Takayuki Katsube

Pharmacokinetic–Pharmacodynamic Modeling and Simulation for Bactericidal Effect in an In Vitro Dynamic Model

A pharmacokinetic (PK)/pharmacodynamic (PD) modeling strategy to explain the data from an in vitro dynamic model is proposed. Two carbapenem antibiotics, doripenem and meropenem, and three Pseudomonas aeruginosa strains were used as example drugs and strains. The PD model we originally developed to explain the in vitro time-kill data was modified by incorporating bactericidal activities and simulated in vivo PK profiles of the drugs. By employing only one parameter regarding the bactericidal activity from the data at a certain dosage regimen, the bacterial profiles at various dosage regimens could be well simulated for both antibiotics by the PK/PD model. Moreover, simulated bacterial counts for various dosage regimens correlated with time above minimum inhibitory concentration derived from free drug concentrations (fT > MIC) for doripenem. The predicted fT > MIC values to achieve PK/PD endpoints for three strains (static effect: 25.0%, 23.9%, and 39.8%, 2-log killing effect: 28.1%, 29.5%, and 49.6%, 90% maximum killing effect: 36.5%, 46.8%, and 80.7%) were similar to those estimated from free drug concentrations in animal infection models. The proposed in vitro PK/PD model would be useful for simulating bactericidal kinetics in the dynamic model and predicting the human therapeutic target for PK/PD indices estimated from animal infection models.

Effect of gentamicin on pharmacokinetics of lysozyme in rats: interaction between megalin substrates in the kidney.

To investigate the pharmacokinetic interaction between substrates of megalin, a 600‐kDa endocytic receptor abundantly expressed in the renal proximal tubules, we examined the effect of gentamicin infusion on the pharmacokinetics of fluorescein isothiocyanate (FITC)‐lysozyme in rats. Infusion of gentamicin did not affect the plasma concentration‐time profile of FITC‐lysozyme. On the other hand, gentamicin significantly decreased the accumulation of FITC‐lysozyme in the renal cortex and medulla, whereas the accumulation in the renal papilla, liver, brain and lung was not changed. Urinary excretion of FITC‐lysozyme was increased by gentamicin, whereas there was no change in the biliary excretion of FITC‐lysozyme or its degradation products. Gentamicin infusion had little influence on the ATP content in the renal cortex and urinary excretion of glucose, indicating that nephrotoxicity is not induced by short‐term infusion of gentamicin. These findings suggest that lysozyme and gentamicin interact with each other in their reabsorption processes in the renal proximal tubules, probably by competing for their binding to megalin expressed in the apical membrane of the renal proximal tubules.

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, for Dose Adjustment based on Renal Function

ABSTRACT Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. Since cefiderocol is excreted primarily via the kidneys, this study was conducted to develop a population pharmacokinetics (PK) model to determine dose adjustment based on renal function. Population PK models were developed based on data for cefiderocol concentrations in plasma, urine, and dialysate with a nonlinear mixed-effects model approach. Monte-Carlo simulations were conducted to calculate the probability of target attainment (PTA) of fraction of time during the dosing interval where the free drug concentration in plasma exceeds the MIC (Tf>MIC) for an MIC range of 0.25 to 16 μg/ml. For the simulations, dose regimens were selected to compare cefiderocol exposure among groups with different levels of renal function. The developed models well described the PK of cefiderocol for each renal function group. A dose of 2 g every 8 h with 3-h infusions provided >90% PTA for 75% Tf>MIC for an MIC of ≤4 μg/ml for patients with normal renal function, while a more frequent dose (every 6 h) could be used for patients with augmented renal function. A reduced dose and/or extended dosing interval was selected for patients with impaired renal function. A supplemental dose immediately after intermittent hemodialysis was proposed for patients requiring intermittent hemodialysis. The PK of cefiderocol could be adequately modeled, and the modeling-and-simulation approach suggested dose regimens based on renal function, ensuring drug exposure with adequate bactericidal effect.

Cefiderocol, a Siderophore Cephalosporin for Gram‐Negative Bacterial Infections: Pharmacokinetics and Safety in Subjects With Renal Impairment

Cefiderocol, a new injectable siderophore cephalosporin antibiotic, has promising in vitro and in vivo activity against Gram‐negative bacteria including multidrug‐resistant Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. Cefiderocol is mainly renally eliminated. The pharmacokinetics and safety of cefiderocol in subjects with renal impairment were assessed following a single 1000‐mg intravenous 1‐hour infusion of cefiderocol. Subjects with mild, moderate, or severe renal impairment and end‐stage renal disease (ESRD) requiring hemodialysis were compared with demographically (age, body mass index, and sex) matched healthy subjects with normal renal function. The effect of hemodialysis on the clearance of cefiderocol was also assessed. Total drug clearance from plasma (CL) and terminal half‐life (t1/2) correlated with renal function. Ratios (90% confidence intervals) of area under the plasma concentration‐time curve from 0 to infinity (AUC) in mild, moderate, severe, and ESRD groups compared to those with normal renal function were 1.0 (0.8‐1.3), 1.5 (1.2‐1.9), 2.5 (2.0‐3.3), and 4.1 (3.3‐5.2), respectively. Maximum plasma concentration (Cmax) was similar between renal‐impairment groups and the normal‐renal‐function group. Approximately 60% of cefiderocol was removed by hemodialysis for 3 to 4 hours. The plasma‐protein‐unbound fraction was similar between various renal function groups. The incidence of adverse events did not appear to have any correlation with the degree of renal impairment. Single 1000‐mg intravenous doses of cefiderocol were generally well tolerated in subjects with impaired renal function except for 1 subject who discontinued due to urticaria. In conclusion, renal impairment impacted AUC, CL, and t1/2 without affecting Cmax. Cefiderocol was significantly removed by intermittent hemodialysis.

