Pharmacokinetics of aminoglycoside antibiotics. Based on population pharmacokinetic data determination of the loading dose, maintenance dose and dosage interval

ABSTRACT Intravenous colistimethate sodium (CMS) is used to treat infections with multiresistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear. In a prospective study, we determined CMS and colistin pharmacokinetics in 10 critically ill patients requiring CRRT (8 underwent continuous venovenous hemodialysis [CVVHD]; median blood flow, 100 ml/min). Intensive sampling was performed on treatment days 1, 3, and 5 after an intravenous CMS loading dose of 9 million international units (MU) (6 MU if body weight was <60 kg) with a consecutive 3-MU (respectively, 2 MU) maintenance dose at 8 h. CMS and colistin concentrations were determined by liquid chromatography with mass spectroscopy. A model-based population pharmacokinetic analysis incorporating CRRT settings was applied to the observations. Sequential model building indicated a monocompartmental distribution for both CMS and colistin, with interindividual variability in both volume and clearance. Hematocrit was shown to affect the efficacy of drug transfer across the filter. CRRT clearance accounted for, on average, 41% of total CMS and 28% of total colistin clearance, confirming enhanced elimination of colistin compared to normal renal function. Target colistin steady-state trough concentrations of at least 2.5 mg/liter were achieved in all patients receiving 3 MU at 8 h. In conclusion, a loading dose of 9 MU followed after 8 h by a maintenance dose of 3 MU every 8 h independent of body weight is expected to achieve therapeutic colistin concentrations in patients undergoing CVVHD using low blood flows. Colistin therapeutic drug monitoring might help to further ensure optimal dosing in individual patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02081560.)

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New Colistin Population Pharmacokinetic Data in Critically Ill Patients Suggesting an Alternative Loading Dose Rationale

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03508-14 ◽

2014 ◽

Vol 58 (12) ◽

pp. 7324-7330 ◽

Cited By ~ 50

Author(s):

N. Grégoire ◽

O. Mimoz ◽

B. Mégarbane ◽

E. Comets ◽

D. Chatelier ◽

...

Keyword(s):

Steady State ◽

Critically Ill ◽

Critically Ill Patients ◽

Plasma Concentrations ◽

Multidrug Resistant ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Loading Dose ◽

Liquid Chromatography Tandem Mass

ABSTRACTColistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventy-three critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (Cmax) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t1/2) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate.

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Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01088-16 ◽

2016 ◽

Vol 60 (11) ◽

pp. 6550-6557 ◽

Cited By ~ 18

Author(s):

Abdulaziz S. Alobaid ◽

Steven C. Wallis ◽

Paul Jarrett ◽

Therese Starr ◽

Janine Stuart ◽

...

Keyword(s):

Population Pharmacokinetics ◽

Critically Ill ◽

Critically Ill Patients ◽

Maintenance Dose ◽

Central Compartment ◽

Pharmacokinetic Analysis ◽

Morbidly Obese ◽

Population Pharmacokinetic ◽

Loading Dose ◽

Intercompartmental Clearance

ABSTRACTOur objective was to describe the population pharmacokinetics of fluconazole in a cohort of critically ill nonobese, obese, and morbidly obese patients. Critically ill patients prescribed fluconazole were recruited into three body mass index (BMI) cohorts, nonobese (18.5 to 29.9 kg/m2), obese (30.0 to 39.9 kg/m2), and morbidly obese (≥40 kg/m2). Serial fluconazole concentrations were determined using a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Twenty-one critically ill patients (11 male) were enrolled, including obese (n= 6) and morbidly obese (n= 4) patients. The patients mean ± standard deviation (SD) age, weight, and BMI were 54 ± 15 years, 90 ± 24 kg, and 31 ± 9 kg/m2, respectively. A two-compartment linear model described the data adequately. The mean ± SD population pharmacokinetic parameter estimates were clearance (CL) of 0.95 ± 0.48 liter/h, volume of distribution of the central compartment (Vc) of 15.10 ± 11.78 liter, intercompartmental clearance from the central to peripheral compartment of 5.41 ± 2.28 liter/h, and intercompartmental clearance from the peripheral to central compartment of 2.92 ± 4.95 liter/h. A fluconazole dose of 200 mg daily was insufficient to achieve an area under the concentration-time curve for the free, unbound drug fraction/MIC ratio of 100 for pathogens with MICs of ≥2 mg/liter in patients with BMI of >30 kg/m2. A fluconazole loading dose of 12 mg/kg and maintenance dose of 6 mg/kg/day achieved pharmacodynamic targets for higher MICs. A weight-based loading dose of 12 mg/kg followed by a daily maintenance dose of 6 mg/kg, according to renal function, is required in critically ill patients for pathogens with a MIC of 2 mg/liter.

