Pharmacokinetic/pharmacodynamic modeling and simulation to determine effective dosage regimens for doripenem

2010 ◽  
Vol 99 (5) ◽  
pp. 2483-2491 ◽  
Author(s):  
Takayuki Katsube ◽  
Yoshitaka Yano ◽  
Toshihiro Wajima ◽  
Yoshinori Yamano ◽  
Mikihisa Takano
Keyword(s):  
Modeling And Simulation ◽  
Effective Dosage ◽  
Pharmacodynamic Modeling ◽  
Dosage Regimens

scholarly journals Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis of CTB-001, Recently Developed Bivalirudin

2017 ◽  
Vol 39 (8) ◽  
pp. e54
Author(s):  
S. Han ◽  
H. Youn Choi ◽  
Y. Han Kim ◽  
W. Joo Kim ◽  
K.-S. Bae ◽  
...  
Keyword(s):  
Modeling And Simulation ◽  
Simulation Analysis ◽  
Pharmacodynamic Modeling

Maxacalcitol Pharmacokinetic–Pharmacodynamic Modeling and Simulation for Secondary Hyperparathyroidism in Patients Receiving Maintenance Hemodialysis

Drug Research ◽  
2021 ◽  
Author(s):  
Mizuki Fukazawa-Shinotsuka ◽  
Tomohisa Saito ◽  
Masaichi Abe ◽  
Satofumi Iida ◽  
I-Ting Wang ◽  
...  
Keyword(s):  
Clinical Study ◽  
Modeling And Simulation ◽  
Secondary Hyperparathyroidism ◽  
Compartment Model ◽  
Japanese Patients ◽  
Pharmacodynamic Modeling ◽  
Maintenance Hemodialysis ◽  
Population Pharmacokinetic ◽  
Limit Of Quantification ◽  
Clinical Pharmacology Study

Abstract Background Maxacalcitol was approved in Taiwan in 2018 as the first active vitamin D3 injection for secondary hyperparathyroidism (SHPT) in patients on maintenance hemodialysis. However, no data from any clinical study with maxacalcitol in Taiwanese patients is available. Objectives This analysis aimed to evaluate the profiles of parathyroid hormone (PTH) and calcium (Ca) concentrations in Taiwanese SHPT patients on hemodialysis and maxacalcitol. Methods We developed population pharmacokinetic (PK) and pharmacodynamic (PD) models using a modeling and simulation approach. The data for these analyses were obtained from two studies: a clinical pharmacology study in Japanese patients and an ethnic comparison study in healthy Japanese and -Taiwanese volunteers. We then conducted a simulation study with a PK-PD model comprising the PK and PD models developed here. Results Serum maxacalcitol concentration profile was modeled using a two-compartment model that took into consideration the distribution of concentrations below the lower limit of quantification. An ethnic difference in clearance was included in the PK model as a covariate. A PD model that used a PTH/Ca feedback loop best described the observed data. There were no significant differences in Ca or PTH concentrations between Taiwanese and Japanese based on the simulation results from our PK-PD model, even though maxacalcitol exposure was approximately 40% higher in Taiwanese than in Japanese. Conclusions On the basis of these population PK and PD analyses and the clinical study conducted in Japan, there is no clinically relevant difference between Taiwanese and Japanese in terms of serum Ca or PTH levels.

scholarly journals Optimization of Synergistic Combination Regimens against Carbapenem- and Aminoglycoside-Resistant Clinical Pseudomonas aeruginosa Isolates via Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Rajbharan Yadav ◽  
Jürgen B. Bulitta ◽  
Roger L. Nation ◽  
Cornelia B. Landersdorfer
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Multidrug Resistant ◽  
Viable Count ◽  
Resistant Isolate ◽  
Pharmacodynamic Modeling ◽  
Combination Regimen ◽  
Bacterial Killing ◽  
Content Type ◽  
Dosage Regimens ◽  
Combination Regimens

