Population Pharmacokinetics and Safety of Piperacillin-Tazobactam Extended Infusions in Infants and Children

ABSTRACT Piperacillin-tazobactam (TZP) is frequently used to treat severe hospital-acquired infections in children. We performed a single-center, pharmacokinetic (PK) trial of TZP in children ranging in age from 2 months to 6 years from various clinical subpopulations. Children who were on TZP per the standard of care were prospectively included and assigned to receive a dose of 80 mg/kg of body weight every 6 h infused over 2 h (ages 2 to 5 months) or a dose of 90 mg/kg every 8 h infused over 4 h (ages 6 months to 6 years). Separate population PK models were developed for piperacillin and tazobactam using nonlinear mixed-effects modeling. Optimal dosing was judged based on the ability to maintain free piperacillin concentrations above the piperacillin MIC for enterobacteria and Pseudomonas aeruginosa for ≥50% of the dosing interval. Any untoward event occurring during treatment was collected as an adverse event. A total of 79 children contributed 174 PK samples. The median (range) age and weight were 1.7 years (2 months to 6 years) and 11.4 kg (3.8 to 27.6 kg), respectively. A 2-compartment model with first-order elimination best described the piperacillin and tazobactam data. Both final population PK models included weight and concomitant furosemide administration on clearance and weight on the volume of distribution of the central compartment. The optimal dosing regimens in children with normal renal function, based on the piperacillin component, were 75 mg/kg/dose every 4 h infused over 0.5 h in infants ages 2 to ≤6 months and 130 mg/kg/dose every 8 h infused over 4 h in children ages >6 months to 6 years against bacteria with MICs up to 16 mg/liter. A total of 44 children (49%) had ≥1 adverse event, with 3 of these (site infiltrations) considered definitely associated with the extended infusions.

Download Full-text

Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03086-15 ◽

2016 ◽

Vol 60 (5) ◽

pp. 2888-2894 ◽

Cited By ~ 15

Author(s):

Daniel Gonzalez ◽

Paula Delmore ◽

Barry T. Bloom ◽

C. Michael Cotten ◽

Brenda B. Poindexter ◽

...

Keyword(s):

Volume Of Distribution ◽

Safety Study ◽

Term Infants ◽

Content Type ◽

Acid Glycoprotein ◽

Optimal Dosing ◽

Population Pk ◽

Postmenstrual Age ◽

Dosing Regimens ◽

State Concentration

ABSTRACTClindamycin may be active against methicillin-resistantStaphylococcus aureus, a common pathogen causing sepsis in infants, but optimal dosing in this population is unknown. We performed a multicenter, prospective pharmacokinetic (PK) and safety study of clindamycin in infants. We analyzed the data using a population PK analysis approach and included samples from two additional pediatric trials. Intravenous data were collected from 62 infants (135 plasma PK samples) with postnatal ages of <121 days (median [range] gestational age of 28 weeks [23 to 42] and postnatal age of 17 days [1 to 115]). In addition to body weight, postmenstrual age (PMA) and plasma protein concentrations (albumin and alpha-1 acid glycoprotein) were found to be significantly associated with clearance and volume of distribution, respectively. Clearance reached 50% of the adult value at PMA of 39.5 weeks. Simulated PMA-based intravenous dosing regimens administered every 8 h (≤32 weeks PMA, 5 mg/kg; 32 to 40 weeks PMA, 7 mg/kg; >40 to 60 weeks PMA, 9 mg/kg) resulted in an unbound, steady-state concentration at half the dosing interval greater than a MIC forS. aureusof 0.12 μg/ml in >90% of infants. There were no adverse events related to clindamycin use. (This study has been registered at ClinicalTrials.gov under registration no. NCT01728363.)

Download Full-text

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.

Download Full-text

Population Pharmacokinetics Analysis of Amikacin Initial Dosing Regimen in Elderly Patients

Antibiotics ◽

10.3390/antibiotics10020100 ◽

2021 ◽

Vol 10 (2) ◽

pp. 100

Author(s):

Hideo Kato ◽

Suzanne L. Parker ◽

Jason A. Roberts ◽

Mao Hagihara ◽

Nobuhiro Asai ◽

...