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Exploring population pharmacokinetic models in patients treated with vancomycin during continuous venovenous haemodiafiltration (CVVHDF)

Critical Care ◽

10.1186/s13054-021-03863-4 ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Marcus Kirwan ◽

Reema Munshi ◽

Hannah O’Keeffe ◽

Conor Judge ◽

Mary Coyle ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Maintenance Dose ◽

Structural Model ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Loading Dose ◽

Dose Monitoring ◽

Population Pk ◽

Vasopressor Use

Abstract Background Therapeutic antibiotic dose monitoring can be particularly challenging in septic patients requiring renal replacement therapy. Our aim was to conduct an exploratory population pharmacokinetic (PK) analysis on PK of vancomycin following intermittent infusion in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF); focussing on the influence of dialysis-related covariates. Methods This was a retrospective single-centre tertiary level intensive care unit (ICU) study, which included patients treated concurrently with vancomycin and CVVHDF between January 2015 and July 2016. We extracted clinical, laboratory and dialysis data from the electronic healthcare record (EHR), using strict inclusion criteria. A population PK analysis was conducted with a one-compartment model using the PMetrics population PK modelling package. A base structural model was developed, with further analyses including clinical and dialysis-related data to improve model prediction through covariate inclusion. The final selected model simulated patient concentrations using probability of target attainment (PTA) plots to investigate the probability of different dosing regimens achieving target therapeutic concentrations. Results A total of 106 vancomycin dosing intervals (155 levels) in 24 patients were examined. An acceptable 1-compartment base model was produced (Plots of observed vs. population predicted concentrations (Obs–Pred) R2 = 0.78). No continuous covariates explored resulted in a clear improvement over the base model. Inclusion of anticoagulation modality and vasopressor use as categorical covariates resulted in similar PK parameter estimates, with a trend towards lower parameter estimate variability when using regional citrate anti-coagulation or without vasopressor use. Simulations using PTA plots suggested that a 2 g loading dose followed by 750 mg 12 hourly as maintenance dose, commencing 12 h after loading, is required to achieve adequate early target trough concentrations of at least 15 mg/L. Conclusions PTA simulations suggest that acceptable trough vancomycin concentrations can be achieved early in treatment with a 2 g loading dose and maintenance dose of 750 mg 12 hourly for critically ill patients on CVVHDF.

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Pharmacokinetics of Intraperitoneal Piperacillin/Tazobactam in Patients on Peritoneal Dialysis with and without Pseudomonas Peritonitis

Peritoneal Dialysis International ◽

10.1177/089686080002000211 ◽

2000 ◽

Vol 20 (2) ◽

pp. 227-231 ◽

Cited By ~ 4

Author(s):

Ronit Zaidenstein ◽

Joshua Weissgarten ◽

Victor Dishi ◽

Maya Koren ◽

Stefan Soback ◽

...

Keyword(s):

Peritoneal Dialysis ◽

Intravenous Administration ◽

Maintenance Dose ◽

High Performance ◽

Medical Center ◽

Plasma Concentrations ◽

Loading Dose ◽

Maintenance Period ◽

Therapeutic Implications

Objective The objective of this study was to assess the pharmacokinetics of intraperitoneal (IP) administration of the antibiotic combination piperacillin/tazobactam (PIP/TAZ) to patients on chronic ambulatory peritoneal dialysis (CAPD) with and without pseudomonas peritonitis. Design Open-labeled study. Setting The study was carried out in the CAPD unit of Assaf Harofeh Medical Center, Zerifin, Israel. Patients and Methods Six patients participated in the study, 4 had pseudomonas peritonitis, all were given an IP loading dose of 4 g/0.5 g PIP/TAZ. Twenty-four hours after the initial dose, a maintenance dose of 0.5 g/0.0625 g PIP/TAZ was administered with each dialysate exchange for a period of 1 week. The patients without peritonitis received only the loading dose. High performance liquid chromatography was used to determine the concentrations of PIP/TAZ in plasma obtained at 0, 30, 60, 90, 120, 360, 480, 600, 720, and 1440 minutes after administration. Samples of the dialysate fluid for determination of PIP/TAZ concentration were collected at 6, 10, 14, 24, and 72, 120, and 168 hours. Results After the loading dose, the highest plasma PIP concentration (Cmax) was 51.6 ± 21.25 μg/mL and appeared at 1.5 ± 0.45 hours (tmax). During the maintenance period plasma PIP concentration was 5.2 ± 4.75 μg/mL. Tazobactam was detected in the plasma of 1 patient only. The concentration of TAZ in the dialysate fluid during the maintenance period was 2.3 ± 0.5 μg/mL. Conclusions Piperacillin administered IP at 4 g reached plasma concentrations comparable to intravenous administration and considered therapeutic (above the MIC90 for Pseudomonas aeruginosa) in CAPD patients with or without peritonitis. The maintenance dose, however, should be augmented. Tazobactam could not be detected in the plasma of most patients and the therapeutic implications of IP administration of TAZ cannot be directly correlated to intravenous administration.

