Erratum to: Population pharmacokinetics of piperacillin in febrile children receiving cancer chemotherapy: the impact of body weight and target on an optimal dosing regimen

Abstract Background The β-lactam antibiotic piperacillin (in combination with tazobactam) is commonly chosen for empirical treatment of suspected bacterial infections. However, pharmacokinetic variability among patient populations and across ages leads to uncertainty when selecting a dosing regimen to achieve an appropriate pharmacodynamic target. Objectives To guide dosing by establishing a population pharmacokinetic model for unbound piperacillin in febrile children receiving cancer chemotherapy, and to assess pharmacokinetic/pharmacodynamic target attainment (100% fT > 1×MIC and 50% fT > 4×MIC) and resultant exposure, across body weights. Methods Forty-three children admitted for 89 febrile episodes contributed 482 samples to the pharmacokinetic analysis. The typical doses required for target attainment were compared for various dosing regimens, in particular prolonged infusions, across MICs and body weights. Results A two-compartment model with inter-fever-episode variability in CL, and body weight included through allometry, described the data. A high CL of 15.4 L/h (70 kg) combined with high glomerular filtration rate (GFR) values indicated rapid elimination and hyperfiltration. The target of 50% fT > 4×MIC was achieved for an MIC of 4.0 mg/L in a typical patient with extended infusions of 2–3 (q6h) or 3–4 (q8h) h, at or below the standard adult dose (75 and 100 mg/kg/dose for q6h and q8h, respectively). Higher doses or continuous infusion were needed to achieve 100% fT > 1×MIC due to the rapid piperacillin elimination. Conclusions The licensed dose for children with febrile neutropenia (80 mg/kg q6h as a 30 min infusion) performs poorly for attainment of fT>MIC pharmacokinetic/pharmacodynamic targets. Given the population pharmacokinetic profile, feasible dosing regimens with reasonable exposure are continuous infusion (100% fT > 1×MIC) or prolonged infusions (50% fT > 4×MIC).

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Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00686-18 ◽

2018 ◽

Vol 62 (9) ◽

Cited By ~ 3

Author(s):

Yi Zheng ◽

Shu-Ping Liu ◽

Bao-Ping Xu ◽

Zhong-Ren Shi ◽

Kai Wang ◽

...

Keyword(s):

Body Weight ◽

Population Pharmacokinetics ◽

Pediatric Patients ◽

Community Acquired Pneumonia ◽

Pharmacodynamic Modeling ◽

Pharmacokinetic Data ◽

Loading Dose ◽

Dosing Regimen ◽

Time Curve ◽

Dose Strategy

ABSTRACT Azithromycin is extensively used in children with community-acquired pneumonia (CAP). Currently, the intravenous azithromycin is used off-label in children partly due to lacking of pharmacokinetic data. Our objective was to evaluate the population pharmacokinetics (PPK) and optimize dose strategy in order to improve treatment in this distinctive population. This was a prospective, multicenter, open-labeled pharmacokinetic study. Blood samples were collected from hospitalized pediatric patients and concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PPK analysis was conducted using NONMEM software. The pharmacokinetic data from 95 pediatric patients (age range, 2.1 to 11.7 years) were available for analysis. The PPK was best fitted by a two-compartment model with linear elimination. Covariate analysis verified that body weight and alanine aminotransferase (ALT) had significant effects on azithromycin pharmacokinetics, yielding a 24% decrease of clearance in patients with ALT of >40. Monte Carlo simulation showed that for children with normal liver function, a loading-dose strategy (a loading dose of 15 mg/kg of body weight followed by maintenance doses of 10 mg/kg) would achieve the ratio of the area under free drug plasma concentration-time curve over 24 h (fAUC) to MIC90 (fAUC/MIC) target of 3 h in 53.2% of hypothetical patients, using a normative MIC susceptibility breakpoint of 2 mg/liter. For children with ALT of >40, the proposed dose needed to decrease by 15% to achieve comparable exposure. The corresponding risk of overdose for the recommended dosing regimen was less than 5.8%. In conclusion, the PPK of azithromycin was evaluated in children with CAP and an optimal dosing regimen was constructed based on developmental pharmacokinetic-pharmacodynamic modeling and simulation.