Keyword(s):

Elderly Patients ◽

Compartment Model ◽

The Elderly ◽

Volume Of Distribution ◽

Parameter Estimates ◽

Limited Data ◽

Dosing Regimen ◽

Population Pk ◽

Dosing Regimens ◽

Dosing Intervals

There are limited data of amikacin pharmacokinetics (PK) in the elderly population. Hence, we aimed to describe the population PK of amikacin in elderly patients (>70 years old) and to establish optimized initial dosing regimens. We simulated individual maximum concentrations in plasma (Cmax) and minimal concentrations (Cmin) for several dosing regimens (200–2000 mg every 24, 48, and 72 h) for patients with creatinine clearance (CCr) of 10–90 mL/min and analyzed efficacy (Cmax/minimal inhibitory concentration (MIC) ≥ 8) for MICs of 4, 8, and 16 mg/L and safety (Cmin < 4 mg/L). A one-compartment model best described the data. CCr was the only covariate associated with amikacin clearance. The population PK parameter estimates were 2.25 L/h for clearance and 18.0 L for volume of distribution. Dosing simulations recommended the dosing regimens (1800 mg) with dosing intervals ranging 48–72 h for patients with CCr of 40–90 mL/min based on achievement of both efficacy for the MIC of 8 mg/L and safety. None of the dosing regimens achieved the targets for an MIC of 16 mg/L. We recommend the initial dosing regimen using a nomogram based on CCr for an MIC of ≤8 mg/L in elderly patients with CCr of 40–90 mL/min.

Download Full-text

Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01813-17 ◽

2017 ◽

Vol 62 (1) ◽

Cited By ~ 4

Author(s):

Julie Autmizguine ◽

Chiara Melloni ◽

Christoph P. Hornik ◽

Samantha Dallefeld ◽

Barrie Harper ◽

...

Keyword(s):

Oral Administration ◽

Compartment Model ◽

Interval Data ◽

Volume Of Distribution ◽

Infants And Children ◽

Content Type ◽

Mixed Effects Modeling ◽

Optimal Dosing ◽

Separate Population ◽

In Infants And Children

ABSTRACTTrimethoprim (TMP)-sulfamethoxazole (SMX) is used to treat various types of infections, including community-acquired methicillin-resistantStaphylococcus aureus(CA-MRSA) andPneumocystis jiroveciiinfections in children. Pharmacokinetic (PK) data for infants and children are limited, and the optimal dosing is not known. We performed a multicenter, prospective PK study of TMP-SMX in infants and children. Separate population PK models were developed for TMP and SMX administered by the enteral route using nonlinear mixed-effects modeling. Optimal dosing was determined on the basis of the matching adult TMP exposure and attainment of the surrogate pharmacodynamic (PD) target for efficacy, a free TMP concentration above the MIC over 50% of the dosing interval. Data for a total of 153 subjects (240 samples for PK analysis) with a median postnatal age of 8 years (range, 0.1 to 20 years) contributed to the analysis for both drugs. A one-compartment model with first-order absorption and elimination characterized the TMP and SMX PK data well. Weight was included in the base model for clearance (CL/F) and volume of distribution (V/F). Both TMP and SMX CL/Fincreased with age. In addition, TMP and SMX CL/Fwere inversely related to the serum creatinine and albumin concentrations, respectively. The exposure achieved in children after oral administration of TMP-SMX at 8/40 mg/kg of body weight/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 320/1,600 mg/day divided into administration every 12 h and achieved the PD target for bacteria with an MIC of 0.5 mg/liter in >90% of infants and children. The exposure achieved in children after oral administration of TMP-SMX at 12/60 and 15/75 mg/kg/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 640/3,200 mg/day divided into administration every 12 h in subjects 6 to <21 years and 0 to <6 years of age, respectively, and was optimal for bacteria with an MIC of up to 1 mg/liter.

Download Full-text

Pharmacokinetics of Intravenous and Oral Linezolid in Adults with Cystic Fibrosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01797-10 ◽

2011 ◽

Vol 55 (7) ◽

pp. 3393-3398 ◽

Cited By ~ 33

Author(s):

Rebecca A. Keel ◽

Andre Schaeftlein ◽

Charlotte Kloft ◽

J. Samuel Pope ◽

R. Frederic Knauft ◽

...

