Population Pharmacokinetic Analysis of Meropenem in Critically Ill Patients With Acute Kidney Injury Treated With Continuous Hemodiafiltration

ABSTRACT Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.

Download Full-text

Using Population Pharmacokinetics To Determine Gentamicin Dosing during Extended Daily Diafiltration in Critically Ill Patients with Acute Kidney Injury

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00222-10 ◽

2010 ◽

Vol 54 (9) ◽

pp. 3635-3640 ◽

Cited By ~ 34

Author(s):

Jason A. Roberts ◽

Jonathan Field ◽

Adam Visser ◽

Rosemary Whitbread ◽

Mandy Tallot ◽

...

Keyword(s):

Acute Kidney Injury ◽

Monte Carlo ◽

Monte Carlo Simulations ◽

Critically Ill ◽

Critically Ill Patients ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Kidney Injury ◽

Therapeutic Drug ◽

Population Pharmacokinetic

ABSTRACT The objective of the present prospective pharmacokinetic study was to describe the variability of plasma gentamicin concentrations in critically ill patients with acute kidney injury (AKI) necessitating extended daily diafiltration (EDD-f) using a population pharmacokinetic model and to subsequently perform Monte Carlo dosing simulations to determine which dose regimen achieves the pharmacodynamic targets the most consistently. We collected data from 28 gentamicin doses in 14 critically ill adult patients with AKI requiring EDD-f and therapeutic gentamicin. Serial plasma samples were collected. A population pharmacokinetic model was used to describe the pharmacokinetics of gentamicin and perform Monte Carlo simulations with doses of between 3 mg/kg of body weight and 7 mg/kg and at various time points before commencement of EDD-f to evaluate the optimal dosing regimen for achieving pharmacodynamic targets. A two-compartment pharmacokinetic model adequately described the gentamicin clearance while patients were on and off EDD-f. The plasma half-life of gentamicin during EDD-f was 13.8 h, whereas it was 153.4 h without EDD-f. Monte Carlo simulations suggest that dosing with 6 mg/kg every 48 h either 30 min or 1 h before the commencement of EDD-f results in 100% attainment of the target maximum concentration drug in plasma (<10 mg/liter) and sufficient attainment of the target area under the concentration-time curve from 0 to 24 h (AUC0-24; 70 to 120 mg·h/liter). None of the simulated dosing regimens satisfactorily achieved the targets of the minimum concentrations of drug in plasma (<1.0 mg/liter) at 24 h. In conclusion, dosing of gentamicin 30 min to 1 h before the commencement of an EDD-f treatment enables attainment of target peak concentrations for maximal therapeutic effect while enhancing drug clearance to minimize toxicity. Redosing in many patients should occur after 48 h, and we recommend the use of therapeutic drug monitoring to guide dosing to optimize achievement of the AUC0-24 targets.

Download Full-text

Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00554-15 ◽

2015 ◽

Vol 59 (12) ◽

pp. 7240-7248 ◽

Cited By ~ 61

Author(s):

Ilias Karaiskos ◽

Lena E. Friberg ◽

Konstantinos Pontikis ◽

Konstantinos Ioannidis ◽

Vasiliki Tsagkari ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Loading Dose ◽

Gram Negative ◽

Link Type ◽

Colistin Methanesulfonate

ABSTRACTColistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430–3436, 2009,http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241– 4249, 2012,http://dx.doi.org/10.1128/AAC.06426-11; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284–3294, 2011,http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (∼270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while colistin disposition followed a 1-compartment model. The average observed maximum colistin A plus B concentration was 2.65 mg/liter after the loading dose (maximum time was 8 h). A significantly higher availability of the measured A and B forms of colistimethate and colistin explained the higher-than-expected concentrations in the present study compared to those in previous studies. Creatinine clearance was a time-varying covariate of colistimethate clearance. The incidence of acute renal injury was 20%.

Download Full-text

Semi-mechanistic autoinduction model of midazolam in critically ill patients: population pharmacokinetic analysis

Journal of Clinical Pharmacy and Therapeutics ◽

10.1111/jcpt.12395 ◽

2016 ◽

Vol 41 (4) ◽

pp. 392-398 ◽

Cited By ~ 4

Author(s):

T. Aoyama ◽

K. Hirata ◽

Y. Yamamoto ◽

H. Yokota ◽

H. Hayashi ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic

Download Full-text

Quantification and Explanation of the Variability of First-Dose Amikacin Concentrations in Critically Ill Patients Admitted to the Emergency Department: A Population Pharmacokinetic Analysis

European Journal of Drug Metabolism and Pharmacokinetics ◽

10.1007/s13318-021-00698-w ◽

2021 ◽

Author(s):

Sabrina De Winter ◽

Reinier van Hest ◽

Erwin Dreesen ◽

Pieter Annaert ◽

Joost Wauters ◽

...

