Pharmacokinetic/pharmacodynamic analysis of voriconazole against Candida spp. and Aspergillus spp. in children, adolescents and adults by Monte Carlo simulation

BackgroundCaspofungin is the first echinocandin to be used as a first-line antifungal agent for Candida spp. infections in febrile, neutropenic adult and paediatric patients. To date, the optimal dosing of capofungin in children has not been determined. We evaluated the population pharmacokinetics of caspofungin in children (2–12 years old) and defined an appropriate dose in order to optimize caspofungin treatment in this vulnerable population.MethodsBlood samples were collected from 48 children treated with caspofungin and drug concentrations were quantified by HPLC-MS. Population pharmacokinetic analysis and Monte-Carlo simulation were performed using NONMEM softwareResultsData from 48 children was available for population pharmacokinetic analysis. A two-compartment model with first-order elimination had the best fit with the data. Subsequent covariate analysis demonstrated that body surface area had a significant correlation with caspofungin pharmacokinetics compared to body weight. Monte Carlo simulation demonstrated that >90% of a simulated paediatric population (age range, 2–12 years) treated with a loading dose of 70 mg/m2 followed by a 50 mg/m2 maintenance dose once daily would reach a minimum inhibitory concentration of 1 µg/mL, the proposed susceptibility breakpoint for caspofungin against Candida spp.ConclusionThe population pharmacokinetics of caspofungin was evaluated and revealed that adjustment of caspofungin based on body surface area is most appropriate for paediatric use.Disclosure(s)Nothing to disclose

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Pharmacodynamic Analysis of Ceftriaxone, Gatifloxacin,and Levofloxacin AgainstStreptococcus pneumoniaewith the Use of Monte Carlo Simulation

Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy ◽

10.1592/phco.2005.25.9.1161 ◽

2005 ◽

Vol 25 (9) ◽

pp. 1161-1167 ◽

Cited By ~ 18

Author(s):

Christopher R. Frei ◽

David S. Burgess

Keyword(s):

Monte Carlo Simulation ◽

Monte Carlo ◽

Pharmacodynamic Analysis

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Optimizing the dosing regimen of linezolid in critically ill septic patients undergoing continuous hemodiafiltration using a pharmacokinetic/pharmacodynamic analysis and monte carlo simulation

Intensive Care Medicine Experimental ◽

10.1186/2197-425x-3-s1-a395 ◽

2015 ◽

Vol 3 (S1) ◽

Author(s):

H Barrasa González ◽

A Martín López ◽

A Isla Ruiz ◽

A Rodríguez Gascón ◽

A Soraluce Olañeta ◽

...

Keyword(s):

Monte Carlo Simulation ◽

Monte Carlo ◽

Critically Ill ◽

Dosing Regimen ◽

Continuous Hemodiafiltration ◽

Pharmacodynamic Analysis

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Pharmacokinetic/pharmacodynamic analysis of weight- and height-scaled tobramycin dosage regimens for patients with cystic fibrosis

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz192 ◽

2019 ◽

Vol 74 (8) ◽

pp. 2311-2317

Author(s):

S S Alghanem ◽

D J Touw ◽

A H Thomson

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Monte Carlo Simulation ◽

Monte Carlo ◽

Simulated Dataset ◽

Dosage Regimens ◽

Pharmacodynamic Analysis ◽

Dosing Regimens ◽

Lower Height ◽

Higher Doses

Abstract Objectives To determine the outcomes of weight- and height-based tobramycin dosing regimens for patients with cystic fibrosis (CF). Methods A simulated dataset of 5000 patients based on 331 patients with CF was created using NONMEM. Pharmacokinetic (PK) parameters were derived for each patient from a published model using Monte Carlo simulation. The abilities of 10 and 12 mg/kg/day and 3 and 4 mg/cm/day to achieve standard and extended Cmax (20–30 and 20–40 mg/L) and AUC0–24 (80–120 and 80–150 mg·h/L) targets were evaluated. PK/pharmacodynamic (PK/PD) indices were a Cmax/MIC ratio ≥10 and an AUC0–24/MIC ratio ≥110. For these indices and a range of MICs, cumulative fractions of response (CFRs) for Pseudomonas aeruginosa were also determined. Results More patients achieved standard Cmax and AUC0–24 targets with 3 mg/cm/day (64% and 62%, respectively) than with 10 mg/kg/day (43% and 48%, respectively). AUC0–24 estimates >120 mg·h/L were more common with weight-based dosing. With higher doses, 72% achieved high target peaks with 4 mg/cm/day and 65% with 12 mg/kg/day. For the Cmax/MIC index, the maximal MIC for the target microorganism was 2 mg/L with lower doses, 2.5 mg/L with higher doses and 0.5 mg/L for AUC0–24/MIC-based regimens. The CFR for all regimens was >90% for Cmax targets and 66% to 79% for AUC0–24 targets. Conclusions A tobramycin dose of 3 mg/cm/day rather than 10 mg/kg/day achieved similar PK/PD outcomes but dose and AUC0–24 ranges were narrower and the incidence of high AUC0–24 values was lower. Height-based doses should therefore be considered for patients with CF.

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