Pharmacokinetics of piperacillin in critically ill Australian Indigenous patients with severe sepsis

Objectives: There are no available pharmacokinetic data to guide piperacillin dosing in critically ill Australian Indigenous patients despite numerous reported physiological differences. This study aimed to describe the population pharmacokinetics of piperacillin in critically ill Australian Indigenous patients with severe sepsis.Methods: A population pharmacokinetic study of Indigenous patients with severe sepsis was conducted in a remote hospital intensive care unit. Plasma samples were collected over two dosing intervals and assayed by validated chromatography. Population pharmacokinetic modelling was conducted using Pmetrics®.Results: Nine patients were recruited and a two compartment model adequately described the data. Piperacillin clearance (CL), volume of distribution of the central compartment (Vc), distribution rate constant from central to peripheral compartment and from peripheral to central compartment were 5.6 ± 3.2 L/h, 14.5 ± 6.6 L, 1.5 ± 0.4 h-1and 1.8 ± 0.9 h-1respectively, where CL and Vcwere found to be described by creatinine clearance (CrCL) and total body weight respectively.Conclusion: In this patient population, piperacillin demonstrated high interindividual pharmacokinetic variability. CrCL were found to be the most important determinant of piperacillin pharmacokinetics.

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Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01914-19 ◽

2019 ◽

Vol 64 (1) ◽

Author(s):

James M. Kidd ◽

Colleen M. Sakon ◽

Louise-Marie Oleksiuk ◽

Jeffrey J. Cies ◽

Rebecca S. Pettit ◽

...

Keyword(s):

Cystic Fibrosis ◽

Body Weight ◽

Total Body Weight ◽

Central Compartment ◽

Volume Of Distribution ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Minimal Risk ◽

Content Type ◽

Total Body

ABSTRACT Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus. Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (n = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment (Vc) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight (Vθ) normalized by the median observed value (Vc = Vθ × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CLNR + CLθ × CRCL), where CLNR represents nonrenal clearance and CLθ represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: Vθ, 4.92 ± 0.76 liters · kg−1; CLNR, 0.59 ± 0.30 liters · h−1; CLθ, 5.97 × 10−3 ± 1.24 × 10−3; Vp (volume of the peripheral compartment), 3.77 ± 1.41 liters; Q (intercompartmental clearance), 4.08 ± 2.17 liters · h−1. The free area under the concentration-time curve (fAUC) values for 7.5 and 10 mg/kg were 30 ± 4.6 and 52 ± 12 mg · h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a fAUC/MIC threshold of >215, respectively, for MIC of ≤0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg · h · liter−1) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.)

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Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?

Pharmaceutics ◽

10.3390/pharmaceutics12040380 ◽

2020 ◽

Vol 12 (4) ◽

pp. 380 ◽

Cited By ~ 2

Author(s):

Quentin Allard ◽

Zoubir Djerada ◽

Claire Pouplard ◽

Yohann Repessé ◽

Dominique Desprez ◽

...

Keyword(s):

Half Life ◽

Random Effect ◽

Real Life ◽

Compartment Model ◽

Central Compartment ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Severe Haemophilia ◽

Fviii Activity ◽

Data Files

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.

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A Population Pharmacokinetic Modeling Approach Shows that Serum Penicillin G Concentrations Are Below Inhibitory Concentrations by Two Weeks after Benzathine Penicillin G Injection in the Majority of Young Adults

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02744-14 ◽

2014 ◽

Vol 58 (11) ◽

pp. 6735-6741 ◽

Cited By ~ 5

Author(s):

Michael Neely ◽

Edward L. Kaplan ◽

Jeffrey L. Blumer ◽

Dennis J. Faix ◽

Michael P. Broderick

Keyword(s):

Young Adults ◽

Central Compartment ◽

Penicillin G ◽

Simulated Patients ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Benzathine Penicillin ◽

