Alejandro Pérez-Pitarch1, Rafael Ferriols-Lisart2, Gerardo Aguilar3, Carlos Ezquer-Garín4, F Javier Belda5, Beatriz Guglieri-López6. 1. Department of Pharmacy, University Clinical Hospital of Valencia, Valencia, Spain; Pharmacy and Pharmaceutical Technology Department, Pharmacy School, University of Valencia, Valencia, Spain. Electronic address: alejandroperezpitarch@gmail.com. 2. Department of Pharmacy, University Clinical Hospital of Valencia, Valencia, Spain. 3. Surgical Intensive Care Unit, Department of Anaesthesiology and Intensive Care, Hospital Clínico Universitario, Valencia, Spain. 4. Health Research Institute, INCLIVA, Avenida Blasco Ibáñez, 17, 46010 Valencia, Spain. 5. Surgical Intensive Care Unit, Department of Anaesthesiology and Intensive Care, Hospital Clínico Universitario, Valencia, Spain; School of Medicine, University of Valencia, Spain. 6. Pharmacy and Pharmaceutical Technology Department, Pharmacy School, University of Valencia, Valencia, Spain.
Abstract
INTRODUCTION: The study objective was to evaluate the efficacy of different dosages of caspofungin in the treatment of invasive candidiasis and aspergillosis, in relation to the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment, using modelling and Monte Carlo simulations in critically ill adult patients on continuous haemodiafiltration. METHODS: Critically ill adult patients on continuous venovenous haemodiafiltration treated with caspofungin were analysed. A population PK model was developed. Four caspofungin dosing regimens were simulated: the licensed regimen, 70 mg/day, 100 mg/day or 200 mg/day. A PK/PD target was defined as the ratio between the area under the caspofungin concentration-time curve over 24 hours and the minimal inhibitory concentration (AUC/MIC) for candidiasis or the minimal effective concentrations (AUC/MEC) for Aspergillus spp. Target attainment based on preclinical target for Candida and Aspergillus was assessed for different MIC or MEC, respectively. RESULTS: Concentration-time data were described by a two-compartment model. Body-weight and protein concentration were the only covariates identified by the model. Goodness-of-fit plots and bootstrap analysis proved the model had a satisfactory performance. As expected, a higher maintenance dose resulted in a higher exposure. Target attainment was >90% for candidiasis (MIC≤0.06 mg/L) and aspergillosis (MEC≤0.5 mg/L), irrespective of the dosing regimen, but not for C. parapsilosis. Standard regimen was insufficient to reach the target for C. albicans and C. parapsilosis with MIC≥0.1 mg/L. CONCLUSION: The licensed regimen of caspofungin is insufficient to achieve the PK/PD targets in critically ill patients on haemodiafiltration. The determination of MICs will enable dose scheme selection.
INTRODUCTION: The study objective was to evaluate the efficacy of different dosages of caspofungin in the treatment of invasive candidiasis and aspergillosis, in relation to the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment, using modelling and Monte Carlo simulations in critically ill adult patients on continuous haemodiafiltration. METHODS: Critically ill adult patients on continuous venovenous haemodiafiltration treated with caspofungin were analysed. A population PK model was developed. Four caspofungin dosing regimens were simulated: the licensed regimen, 70 mg/day, 100 mg/day or 200 mg/day. A PK/PD target was defined as the ratio between the area under the caspofungin concentration-time curve over 24 hours and the minimal inhibitory concentration (AUC/MIC) for candidiasis or the minimal effective concentrations (AUC/MEC) for Aspergillus spp. Target attainment based on preclinical target for Candida and Aspergillus was assessed for different MIC or MEC, respectively. RESULTS: Concentration-time data were described by a two-compartment model. Body-weight and protein concentration were the only covariates identified by the model. Goodness-of-fit plots and bootstrap analysis proved the model had a satisfactory performance. As expected, a higher maintenance dose resulted in a higher exposure. Target attainment was >90% for candidiasis (MIC≤0.06 mg/L) and aspergillosis (MEC≤0.5 mg/L), irrespective of the dosing regimen, but not for C. parapsilosis. Standard regimen was insufficient to reach the target for C. albicans and C. parapsilosis with MIC≥0.1 mg/L. CONCLUSION: The licensed regimen of caspofungin is insufficient to achieve the PK/PD targets in critically ill patients on haemodiafiltration. The determination of MICs will enable dose scheme selection.
Authors: Siang Fei Yeoh; Tae Jin Lee; Ka Lip Chew; Stephen Lin; Dennis Yeo; Sajita Setia Journal: Infect Drug Resist Date: 2018-05-30 Impact factor: 4.003
Authors: Michael Neely; Jan-Willem Alffenaar; Anne-Grete Märtson; Kim C M van der Elst; Anette Veringa; Jan G Zijlstra; Albertus Beishuizen; Tjip S van der Werf; Jos G W Kosterink Journal: Antimicrob Agents Chemother Date: 2020-08-20 Impact factor: 5.191