Keyword(s):

Cystic Fibrosis ◽

Compartment Model ◽

Central Compartment ◽

Time Dependent ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Content Type ◽

Mixed Effects Modeling ◽

Dosing Regimens

ABSTRACTLinezolid is a treatment option for methicillin-resistantStaphylococcus aureus(MRSA) infections in cystic fibrosis (CF) patients. Little is known, however, about its pharmacokinetics in this population. Eight adults with CF were randomized to receive intravenous (i.v.) and oral linezolid at 600 mg twice daily for 9 doses in a crossover design with a 9-day washout. Plasma samples were collected after the first and ninth doses of each phase. Population pharmacokinetic analyses were performed by nonlinear mixed-effects modeling using a previously described 2-compartment model with time-dependent clearance inhibition. Monte Carlo simulation was performed to assess the activities of the linezolid dosing regimens against 42 contemporary MRSA isolates recovered from CF patients. The following pharmacokinetic parameter estimates were observed for the population: absorption rate constant, 1.91 h−1; clearance, 9.54 liters/h; volume of central compartment, 26.8 liters; volume of peripheral compartment, 17.3 liters; and intercompartmental clearance, 104 liters/h. Linezolid demonstrated nonlinear clearance after 9 doses, which was reduced by a mean of 38.9% (range, 28.8 to 59.9%). Mean bioavailability was 85% (range, 47 to 131%). At steady state, 600 mg given twice daily produced 93.0% and 87.2% probabilities of obtaining the target pharmacodynamic exposure against the MRSA isolates for the i.v. and oral formulations, respectively. Thrice-daily dosing increased the probabilities to 97.0% and 95.6%, respectively. Linezolid pharmacokinetics in these adults with CF were well described by a 2-compartment model with time-dependent clearance inhibition. Standard i.v. and oral dosing regimens should be sufficient to reliably attain pharmacodynamic targets against most MRSA isolates; however, more frequent dosing may be required for isolates with MICs of ≥2 μg/ml.

Download Full-text

Population Pharmacokinetics and Probability of Target Attainment of Different Dosing Regimens of Ceftazidime in Critically Ill Patients with a Proven or Suspected Pseudomonas aeruginosa Infection

Antibiotics ◽

10.3390/antibiotics10060612 ◽

2021 ◽

Vol 10 (6) ◽

pp. 612

Author(s):

Annabel Werumeus Buning ◽

Caspar J. Hodiamont ◽

Natalia M. Lechner ◽

Margriet Schokkin ◽

Paul W. G. Elbers ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Critically Ill ◽

Critically Ill Patients ◽

Hematologic Malignancy ◽

Compartment Model ◽

Target Attainment ◽

Worst Case ◽

Optimal Dosing ◽

Population Pk ◽

Pseudomonas Aeruginosa Infection

Altered pharmacokinetics (PK) of hydrophilic antibiotics in critically ill patients is common, with possible consequences for efficacy and resistance. We aimed to describe ceftazidime population PK in critically ill patients with a proven or suspected Pseudomonas aeruginosa infection and to establish optimal dosing. Blood samples were collected for ceftazidime concentration measurement. A population PK model was constructed, and probability of target attainment (PTA) was assessed for targets 100% T > MIC and 100% T > 4 × MIC in the first 24 h. Ninety-six patients yielded 368 ceftazidime concentrations. In a one-compartment model, variability in ceftazidime clearance (CL) showed association with CVVH. For patients not receiving CVVH, variability in ceftazidime CL was 103.4% and showed positive associations with creatinine clearance and with the comorbidities hematologic malignancy, trauma or head injury, explaining 65.2% of variability. For patients treated for at least 24 h and assuming a worst-case MIC of 8 mg/L, PTA was 77% for 100% T > MIC and 14% for 100% T > 4 × MIC. Patients receiving loading doses before continuous infusion demonstrated higher PTA than patients who did not (100% T > MIC: 95% (n = 65) vs. 13% (n = 15); p < 0.001 and 100% T > 4 × MIC: 20% vs. 0%; p = 0.058). The considerable IIV in ceftazidime PK in ICU patients could largely be explained by renal function, CVVH use and several comorbidities. Critically ill patients are at risk for underexposure to ceftazidime when empirically aiming for the breakpoint MIC for P. aeruginosa. A loading dose is recommended.