Final Population ◽

Benzathine Penicillin G

ABSTRACTSerum penicillin G falls to low levels 2 weeks after injection as benzathine penicillin G (BPG) in young adults. Using Pmetrics and previously reported penicillin G pharmacokinetic data after 1.2 million units were given as BPG to 329 male military recruits, here we develop the first reported population pharmacokinetic model of penicillin G after BPG injection. We simulated time-concentration profiles over a broad range of pediatric and adult weights after alternative doses and dose frequencies to predict the probability of maintaining serum penicillin G concentrations of >0.02 mg/liter, a proposed protective threshold against group AStreptococcus pyogenes(GAS). The final population model included linear absorption into a central compartment, distribution to and from a peripheral compartment, and linear elimination from the central compartment, with allometrically scaled volumes and rate constants. With 1.2 million units of BPG given intramuscularly every 4 weeks in four total doses, only 23.2% of 5,000 simulated patients maintained serum penicillin G trough concentrations of >0.02 mg/liter 4 weeks after the last dose. When the doses were 1.8 million units and 2.4 million units, the percentages were 30.2% and 40.7%, respectively. With repeated dosing of 1.2 million units every 3 weeks and every 2 weeks for 4 doses, the percentages of simulated patients with a penicillin G trough concentration of >0.02 mg/liter were 37.8% and 65.2%, respectively. Our simulations support recommendations for more frequent rather than higher BPG doses to prevent recurrent rheumatic heart disease in areas of high GAS prevalence or during outbreaks.

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Population Pharmacokinetic Study of Cefathiamidine in Infants With Augmented Renal Clearance

Frontiers in Pharmacology ◽

10.3389/fphar.2021.630047 ◽

2021 ◽

Vol 12 ◽

Author(s):

Bin Du ◽

Yue Zhou ◽

Bo-Hao Tang ◽

Yue-E Wu ◽

Xin-Mei Yang ◽

...

Keyword(s):

Renal Clearance ◽

Pharmacokinetic Study ◽

Compartment Model ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Pharmacokinetic Studies ◽

Augmented Renal Clearance ◽

Population Pharmacokinetic Study ◽

Dosing Regimens

Objectives: Augmented renal clearance (ARC) of primarily renally eliminated antibacterial agents may result in subtherapeutic antibiotic concentrations and, as a consequence, worse clinical outcomes. Cefathiamidine is frequently used as empirical antimicrobial therapy in children with ARC, but pharmacokinetic studies in infants are lacking. This population pharmacokinetic study in infants with ARC was conducted to determine optimal dosing regimens of cefathiamidine.Methods: The population pharmacokinetics was conducted in 20 infants treated with cefathiamidine. Plasma samples of cefathiamidine were collected using opportunistic sampling, and the concentrations were detected by UPLC-MS/MS. Data analysis was performed to determine pharmacokinetic parameters and to characterize pharmacokinetic variability of cefathiamidine using nonlinear mixed effects modelling (NONMEM) software program.Results: The data (n = 36) from 20 infants (age range, 0.35–1.86 years) with ARC were fitted best with a 1-compartment model. Allometrically scaled weight and age as significant covariates influenced cefathiamidine pharmacokinetics. The median (range) values of estimated clearance and the volume of distribution were 0.22 (0.09–0.29) L/h/kg and 0.34 (0.24–0.41) L/kg, respectively. Monte Carlo simulations showed that the cefathiamidine doses of 100 mg/kg/day q12 h, 50 mg/kg/day q8 h and 75 mg/kg/day q6 h were chosen for bacteria with MIC 0.25, 0.5 and 2 mg/L, respectively.Conclusion: The population pharmacokinetic model of cefathiamidine for infants with ARC was developed. The PTA - based dosing regimens were recommended based on the final model.

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Nemonoxacin Dosage Adjustment in Patients with Severe Renal Impairment Based on Population Pharmacokinetic and Pharmacodynamic Analysis

10.22541/au.161167889.97008719/v1 ◽

2021 ◽

Author(s):

Yi Li ◽

Jianda Lu ◽

Yue Kang ◽

Xiaoyong Xu ◽

Xin Li ◽

...