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Population pharmacokinetics of intra-peritoneal gentamicin and the impact of varying dwell times on pharmacodynamic target attainment in patients with acute peritonitis undergoing peritoneal dialysis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01679-21 ◽

2021 ◽

Author(s):

Andras Farkas ◽

Katerina Oikonomou ◽

Mohammad Ghanbar ◽

Phillip Villasurda ◽

Julie Varghese ◽

...

Keyword(s):

Body Weight ◽

Peritoneal Dialysis ◽

Population Pharmacokinetics ◽

Multiple Dose ◽

Treatment Success ◽

Systemic Exposure ◽

Break Point ◽

Target Attainment ◽

Acute Peritonitis ◽

The Impact

While the use of intraperitoneal (i.p.) gentamicin is common in the treatment of peritoneal dialysis (PD)-related infections, the ability of these regimens to attain pharmacodynamic target indices of interest in blood and dialysate has not been widely reported. Pharmacokinetic (PK) data was obtained and analyzed from a multiple-dose PK study of i.p. gentamicin with 24 patients who received the drug at 0.6 mg/kg dose of body weight. The probability of target attainment (PTA) for indices of treatment success (i.p. peak/MIC ratio >10) and toxicity (plasma AUC < 120 mg*h/L) was determined for 0.3 to 1.2 mg/kg i.p. regimens every 24 h for dwell times of 2 to 6 hours and for the duration of 2-week course. In the peritoneum, successful PTA was achieved by all of the simulated regimens up to an MIC of 1 mg/L, and by doses equal to or greater than 0.6 mg/kg up to the MIC of 2 mg/L. At the susceptibility break point of 4 mg/L only the highest dose of 1.2 mg/kg is likely to provide adequate PTA. Probability of achieving exposure below the threshold of 120 mg*h/L in the daily AUC in plasma seems acceptable for all regimens at or below 0.6 mg/kg. Based on the model we developed, a gentamicin dose of 0.6 mg/kg is sufficient to treat organisms with an MIC of ≤2 mg/L without the risk of significant systemic exposure. The 1.2 mg/kg dose necessary to reach the pharmacodynamic target for efficacy at the clinical break point of 4 mg/L is likely to produce early toxic levels of exposure that is expected to be detrimental to the renal system.

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Population Pharmacokinetics of Abacavir in Pregnant Women

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03469-14 ◽

2014 ◽

Vol 58 (10) ◽

pp. 6287-6289 ◽

Cited By ~ 5

Author(s):

Floris Fauchet ◽

Jean-Marc Treluyer ◽

Laure-Helene Préta ◽

Elodie Valade ◽

Emmanuelle Pannier ◽

...

Keyword(s):

Body Weight ◽

Pregnant Women ◽

Population Pharmacokinetics ◽

Gestational Age ◽

Population Approach ◽

Covariate Effect ◽

Dosing Regimen ◽

First Time

ABSTRACTFor the first time, a population approach was used to describe abacavir (ABC) pharmacokinetics in HIV-infected pregnant and nonpregnant women. A total of 266 samples from 150 women were obtained. No covariate effect (from age, body weight, pregnancy, or gestational age) on ABC pharmacokinetics was found. Thus, it seems unnecessary to adapt the ABC dosing regimen during pregnancy.

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Population pharmacokinetics and dosing optimization of vancomycin in infants, children and adolescents with augmented renal clearance

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00897-21 ◽

2021 ◽

Author(s):

Cui-Yao He ◽

Pan-Pan Ye ◽

Bin Liu ◽

Lin Song ◽

John van den Anker ◽

...

