Pharmacokinetics and pharmacodynamics of intravenous delafloxacin in healthy subjects: model-based dose optimization

Abstract

Delafloxacin, a fluoroquinolone antibiotic to treat skin infections, exhibits a broad-spectrum antimicrobial activity. The first randomized, open-label phase I clinical trial was conducted to assess the safety and pharmacokinetics (PK) of intravenous delafloxacin in the Chinese population. A population pharmacokinetic (PopPK) model based on the clinical trial was conducted by NONMEM software. Monte Carlo simulation was performed to evaluate the antibacterial effects of delafloxacin at different doses in different Chinese populations. The PK characteristics of delafloxacin were best described by a three-compartment model with mixed linear and nonlinear clearance. Body weight was included as a covariate in the model. We simulated the AUC_0-24h in a steady state at five doses in patient groups of various weights. The results indicated that for patients weighing 70 kg and treated with methicillin-resistant Staphylococcus aureus (MRSA) infections, a minimum dose of 300 mg achieved a PTA > 90% at MIC₉₀ of 0.25 µg/mL, suggesting an ideal bactericidal effect. For patients weighing less than 60 kg, a dose of 200 mg achieved a PTA > 90% at MIC₉₀ of 0.25 µg/mL, also suggesting an ideal bactericidal effect. Additionally, this trial demonstrated the high safety of delafloxacin in single-dose and multiple-dose groups of Chinese. Delafloxacin (300 mg, q12h, iv) was recommended for achieving optimal efficacy in Chinese bacterial skin infections patients. To ensure optimal efficacy, an individualized dose of 200 mg (q12h, iv) could be advised for patients weighing less than 60 kg, and 300 mg (q12h, iv) for those weighing more than 60 kg.

Keywords: bacterial skin infections; delafloxacin; dose optimization; pharmacokinetics/pharmacodynamics; population pharmacokinetics.

Fig 1

Mean plasma concentration-time profile of delafloxacin in healthy Chinese subjects. (A) Mean plasma concentration-time profile after one intravenous injection of delafloxacin. (B) Semi-log plot of plasma concentration-time profile after one intravenous injection of delafloxacin. (C) Mean plasma concentration-time profile of delafloxacin after one and multiple intravenous injections of 300 mg.

Fig 2

Schematic structure of the final PopPK model for delafloxacin. Vc, the central volume; Vp, the peripheral volume; CL = total clearance (calculated as CLN +CLi); CLi = linear clearance from the central compartment; CLN = nonlinear clearance from the central compartment (calculated as Vmax*KM/(KM +C1)); C1, concentration of the drug in the central compartment.

Fig 3

Prediction-corrected visual predictive check of the final PopPK model for delafloxacin. (A) Semi-log plot of single ascending dose study. (B) Semi-log plot of multiple ascending dose study on day 1. (C) Semi-log plot of multiple ascending dose study on day 5. Circles represent observed data. Black lines represent the 5% (dashed), 50% (solid), and 95% (dashed) percentiles of the observed data. Shaded areas represent 95% confidence intervals of the median 5% (red), 50% (blue), and 95% (red) percentiles of the predicted concentrations. For A and B, the red and black lines represent the median of predicted and observed BQL fractions, respectively. Shaded areas represent 90% prediction intervals.

Fig 4

The impact of covariates on the steady state exposure of delafloxacin. The demographic characteristics of simulated reference subjects were: weight of 62 kg.

Fig 5

(A) PTA results of different doses of delafloxacin against S. aureus. (B) PTA results of different doses of delafloxacin against MRSA. (C) PTA results of delafloxacin against MRSA in patients with different weights after administering 300 mg. The lines show the calculated PTA of delafloxacin at each simulated dose, and the bar chart is the distribution of MIC.

Fig 6

Simulation of intravenous delafloxacin steady state exposure in ABSSSI patients caused by MRSA at different weights and doses. The dashed line is the AUC_ss,24th values required to achieve the target fAUC/MIC values (24.7) associated with a 1-log10 CFU reduction at MIC = 0.25 µg/mL (MIC₉₀), which is effective against MRSA, and the solid line is the simulated average AUC_ss,24th value after administering 300 mg to individuals weighing of 70 kg. The PTA for delafloxacin, associated with a 1-log10 CFU reduction, represented the percentage of PK/PD parameters achieving the target fAUC/MIC values (24.7) at MIC = 0.25 µg/mL (MIC₉₀) on each box plot.