Keyword(s):

Emergency Department ◽

Critically Ill ◽

Critically Ill Patients ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic

Download Full-text

Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01543-15 ◽

2015 ◽

Vol 60 (1) ◽

pp. 206-214 ◽

Cited By ~ 11

Author(s):

Mohd H. Abdul-Aziz ◽

Azrin N. Abd Rahman ◽

Mohd-Basri Mat-Nor ◽

Helmi Sulaiman ◽

Steven C. Wallis ◽

...

Keyword(s):

Intensive Care Unit ◽

Monte Carlo ◽

Intensive Care ◽

Population Pharmacokinetics ◽

Critically Ill ◽

Critically Ill Patients ◽

Population Pharmacokinetic Analysis ◽

Volume Of Distribution ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic

ABSTRACTDoripenem has been recently introduced in Malaysia and is used for severe infections in the intensive care unit. However, limited data currently exist to guide optimal dosing in this scenario. We aimed to describe the population pharmacokinetics of doripenem in Malaysian critically ill patients with sepsis and use Monte Carlo dosing simulations to develop clinically relevant dosing guidelines for these patients. In this pharmacokinetic study, 12 critically ill adult patients with sepsis receiving 500 mg of doripenem every 8 h as a 1-hour infusion were enrolled. Serial blood samples were collected on 2 different days, and population pharmacokinetic analysis was performed using a nonlinear mixed-effects modeling approach. A two-compartment linear model with between-subject and between-occasion variability on clearance was adequate in describing the data. The typical volume of distribution and clearance of doripenem in this cohort were 0.47 liters/kg and 0.14 liters/kg/h, respectively. Doripenem clearance was significantly influenced by patients' creatinine clearance (CLCR), such that a 30-ml/min increase in the estimated CLCRwould increase doripenem CL by 52%. Monte Carlo dosing simulations suggested that, for pathogens with a MIC of 8 mg/liter, a dose of 1,000 mg every 8 h as a 4-h infusion is optimal for patients with a CLCRof 30 to 100 ml/min, while a dose of 2,000 mg every 8 h as a 4-h infusion is best for patients manifesting a CLCRof >100 ml/min. Findings from this study suggest that, for doripenem usage in Malaysian critically ill patients, an alternative dosing approach may be meritorious, particularly when multidrug resistance pathogens are involved.

Download Full-text

β-Lactam antimicrobial pharmacokinetics and target attainment in critically ill patients aged 1 day to 90 years: the ABDose study

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa363 ◽

2020 ◽

Vol 75 (12) ◽

pp. 3625-3634

Author(s):

Dagan O Lonsdale ◽

Karin Kipper ◽

Emma H Baker ◽

Charlotte I S Barker ◽

Isobel Oldfield ◽

...

Keyword(s):

Critically Ill ◽

Gestational Age ◽

Pharmacokinetic Study ◽

Critically Ill Patients ◽

Clinical Success ◽

The Elderly ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Critically Ill Adults

Abstract Background The pharmacokinetics of β-lactam antibiotics in critical illness remain poorly characterized, particularly in neonates, children and the elderly. We undertook a pharmacokinetic study of commonly used β-lactam antibiotics in critically ill patients of all ages. The aims were to produce a whole-life β-lactam pharmacokinetic model and describe the extent to which standard doses achieve pharmacokinetic/pharmacodynamic targets associated with clinical cure. Patients and methods A total of 212 critically ill participants with an age range from 1 day (gestational age 24 weeks) to 90 years were recruited from a UK hospital, providing 1339 pharmacokinetic samples. Population pharmacokinetic analysis was undertaken using non-linear mixed-effects modelling (NONMEM) for each drug. Pooled data were used to estimate maturation and decline of β-lactam pharmacokinetics throughout life. Results Pharmacokinetic models for eight drugs were described, including what is thought to be the first benzylpenicillin model in critically ill adults. We estimate that 50% of adult β-lactam clearance is achieved by 43 weeks post-menstrual age (chronological plus gestational age). Fifty percent of decline from peak adult clearance occurs by 71 years. Paediatric participants were significantly less likely than adults to achieve pharmacokinetic/pharmacodynamic targets with standard antibiotic doses (P < 0.01). Conclusions We believe this to be the first prospective whole-life antibiotic pharmacokinetic study in the critically ill. The study provides further evidence that standard antibiotic doses fail to achieve pharmacokinetic/pharmacodynamic targets associated with clinical success in adults, children and neonates. Maturation and decline parameters estimated from this study could be adopted as a standard for future prospective studies.

Download Full-text