Keyword(s):

Body Weight ◽

Population Pharmacokinetics ◽

Renal Clearance ◽

Pharmacokinetic Model ◽

Pediatric Patients ◽

Pediatric Population ◽

Dosing Regimen ◽

Augmented Renal Clearance ◽

Vancomycin Dose ◽

First Order

Augmented renal clearance (ARC) can cause underexposure to vancomycin, thereby increasing the risk of treatment failure. Our objective was to evaluate population pharmacokinetics and optimize the dosing regimen of vancomycin in the pediatric population with ARC. Sparse pharmacokinetic sampling and therapeutic drug monitoring (TDM) data were collected from pediatric patients with ARC treated with vancomycin. A pharmacokinetic model was developed using NONMEM 7.2. The dosing regimen was optimized using Monte Carlo dose simulations. A total of 242 vancomycin serum concentrations from 113 patients (age range 0.4 to 14.9 years, 49 females and 64 males) were available. Mean vancomycin dose was 58.8 mg/kg/day (13.6 mg/kg/dose), and mean vancomycin serum trough concentration was 6.5 mg/L. A one-compartment pharmacokinetic model with first order elimination was developed. Body weight and age were the most significant and positive covariates for clearance and volume of distribution. To the pediatric population with ARC, the current recommended vancomycin dose of 60 mg/kg/day was associated with a high risk of underdosing. To reach the target AUC/MIC of 400-700 in these pediatric patients, the vancomycin dose should be increased to 75 mg/kg/day for infants and children between 1 month and 12 years of age, and 70 mg/kg/day for adolescents between 12 and 18 years of age. In conclusion, a one-compartment pharmacokinetic model with first-order elimination was established with body weight and age as significant covariates. An optimal dosing regimen was developed in pediatric patients with ARC aged 1 month -18 years.

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Population Pharmacokinetic Properties of Sulfadoxine and Pyrimethamine: a Pooled Analysis To Inform Optimal Dosing in African Children with Uncomplicated Malaria

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01370-17 ◽

2018 ◽

Vol 62 (5) ◽

Cited By ~ 1

Author(s):

Miné de Kock ◽

Joel Tarning ◽

Lesley Workman ◽

Elizabeth N. Allen ◽

Mamadou M. Tekete ◽

...

Keyword(s):

Body Weight ◽

Young Children ◽

Total Body Weight ◽

Pooled Analysis ◽

World Health ◽

Population Pharmacokinetic ◽

Z Score ◽

Dosing Regimen ◽

Optimal Dosing ◽

Health Organization

ABSTRACT Sulfadoxine-pyrimethamine with amodiaquine is recommended by the World Health Organization as seasonal malaria chemoprevention for children aged 3 to 59 months in the sub-Sahel regions of Africa. Suboptimal dosing in children may lead to treatment failure and increased resistance. Pooled individual patient data from four previously published trials on the pharmacokinetics of sulfadoxine and pyrimethamine in 415 pediatric and 386 adult patients were analyzed using nonlinear mixed-effects modeling to evaluate the current dosing regimen and, if needed, to propose an optimized dosing regimen for children under 5 years of age. The population pharmacokinetics of sulfadoxine and pyrimethamine were both best described by a one-compartment disposition model with first-order absorption and elimination. Body weight, age, and nutritional status (measured as the weight-for-age Z-score) were found to be significant covariates. Allometric scaling with total body weight and the maturation of clearance in children by postgestational age improved the model fit. Underweight-for-age children were found to have 15.3% and 26.7% lower bioavailabilities of sulfadoxine and pyrimethamine, respectively, for each Z-score unit below −2. Under current dosing recommendations, simulation predicted that the median day 7 concentration was below the 25th percentile for a typical adult patient (50 kg) for sulfadoxine for patients in the weight bands of 8 to 9, 19 to 24, 46 to 49, and 74 to 79 kg and for pyrimethamine for patients in the weight bands of 8 to 9, 14 to 24, and 42 to 49 kg. An evidence-based dosing regimen was constructed that would achieve sulfadoxine and pyrimethamine exposures in young children and underweight-for-age young children that were similar to those currently seen in a typical adult.