Pharmacokinetics, Safety, and Tolerability of Cefiderocol, a Novel Siderophore Cephalosporin for Gram-Negative Bacteria, in Healthy Subjects

ABSTRACT Cefiderocol is a novel parenteral siderophore cephalosporin that shows potent efficacy against various Gram-negative bacteria, including carbapenem-resistant strains, in vitro and in preclinical models of infection. The aim of the present study was to evaluate the pharmacokinetics (PK), safety, and tolerability of cefiderocol after both single and multiple dosing by intravenous infusion over 60 min in healthy adult subjects. A single-ascending-dose study at doses of 100, 250, 500, 1,000, and 2,000 mg was conducted in 40 healthy Japanese males and females (6 individuals receiving the active drug and 2 individuals receiving a placebo per cohort). A multiple-ascending-dose study at doses of 1,000 (two groups) and 2,000 mg every 8 h (q8h) was conducted in 30 healthy Japanese and Caucasian males (8 individuals receiving the active drug and 2 individuals receiving a placebo per cohort). There were no serious or clinically significant adverse events (AEs) observed in either study. A single subject receiving 1,000 mg cefiderocol q8h was withdrawn due to AEs. Dose-proportional increases in the maximum plasma concentration (Cmax), the area under the concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration after dosing, and the area under the concentration-time curve extrapolated from time zero to infinity were observed across the dose range of 100 to 2,000 mg. The mean plasma half-life of cefiderocol was 1.98 to 2.74 h. Cefiderocol was primarily excreted unchanged in the urine (61.5% to 68.4% of the dose). There was little accumulation of Cmax and AUC by dosing q8h, and the PK of cefiderocol did not change with multiple dosing. This study indicates that single and multiple intravenous doses of cefiderocol at up to 2,000 mg are well tolerated in healthy subjects and exhibit linear PK at doses up to 2,000 mg.

Pharmacokinetic/Pharmacodynamic Modeling for Concentration-Dependent Bactericidal Activity of a Bicyclolide, Modithromycin

The aim of this study was to develop a pharmacokinetic (PK)/pharmacodynamic (PD) model of a bicyclolide, modithromycin, to explain its concentration-dependent bactericidal activity based on the drug-bacterium interaction model that we developed. We have already reported the applicability of model to the time-dependent activity of β-lactams, and we further applied the model to the concentration-dependent activity in this study. In vitro time-kill data of modithromycin, telithromycin, and clarithromycin against Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pneumoniae were used for the modeling. An effect compartment model was incorporated into our original model to explain the time lag between PK and PD profiles. Also, a turnover model for reversible reduction of efficacy was incorporated to explain the regrowth. The developed model well described the time-kill profiles for each drug-bacterium combination. The estimated parameter related to efficacy strongly correlated with minimum inhibitory concentration (MIC), and the simulated bacterial counts at 24 h strongly correlated with both the ratio of the area under the concentration-time curve to MIC (AUC/MIC) and the ratio of the maximum concentration to MIC (Cmax /MIC). These results suggested that the proposed model can be applied to both concentration-dependent and time-dependent bactericidal kinetics, and would be useful for predicting the bactericidal activity of modithromycin.

Population Pharmacokinetic Analysis of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Healthy Subjects, Subjects with Varying Renal Function, and Patients with Complicated Urinary Tract Infection or Acute Uncomplicated Pyelonephritis

ABSTRACT Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. The aim of this study was to perform a population pharmacokinetic (PK) analysis based on plasma cefiderocol concentrations in healthy subjects, subjects with various degrees of renal function, and patients with complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP) caused by Gram-negative pathogens and to calculate the fraction of the time during the dosing interval where the free drug concentration in plasma exceeds the MIC (fTMIC). Population PK models were developed with three renal function markers, body surface area-adjusted estimated glomerular filtration rate (eGFR), absolute eGFR, and creatinine clearance, on the basis of 2,571 plasma concentrations from 91 subjects without infection and 238 patients with infection. The population PK models with each renal function marker adequately described the plasma cefiderocol concentrations. Clear relationships of total clearance (CL) to all renal function markers were observed. Body weight and disease status (with or without infection) were also significant covariates. The CL in patients with infection was 26% higher than that in subjects without infection. The fTMIC values were more than 75% in all patients (and were 100% in most patients), suggesting that a sufficient exposure to cefiderocol was provided by the tested dose regimens (2 g every 8 h as the standard dose regimen) for the treatment of cUTI or AUP caused by Gram-negative pathogens.