Keyword(s):

Renal Impairment ◽

Severe Renal Impairment ◽

Compartment Model ◽

Central Compartment ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Healthy Controls ◽

Dosing Regimen ◽

Open Label ◽

Optimal Dosing

Aims: To optimize the dosing regimen in patients with severe renal impairment based on population pharmacokinetic/pharmacodynamic (PPK/PD) analysis. Methods: The pharmacokinetics and safety of nemonoxacin was evaluated in a single-dose, open-label, nonrandomized, parallel-group study after single oral dose of 0.5 g nemonoxacin capsule in 10 patients with severe renal impairment and 10 healthy controls. Both blood and urine samples were collected within 48 hours after admission and determined the concentrations. A PPK model was built using nonlinear mixed effects modelling. The probability of target attainment (PTA) and the cumulative fraction of response (CFR) against S. Pneumoniae and S. aureus was calculated by Monte Carlo simulation. Results: The data best fitted to a two-compartment model, from which the PPK parameters were estimated, including clearance (8.55 L/h), central compartment volume (80.8 L), and peripheral compartment volume (50.6 L). The accumulative urinary excretion was 23.4±6.5% in severe renal impairment patients and 66.1±16.8% in healthy controls. PPK/PD modeling and simulation of 4 dosage regimens found that nemonoxacin 0.5 g q48h was the optimal dosing regimen in severe renal impairment patients, evidenced by higher PTA (92.7%) and CFR (>99%) at nemonoxacin MIC ≤ 1 mg/L against S. pneumoniae and S. aureus. The alternative regimens (0.25 g q24h; loading dose 0.5 g on Day 1 followed by 0.25 g q24h) were insufficient to cover the pathogens even if MIC ≤ 0.5 mg/L. Conclusion: An extended dosing interval (0.5 g q48h) may be appropriate for optimal efficacy of nemonoxacin in case of severe renal impairment.

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Population Pharmacokinetic Model for Vancomycin Used in Open Heart Surgery: Model-Based Evaluation of Standard Dosing Regimens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00088-18 ◽

2018 ◽

Vol 62 (7) ◽

Cited By ~ 1

Author(s):

Saeed A. Alqahtani ◽

Abdullah S. Alsultan ◽

Hussain M. Alqattan ◽

Ahmed Eldemerdash ◽

Turki B. Albacker

Keyword(s):

Heart Surgery ◽

Open Heart Surgery ◽

Central Compartment ◽

Volume Of Distribution ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Albumin Concentration ◽

Open Heart ◽

Blood Samples ◽

Dosing Regimens

ABSTRACTThe purpose of this study was to investigate the population pharmacokinetics of vancomycin in patients undergoing open heart surgery. In this observational pharmacokinetic study, multiple blood samples were drawn over a 48-h period of intravenous vancomycin in patients who were undergoing open heart surgery. Blood samples were analyzed using an Architect i4000SR immunoassay analyzer. Population pharmacokinetic models were developed using Monolix 4.4 software. Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. A total of 168 blood samples were analyzed from 28 patients. The pharmacokinetics of vancomycin are best described by a two-compartment model with between-subject variability in clearance (CL), the volume of distribution of the central compartment (V1), and volume of distribution of the peripheral compartment (V2). The CL and theV1of vancomycin were related to creatinine CL (CLCR), body weight, and albumin concentration. Dosing simulations showed that standard dosing regimens of 1 and 1.5 g failed to achieve the PK-PD target of AUC0–24/MIC > 400 for an MIC of 1 mg/liter, while high weight-based dosing regimens were able to achieve the PK-PD target. In summary, the administration of standard doses of 1 and 1.5 g of vancomycin two times daily provided inadequate antibiotic prophylaxis in patients undergoing open heart surgery. The same findings were obtained when 15- and 20-mg/kg doses of vancomycin were administered. Achieving the PK-PD target required higher doses (25 and 30 mg/kg) of vancomycin.