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Predicting the Dose of Warfarin for Therapeutic Anticoagulation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657174 ◽

1982 ◽

Vol 47 (03) ◽

pp. 230-231 ◽

Cited By ~ 8

Author(s):

N K Sharma ◽

P A Routledge ◽

M D Rawlins ◽

D M Davies

Keyword(s):

Therapeutic Range ◽

Significant Relationship ◽

Maintenance Dose ◽

Warfarin Dose ◽

Loading Dose ◽

Intravenous Injections ◽

Therapeutic Anticoagulation ◽

Close Relationship ◽

The Relationship ◽

Anticoagulant Response

SummaryThe validity of a previously described technique for predicting warfarin requirements based on the anticoagulant response to a fixed loading dose was assessed prospectively in 57 patients. There was a close relationship between the predicted and initially observed daily warfarin dose required to maintain the patient within the therapeutic range for anticoagulation. The significant relationship between predicted and observed maintenance dose persisted at 4 and 12 weeks although it decreased with increasing time.The relationship between observed and predicted maintenance requirement of warfarin was not affected by the concomitant use of intermittent intravenous injections of heparin when 9 hr was allowed to elapse between the previous dose of heparin and the thrombotest estimation on which the prediction was based.It is concluded that the method is valuable in predicting an individual’s warfarin requirement, although it does not obviate the need for regular monitoring of anticoagulant control.

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The Development of a Turbidimetric Method for the Quantitative Determination of Antibiotics of the Aminoglycoside Group in Medications

Antibiotics and Chemotherapy ◽

10.37489/0235-2990-2020-65-7-8-37-41 ◽

2020 ◽

Vol 65 (7-8) ◽

pp. 37-41

Author(s):

E. N. Semenova ◽

S. I. Kuleshova ◽

E. I. Sakanyan

Keyword(s):

Quantitative Determination ◽

Quality Assessment ◽

Aminoglycoside Antibiotics ◽

Metrological Characteristics ◽

Streptomycin Sulfate ◽

Turbidimetric Method ◽

Validation Criteria ◽

Validation Parameters ◽

Validation Tests

A method for the quantitative determination of streptomycin sulfate in medicines by the turbidimetric method has been developedand validated. Based on the results of the experiments, it was found that the metrological characteristics of such validation parameters of the method as linearity, precision, and correctness do not exceed the validation criteria. Linearity was noted in the range of streptomycin concentrations from 3.75 to 8.43 μg/ml. The results of validation tests of the method for the quantitative determination of streptomycin indicate the prospects and feasibility of introducing the turbidimetric method into the domestic system for standardization and quality assessment of aminoglycoside antibiotics.

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LC–MS–MS Analysis of Mirtazapine in Plasma, and Determination of Pharmacokinetic Data for Rats

Chromatographia ◽

10.1365/s10337-008-0656-9 ◽

2008 ◽

Vol 68 (1-2) ◽

pp. 65-70 ◽

Cited By ~ 10

Author(s):

Xiao Hong ◽

Yao Yao ◽

Shen Hong ◽

Chen Lei

Keyword(s):

Pharmacokinetic Data ◽

Ms Analysis

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Fluoxetine pharmacokinetics and tissue distribution suggest a possible role in reducing SARS-CoV-2 titers

F1000Research ◽

10.12688/f1000research.53275.1 ◽

2021 ◽

Vol 10 ◽

pp. 477

Author(s):

Andy R. Eugene

Keyword(s):

Tissue Distribution ◽

Day Treatment ◽

Compartment Model ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Pharmacokinetic Data ◽

Human Lung Cells ◽

Retrospective Clinical Study ◽

Target Plasma Concentration

Background. Recent in vitro studies have shown fluoxetine inhibits the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen, including variants B.1.1.7 and B.1.351, SARS-CoV-2 spike mutations (E484K, K417N, N501Y), and one retrospective clinical study reported fluoxetine exposure at a median dose of 20 mg in patients with the SARS-CoV-2 coronavirus disease 2019 (COVID-19) had a significantly lower risk of intubation and death. The aim of this study is to conduct in silico population pharmacokinetic dosing simulations to quantify the percentage of patients achieving a trough level for the effective concentration resulting in 90% inhibition (EC90) of SARS-CoV-2 as reported in Calu-3 human lung cells. Methods. Population pharmacokinetic parameter estimates for a structural one-compartment model with first-order absorption were used to simulate fluoxetine pharmacokinetic data. A population of 1,000 individuals were simulated at standard fluoxetine doses (20 mg/day, 40 mg/day, and 60 mg/day) to estimate the percentage of the patients achieving a trough plasma level for the EC90 SARS-CoV-2 inhibitory concentration for a 10 day treatment period. All analyses were conducted via statistical programming in R. Results. Standard fluoxetine antidepressant doses resulted in a range of 81% to 97% of the patient population achieving a trough target plasma concentration of 23.2 ng/ml at day 10 and translates to a lung-tissue distribution coefficient of 60-times higher (EC90 of 4.02 mM). At a dose of 40 mg per day, at least 87% of patients will reach the trough target EC90 concentration within three days. Conclusion. Overall, the findings of this population pharmacokinetic dosing study corroborates in vitro and observational clinical studies reporting the first selective serotonin reuptake inhibitor fluoxetine inhibits the SARS-CoV-2 pathogen at commonly treated doses in the practice of psychiatry.

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