian wt (kg) (range)Median ht (cm) (range)Median age (yr) (range)No. of male patients
    I7775.3 (61–97.7)176.7 (161–190)42.5 (19–55)71
    II5076.5 (50.9–112.4)174.5 (138–200)41.5 (19–63)42
    III13973.5 (64–140)164 (145–186)61 (19–90)21
    • ↵a Summary statistics of demographic data from healthy volunteers receiving oral (trial I) or intravenous (trial II) administrations and from patients receiving intravenous administrations (trial III) of finafloxacin. Medians and ranges (minimum to maximum) are presented.

  • TABLE 2

    Point estimates and coefficients of variation of a basic model fitted to intravenous data from healthy volunteers and healthy volunteers/patientsa

    ParameterPoint estimate (coefficient of variation [%])
    VolunteersVolunteers/patients
    CL (liters/h)23 (31)19.4 (47)
    Vc (liters)52 (23)49.8 (25)
    Q (liters/h)2.96 (41)2.97 (42)
    Vp (liters)47.6 (57)48.7 (58)
    • ↵a Shown are point estimates (coefficients of variation) of clearance (CL), central volume of distribution (Vc), peripheral volume of distribution (Vp), and intercompartmental clearance (Q) obtained when fitting a two-compartment model solely to data from healthy volunteers receiving intravenous infusions or from healthy volunteers and patients. A distinct change was observed for CL only, with a point estimate reduction and an increase in the coefficient of variation by >10%.

  • TABLE 3

    Final bootstrap parameter estimates of pharmacokinetic and covariate parameters for plasma and urine dataa

    ParameterMedian value95% CIIIV (%)IOV (%)
    Intravenous data
        CL (liters/h)20.918.5, 23.4548
        Vc (liters)46.945.1, 49.0208
        Q (liters/h)2.802.47, 3.175718
        Vp (liters)43.137.2, 49.86722
        BSA on Vc1.500.96, 1.96
        Patient status on CL−0.29−0.38, −0.18
        FER10.400.38, 0.4319
        FER20.210.17, 0.2662
        Additive RUV, plasma0.0010.001, 0.002
        Proportional RUV, plasma0.240.22, 0.26
        Additive RUV, urine0.0010.001, 0.154
        Proportional RUV, urine0.330.29, 0.36
    Oral data
        F0.750.59, 0.793332
        f1st0.770.77, 0.953936
        Ka (h−1)6.613.19, 6.6133168
        LAG1 (h)0.220.14, 0.243028
        D0 (h)7.777.39, 12.173131
        LAG2 (h)0.540.41, 1.133332
        Proportional RUV0.140.13, 0.24
        Additive RUV0.030.00, 0.03
    • ↵a Median estimates as well as 95% confidence intervals (CIs) of population pharmacokinetic parameters from bootstrap statistics (n = 1,000) based on intravenous (healthy volunteers and patients) and oral (healthy volunteers) data. Shown are percent coefficients of variation for interindividual variability (IIV) and interoccasion variability (IOV). BSA, body surface area (given parameter estimates are exponents of BSA values normalized to a standard individual with a weight of 70 kg and a height of 172 cm); FER, fraction of finafloxacin excreted unchanged renally in healthy volunteers (FER1) and patients (FER2); F, absolute oral bioavailability; f1st, fraction of drug absorbed by a first-order process; Ka, absorption rate constant for a first-order process; LAG1, lag time for a first-order process; D0, duration of a zero-order process; LAG2, lag time of a zero-order process; RUV, residual unexplained variability given a combined additive- and proportional-error model.

  • TABLE 4

    Pharmacokinetic steady-state plasma parameters from simulated intravenous administration of 800 mg finafloxacin per daya

    ParameterMedian value for trial (95% prediction interval)
    IIIII
    AUC (mg · h/liter)38 (15–96)54 (22–134)
    AUCW (mg · h/liter)39 (15–101)53 (19–143)
    Cmax (mg/liter)14 (9–23)16 (10–27)
    Tmax (h)1.12 (1.01–1.37)1.13 (1.01–1.45)
    T1/2 (P) (h)1.66 (0.67–4.0)2.15 (0.87–5.27)
    T1/2 (T) (h)12.5 (6.21–25.2)13.3 (6.5–27.1)
    • ↵a Shown are plasma predictions (medians and 95% prediction intervals) of the AUC normalized to a body weight of 75 kg (AUCW), the maximum attained concentration (Cmax), the time at which the maximum concentration was reached (Tmax), as well as plasma (P) and terminal (T) elimination-half-lives (T1/2) given a simulated intravenous administration of 800 mg finafloxacin per day at steady state. Presented values were calculated via a Monte Carlo simulation using covariate data from all healthy volunteers from trial II and data from all patients from trial III.

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Population Pharmacokinetics of Finafloxacin in Healthy Volunteers and Patients with Complicated Urinary Tract Infections
Max Taubert, Mark Lückermann, Andreas Vente, Axel Dalhoff, Uwe Fuhr
Antimicrobial Agents and Chemotherapy Mar 2018, 62 (4) e02328-17; DOI: 10.1128/AAC.02328-17

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Population Pharmacokinetics of Finafloxacin in Healthy Volunteers and Patients with Complicated Urinary Tract Infections
Max Taubert, Mark Lückermann, Andreas Vente, Axel Dalhoff, Uwe Fuhr
Antimicrobial Agents and Chemotherapy Mar 2018, 62 (4) e02328-17; DOI: 10.1128/AAC.02328-17
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KEYWORDS

clinical trials
finafloxacin
pharmacodynamics
population pharmacokinetics
urinary tract infection

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