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Altered Aminoglycoside Pharmacokinetics in the Critically Ill

Anaesthesia and Intensive Care ◽

10.1177/0310057x8801600406 ◽

1988 ◽

Vol 16 (4) ◽

pp. 418-422 ◽

Cited By ~ 41

Author(s):

M. J. Beckhouse ◽

I. M. Whyte ◽

P. L. Byth ◽

J. C. Napier ◽

A. J. Smith

Keyword(s):

Critically Ill ◽

Compartment Model ◽

Serum Levels ◽

Apparent Volume ◽

Volume Of Distribution ◽

Pharmacokinetic Data ◽

Post Dose ◽

Apparent Volume Of Distribution ◽

Trough Levels ◽

Volumes Of Distribution

We studied prospectively 49 patients being treated in an intensive care unit with aminoglycosides for gram-negative sepsis. Pharmacokinetic data were calculated from three post-dose serum levels using a one-compartment model. Doses required to achieve peak levels between 5 and 10 mg/l with trough levels approximately 1.0 mg/l ranged between 2 and 12 mg/kg per day (mean dose 7 mg/kg per day). During therapy 60% of the patients had a change in their apparent volume of distribution (Vd) of greater than 20%. These patients were likely to have confirmed infection and to be febrile at the start of treatment. Two to three weeks after discharge ten patients were restudied after a single dose of aminoglycoside. There was a reduction in mean Vd from 0.24 to 0.18 l/kg (P < 0.02). Critically ill patients have significantly larger volumes of distribution and may require larger doses per kilogram of body weight of aminoglycoside to achieve therapeutic concentrations. Due to considerable variation in kinetic parameters, the use of standard doses or dosing nomograms is not recommeded.

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Population Pharmacokinetics of Propofol

Anesthesiology ◽

10.1097/00000542-200003000-00017 ◽

2000 ◽

Vol 92 (3) ◽

pp. 727-738 ◽

Cited By ~ 295

Author(s):

Jürgen Schüttler ◽

Harald Ihmsen

Keyword(s):

San Francisco ◽

Sampling Site ◽

Compartment Model ◽

Central Compartment ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Power Functions ◽

Target Controlled Infusion ◽

Three Compartment Model ◽

Elimination Clearance

Background Target-controlled infusion is an increasingly common type of administration for propofol. This method requires accurate knowledge of pharmacokinetics, including the effects of age and weight. The authors performed a multicenter population analysis to quantitate the effects of covariates. Methods The authors analyzed 4,112 samples of 270 individuals (150 men, 120 women, aged 2-88 yr, weighing 12-100 kg). Population pharmacokinetic modeling was performed using NONMEM (NONMEM Project Group, University of California, San Francisco, CA). Inter- and intraindividual variability was estimated for clearances and volumes. The effects of age, weight, type of administration and sampling site were investigated. Results The pharmacokinetics of propofol were best described by a three-compartment model. Weight was found to be a significant covariate for elimination clearance, the two intercompartmental clearances, and the volumes of the central compartment, the shallow peripheral compartment, and the deep peripheral compartment; power functions with exponents smaller than 1 yielded the best results. The estimates of these parameters for a 70-kg adult were 1.44 l/min, 2.25 l/min, 0.92 l/min, 9.3 l, 44.2 l, and 266 l, respectively. For patients older than 60 yr the elimination clearance decreased linearly. The volume of the central compartment decreased with age. For children, all parameters were increased when normalized to body weight. Venous data showed a decreased elimination clearance; bolus data were characterized by increases in the volumes of the central and shallow peripheral compartments and in the rapid distribution clearance (Cl2) and a decrease in the slow distribution clearance (Cl3). Conclusions Pharmacokinetics of propofol can be well described by a three-compartment model. Inclusion of age and weight as covariates significantly improved the model. Adjusting pharmacokinetics to the individual patient should improve the precision of target-controlled infusion and may help to broaden the field of application for target-controlled infusion systems.

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Optimised Dosing of Vancomycin in Critically Ill Indigenous Australian Patients with Severe Sepsis

Anaesthesia and Intensive Care ◽

10.1177/0310057x1804600405 ◽

2018 ◽

Vol 46 (4) ◽

pp. 374-380 ◽

Cited By ~ 4

Author(s):

D. Tsai ◽

P. C. Stewart ◽

S. Hewagama ◽

S. Krishnaswamy ◽

S. C. Wallis ◽

...