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Model-oriented Dose Optimization of Voriconazole in Critically Ill Children

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00493-21 ◽

2021 ◽

Author(s):

Jun Wang ◽

Hua Xu ◽

Ran Li ◽

Sanlan Wu ◽

Jili Zou ◽

...

Keyword(s):

Body Weight ◽

Critically Ill ◽

Maintenance Dose ◽

Maximum Velocity ◽

Critically Ill Children ◽

Population Pharmacokinetic ◽

Dosing Regimen ◽

Final Model ◽

Optimal Dosing ◽

Dosing Regimens

Objective: This study aimed to employ a population pharmacokinetic (PK) model to optimize the dosing regimen of voriconazole (VRC) in children with a critical illness. Methods: A total of 99 children aged from 0.44 to 13.58 years old were included in this study. The stability and predictive performance of the final model were evaluated by statistical and graphical methods. The optimal dosing regimen was proposed for children with different body weight, CYP2C19 phenotype, and co-administration with omeprazole. Results: The PK of VRC was described by a two-compartment model with nonlinear Michaelis-Menten elimination. Body weight, CYP2C19 phenotype, and omeprazole were significant covariates on maximum velocity of elimination (V max ), which had an estimated typical value of 18.13 mg·h −1 . Bayesian estimation suggested that dose-normalized concentration and total exposure (C max /D, C min /D, AUC 24 /D) were significantly different between extensive metabolizers (EM) patients and poor metabolizer (PM) patients. To achieve the target concentration early, two loading doses of 9 mg·kg −1 q12h were reliable for most children, whereas three loading doses of 6-7.5 mg·kg −1 q8h were warranted for young children weighted ≤18kg (except PM patients). The maintenance doses decreased about 30-40% in PM patients than that in EM patients. For children aged < 2 years in EM, the maintenance dose could be as high as 9 mg·kg −1 . The maintenance dose of VRC was supposed to decrease slightly when co-administration with omeprazole. Conclusion: A population PK model of intravenous VRC for critically ill children has been successful developed. It is necessary to adjust dosing regimens according to CYP2C19 genotype. The optimal dosing regimens have been recommended basing on the final model.

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Initial dose recommendation for sirolimus in paediatric kaposiform haemangioendothelioma patients based on population pharmacokinetics and pharmacogenomics

Journal of International Medical Research ◽

10.1177/0300060520947627 ◽

2020 ◽

Vol 48 (8) ◽

pp. 030006052094762

Author(s):

Xiao Chen ◽

Dong-Dong Wang ◽

Hong Xu ◽

Zhi-Ping Li

Keyword(s):

Body Weight ◽

Population Pharmacokinetics ◽

Initial Dose ◽

Initial Dosage ◽

Population Characteristics ◽

Test Results ◽

Dosing Regimen ◽

The Monte Carlo Method ◽

Laboratory Test Results ◽

Retrospective Clinical Study

Objective Sirolimus has been used to treat paediatric kaposiform haemangioendothelioma patients. However, there is considerable pharmacokinetic variability among individuals, and it is difficult to develop an initial dosing regimen. The goal of the present study is to recommend an initial sirolimus dose in paediatric kaposiform haemangioendothelioma patients based on population pharmacokinetics and pharmacogenomics. Methods This was a retrospective clinical study. A population pharmacokinetics model was established and population characteristics, laboratory test results, drug combinations, and pharmacogenomics were considered as potential covariates. The Monte Carlo method was used to simulate the optimal initial dosage. Results The final covariates that affect sirolimus clearance include weight and the CYP3A5 genotype. The initial dosage of sirolimus for individuals with CYP3A5*3/*3 was 0.20 mg/kg split into two doses for 5 to 60 kg body weight. For individuals with CYP3A5*1, the initial dose was 0.23 mg/kg split into two doses for 5 to 30 kg body weight and 0.20 mg/kg split into two doses for 30 to 60 kg body weight. Conclusion The recommendation for the initial sirolimus dose in paediatric kaposiform haemangioendothelioma patients was based on population pharmacokinetics and pharmacogenomics. This study may provide practical value for sirolimus clinical use in paediatric kaposiform haemangioendothelioma patients.

