Article Figures & Data
Figures
- 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
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
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.
Tables
- TABLE 1
Summary statistics of demographic dataa
Trial No. of patients Median wt (kg) (range) Median ht (cm) (range) Median age (yr) (range) No. of male patients I 77 75.3 (61–97.7) 176.7 (161–190) 42.5 (19–55) 71 II 50 76.5 (50.9–112.4) 174.5 (138–200) 41.5 (19–63) 42 III 139 73.5 (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
Parameter Point estimate (coefficient of variation [%]) Volunteers Volunteers/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
Parameter Median value 95% CI IIV (%) IOV (%) Intravenous data CL (liters/h) 20.9 18.5, 23.4 54 8 Vc (liters) 46.9 45.1, 49.0 20 8 Q (liters/h) 2.80 2.47, 3.17 57 18 Vp (liters) 43.1 37.2, 49.8 67 22 BSA on Vc 1.50 0.96, 1.96 Patient status on CL −0.29 −0.38, −0.18 FER1 0.40 0.38, 0.43 19 FER2 0.21 0.17, 0.26 62 Additive RUV, plasma 0.001 0.001, 0.002 Proportional RUV, plasma 0.24 0.22, 0.26 Additive RUV, urine 0.001 0.001, 0.154 Proportional RUV, urine 0.33 0.29, 0.36 Oral data F 0.75 0.59, 0.79 33 32 f1st 0.77 0.77, 0.95 39 36 Ka (h−1) 6.61 3.19, 6.61 33 168 LAG1 (h) 0.22 0.14, 0.24 30 28 D0 (h) 7.77 7.39, 12.17 31 31 LAG2 (h) 0.54 0.41, 1.13 33 32 Proportional RUV 0.14 0.13, 0.24 Additive RUV 0.03 0.00, 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
Parameter Median value for trial (95% prediction interval) II III 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.
Supplemental material
- Supplemental file 1 -
Supplemental figures and tables
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