Keyword(s):

Severe Sepsis ◽

Severe Renal Impairment ◽

Compartment Model ◽

Central Compartment ◽

Volume Of Distribution ◽

Published Data ◽

Time Data ◽

Indigenous Australian ◽

Final Population ◽

Population Pk

Vancomycin is a commonly used antibiotic due to the high burden of methicillin-resistant Staphylococcus aureus infections. This study aimed to describe the pharmacokinetics (PK) of vancomycin in Australian Indigenous patients with severe sepsis, and advise an optimal dosing strategy. A population PK study was conducted in a remote Australian intensive care unit (ICU). Serial plasma samples were collected over one to two dosing intervals and assayed by validated chromatography. Concentration–time data collected were analysed using Pmetrics® software. The final population PK model was then used for Monte Carlo dosing simulations to determine optimal loading and intermittent maintenance doses. Fifteen Indigenous subjects were included for analysis with a median (interquartile range, IQR) age, weight and creatinine clearance (CrCL) of 43 (34–46) years, 73 (66–104) kg and 99 (56–139) ml/minute respectively. A two-compartment model described the data adequately. Vancomycin clearance (CL) and volume of distribution of the central compartment (Vc) were described by CrCL and patient weight respectively. Median (IQR) CL, Vc, distribution rate constants from central to peripheral, and from peripheral to central compartments were 4.6 (3.8–5.6) litres per hour, 25.4 (16.1–31.3) litres, 0.46 (0.28–0.52)/hour and 0.25 (0.12–0.37)/hour respectively. No significant interethnic PK differences were observed in comparison to published data. Therapeutic loading doses were significantly dependent on both weight and CrCL, whereas maintenance doses were dependent on CrCL. In the absence of severe renal impairment, initiation of maintenance dose eight hours post–loading dose achieved higher probability of target attainment at 24 hours. This is the first report of vancomycin PK in this patient group.

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Pharmacokinetics of Intravenous Linezolid in Moderately to Morbidly Obese Adults

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01453-12 ◽

2012 ◽

Vol 57 (3) ◽

pp. 1144-1149 ◽

Cited By ~ 40

Author(s):

Amira A. Bhalodi ◽

Pavlos K. Papasavas ◽

Darren S. Tishler ◽

David P. Nicolau ◽

Joseph L. Kuti

Keyword(s):

Body Weight ◽

Ideal Body Weight ◽

Total Body Weight ◽

Compartment Model ◽

Central Compartment ◽

Volume Of Distribution ◽

Lean Body Weight ◽

Morbidly Obese ◽

Total Body ◽

Nonobese Patients

ABSTRACTThe pharmacokinetics of linezolid was assessed in 20 adult volunteers with body mass indices (BMI) of 30 to 54.9 kg/m2receiving 5 intravenous doses of 600 mg every 12 h. Pharmacokinetic analyses were conducted using compartmental and noncompartmental methods. The mean (±standard deviation) age, height, and weight were 42.2 ± 12.2 years, 64.8 ± 3.5 in, and 109.5 ± 18.2 kg (range, 78.2 to 143.1 kg), respectively. Linezolid pharmacokinetics in this population were best described by a 2-compartment model with nonlinear clearance (original value, 7.6 ± 1.9 liters/h), which could be inhibited to 85.5% ± 12.2% of its original value depending on the concentration in an empirical inhibition compartment, the volume of the central compartment (24.4 ± 9.6 liters), and the intercompartment transfer constants (K12andK21) of 8.04 ± 6.22 and 7.99 ± 5.46 h−1, respectively. The areas under the curve for the 12-h dosing interval (AUCτ) were similar between moderately obese and morbidly obese groups: 130.3 ± 60.1 versus 109.2 ± 25.5 μg · h/ml (P= 0.32), and there was no significant relationship between the AUC or clearance and any body size descriptors. A significant positive relationship was observed for the total volume of distribution with total body weight (r2= 0.524), adjusted body weight (r2= 0.587), lean body weight (r2= 0.495), and ideal body weight (r2= 0.398), but not with BMI (r2= 0.171). Linezolid exposure in these obese participants was similar overall to that of nonobese patients, implying that dosage adjustments based on BMI alone are not required, and standard doses for patients with body weights up to approximately 150 kg should provide AUCτ values similar to those seen in nonobese participants.

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