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Body Mass, Physical Activity and Eating Habits Changes during the First COVID-19 Pandemic Lockdown in Poland

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18115682 ◽

2021 ◽

Vol 18 (11) ◽

pp. 5682

Author(s):

Hubert Dobrowolski ◽

Dariusz Włodarek

Keyword(s):

Physical Activity ◽

Body Weight ◽

Body Mass ◽

Social Life ◽

Eating Habits ◽

High Energy ◽

High Energy Density ◽

Average Weight ◽

Study Participants ◽

The Impact

The outbreak of the COVID-19 pandemic caused a number of changes in social life around the world. In response to the growing number of infections, some countries have introduced restrictions that may have resulted in the change of the lifestyle. The aim of our study was to investigate the impact of the lockdown on body weight, physical activity and some eating habits of the society. The survey involving 183 people was conducted using a proprietary questionnaire. The mean age of the study participants was 33 ± 11 and mean height 169 ± 8 cm. An average increase in body weight was observed in 49.18% by 0.63 ± 3.7 kg which was the result of a decrease in physical activity and an increase in food consumption. We also observed a decrease in PAL from 1.64 ± 0.15 to 1.58 ± 0.13 and changes in the amount of food and individual groups of products consumption, including alcohol. Among the study participants who did not lose body mass, there was an average weight gain of 2.25 ± 2.5 kg. In conclusion, an increase of weight was shown in about half of the respondents in the study group which was associated with a decrease in physical activity and an increase in the consumption of total food and high energy density products.

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Impact of Weight-Band Dosing of Tinzaparin for Venous Thromboembolism Prophylaxis on Persistent Wound Drainage in Adult Patients Undergoing Hip and Knee Arthroplasty

Annals of Pharmacotherapy ◽

10.1177/10600280211024294 ◽

2021 ◽

pp. 106002802110242

Author(s):

Cassandra Cooper ◽

Ouida Antle ◽

Jennifer Lowerison ◽

Deonne Dersch-Mills ◽

Ashley Kenny

Keyword(s):

Body Weight ◽

Venous Thromboembolism ◽

Knee Arthroplasty ◽

Total Joint Arthroplasty ◽

Joint Arthroplasty ◽

Thromboembolism Prophylaxis ◽

Wound Drainage ◽

Increased Risk ◽

Significant Difference ◽

The Impact

Background: Persistent wound drainage and venous thromboembolism (VTE) are potential complications of total joint arthroplasty, and these risks can be challenging to balance in clinical practice. Anecdotal observation has suggested that following joint arthroplasty, persistent wound drainage occurs more frequently with higher body weight and higher doses of tinzaparin when compared with lower body weight and lower doses of tinzaparin. Objective: The overall purpose of this study was to describe the impact of a tinzaparin weight-band dosing table for VTE prophylaxis on wound healing, thrombosis, and bleeding outcomes in patients undergoing total joint arthroplasty. Methods: This retrospective chart review included patients who underwent total hip or knee arthroplasty and received tinzaparin for thromboprophylaxis per their weight-banding category. The primary outcome was the incidence of persistent wound drainage. Secondary outcomes include the occurrence of VTE and clinically important bleeding during hospital admission. Results: A total of 231 patients were included in the analysis. There was no significant difference in persistent wound drainage between the 3 weight categories, and there were no differences in rates of VTE or clinically important bleeding. Concurrent use of low-dose acetylsalicylic acid was associated with a 3-fold increased risk of persistent wound drainage (risk ratio = 3.35; 95% CI = 2.14-5.24; P = 0.00003). Conclusion and Relevance: In joint arthroplasty patients, we observed no significant difference in rates of persistent wound drainage between various weight categories receiving different weight-banded doses of tinzaparin. Our results do not suggest that the current weight-band dosing table for tinzaparin needs to be adjusted to optimize patient outcomes.

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