ABSTRACT Optimizing antibiotic combinations is promising to combat multidrug-resistant Pseudomonas aeruginosa. This study aimed to systematically evaluate synergistic bacterial killing and prevention of resistance by carbapenem and aminoglycoside combinations and to rationally optimize combination dosage regimens via a mechanism-based mathematical model (MBM). We studied monotherapies and combinations of imipenem with tobramycin or amikacin against three difficult-to-treat double-resistant clinical P. aeruginosa isolates. Viable-count profiles of total and resistant populations were quantified in 48-h static-concentration time-kill studies (inoculum, 107.5 CFU/ml). We rationally optimized combination dosage regimens via MBM and Monte Carlo simulations against isolate FADDI-PA088 (MIC of imipenem [MICimipenem] of 16 mg/liter and MICtobramycin of 32 mg/liter, i.e., both 98th percentiles according to the EUCAST database). Against this isolate, imipenem (1.5× MIC) combined with 1 to 2 mg/liter tobramycin (MIC, 32 mg/liter) or amikacin (MIC, 4 mg/liter) yielded ≥2-log10 more killing than the most active monotherapy at 48 h and prevented resistance. For all three strains, synergistic killing without resistance was achieved by ≥0.88× MICimipenem in combination with a median of 0.75× MICtobramycin (range, 0.032× to 2.0× MICtobramycin) or 0.50× MICamikacin (range, 0.25× to 0.50× MICamikacin). The MBM indicated that aminoglycosides significantly enhanced the imipenem target site concentration up to 3-fold; achieving 50% of this synergistic effect required aminoglycoside concentrations of 1.34 mg/liter (if the aminoglycoside MIC was 4 mg/liter) and 4.88 mg/liter (for MICs of 8 to 32 mg/liter). An optimized combination regimen (continuous infusion of imipenem at 5 g/day plus a 0.5-h infusion with 7 mg/kg of body weight tobramycin) was predicted to achieve >2.0-log10 killing and prevent regrowth at 48 h in 90.3% of patients (median bacterial killing, >4.0 log10 CFU/ml) against double-resistant isolate FADDI-PA088 and therefore was highly promising.

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

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Takayuki Katsube ◽  
Toshihiro Wajima ◽  
Toru Ishibashi ◽  
Juan Camilo Arjona Ferreira ◽  
Roger Echols
Keyword(s):  
Renal Function ◽  
Modeling And Simulation ◽  
Dose Adjustment ◽  
Drug Exposure ◽  
Bactericidal Effect ◽  
Pharmacodynamic Modeling ◽  
Intermittent Hemodialysis ◽  
Nonlinear Mixed Effects Model ◽  
Dosing Interval ◽  
Group A

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.

Integrative pharmacokinetic–pharmacodynamic modeling and simulation of amenamevir (ASP2151) for treatment of recurrent genital herpes

2016 ◽  
Vol 31 (4) ◽  
pp. 323-332 ◽  
Author(s):  
Akitsugu Takada ◽  
Masataka Katashima ◽  
Atsunori Kaibara ◽  
Koji Chono ◽  
Kiyomitsu Katsumata ◽  
...  
Keyword(s):  
Modeling And Simulation ◽  
Genital Herpes ◽  
Pharmacodynamic Modeling ◽  
Recurrent Genital Herpes

scholarly journals Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling of Aerosolized Colistin in a Mouse Lung Infection Model

2017 ◽  
Vol 62 (3) ◽  
Author(s):  
Yu-Wei Lin ◽  
Qi Tony Zhou ◽  
Mei-Ling Han ◽  
Nikolas J. Onufrak ◽  
Ke Chen ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Pharmacodynamic Modeling ◽  
Mouse Lung ◽  
Infection Model ◽  
Bacterial Reduction ◽  
Bacterial Killing ◽  
Deterministic Simulation ◽  
Dosage Regimens

ABSTRACTOptimized dosage regimens of aerosolized colistin (as colistin methanesulfonate [CMS]) are urgently required to maximize bacterial killing against multidrug-resistant Gram-negative bacteria while minimizing toxicity. This study aimed to develop a mechanism-based pharmacokinetic (PK)/pharmacodynamic (PD) model (MBM) for aerosolized colistin based upon PK/PD data in neutropenic infected mice and to perform a deterministic simulation with the PK of aerosolized colistin (as CMS) in critically ill patients.In vivotime-kill experiments were carried out with three different strains ofPseudomonas aeruginosa. An MBM was developed in S-ADAPT and evaluated by assessing its ability to predict the PK/PD index associated with efficacy in mice. A deterministic simulation with human PK data was undertaken to predict the efficacy of current dosage regimens of aerosolized colistin in critically ill patients. In the final MBM, the total bacterial population for each isolate consisted of colistin-susceptible and -resistant subpopulations. The antimicrobial efficacy of aerosolized colistin was best described by a sigmoidalEmaxmodel whereby colistin enhanced the rate of bacterial death. Deterministic simulation with human PK data predicted that an inhalational dosage regimen of 60 mg colistin base activity (CBA) every 12 h is needed to achieve a ≥2-log10bacterial reduction (as the number of CFU per lung) in critically ill patients at 24 h after commencement of inhaled therapy. In conclusion, the developed MBM is a useful tool for optimizing inhalational dosage regimens of colistin. Clinical studies are warranted to validate and refine our MBM for aerosolized colistin.

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