Download Full-text

Population Pharmacokinetics of Fluconazole in Young Infants

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00569-08 ◽

2008 ◽

Vol 52 (11) ◽

pp. 4043-4049 ◽

Cited By ~ 120

Author(s):

K. C. Wade ◽

D. Wu ◽

D. A. Kaufman ◽

R. M. Ward ◽

D. K. Benjamin ◽

...

Keyword(s):

Fixed Effects ◽

Compartment Model ◽

Volume Of Distribution ◽

Relative Standard Error ◽

Data Set ◽

Mixed Effect ◽

Young Infants ◽

Relative Standard ◽

Population Pk ◽

The Impact

ABSTRACT Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 · (weight/1)0.75 · (BGA/26)1.739 · (PNA/2)0.237 · serum creatinine (SCRT)−4.896 (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 · (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

Download Full-text

Population Pharmacokinetics Modelling and Simulation of Mitotane in Patients with Adrenocortical Carcinoma: An Individualized Dose Regimen to Target All Patients at Three Months?

Pharmaceutics ◽

10.3390/pharmaceutics11110566 ◽

2019 ◽

Vol 11 (11) ◽

pp. 566 ◽

Cited By ~ 2

Author(s):

Yoann Cazaubon ◽

Yohann Talineau ◽

Catherine Feliu ◽

Céline Konecki ◽

Jennifer Russello ◽

...

Keyword(s):

Adrenocortical Carcinoma ◽

Plasma Concentrations ◽

Therapeutic Index ◽

Compartment Model ◽

Volume Of Distribution ◽

Pharmacokinetic Analysis ◽

Concentration Data ◽

Starting Dose ◽

Dosing Regimens ◽

Data Files

Mitotane is the most effective agent in post-operative treatment of adrenocortical carcinoma. In adults, the starting dose is 2–3 g/day and should be slightly increased to reach the therapeutic index of 14–20 mg/L. This study developed a population PK model for mitotane and to simulate recommended/high dosing regimens. We retrospectively analyzed the data files of 38 patients with 503 plasma concentrations for the pharmacokinetic analysis. Monolix version 2019R1 was used for non-linear mixed-effects modelling. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA ≥ 14 mg/L) at one month and at three months. Mitotane concentration data were best described by a linear one-compartment model. The estimated PK parameters (between-subject variability) were: 8900 L (90.4%) for central volume of distribution (V) and 70 L·h−1 (29.3%) for clearance (Cl). HDL, Triglyceride (Tg) and a latent covariate were found to influence Cl. The PTA at three months for 3, 6, 9, and 12 g per day was 10%, 55%, 76%, and 85%, respectively. For a loading dose of 15 g/day for one month then 5 g/day, the PTA in the first and third months was 57 and 69%, respectively. This is the first PKpop model of mitotane highlighting the effect of HDL and Tg covariates on the clearance as well as a subpopulation of ultrafast metabolizer. The simulations suggest that recommended dose regimens are not enough to target the therapeutic threshold in the third month.

Download Full-text

Population Pharmacokinetics of Meropenem in Plasma and Subcutis from Patients on Extracorporeal Membrane Oxygenation Treatment

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02390-17 ◽

2018 ◽

Vol 62 (5) ◽

Cited By ~ 9

Author(s):

Pelle Hanberg ◽

Kristina Öbrink-Hansen ◽

Anders Thorsted ◽

Mats Bue ◽

Mikkel Tøttrup ◽

...

Keyword(s):

Extracorporeal Membrane Oxygenation ◽

Continuous Infusion ◽

Prospective Observational Study ◽

Plasma Concentrations ◽

Content Type ◽

Membrane Oxygenation ◽

Population Pk ◽

Dosing Regimens ◽

Subcutaneous Adipose ◽

Ecmo Treatment

ABSTRACTThe objectives of this study were to describe meropenem pharmacokinetics (PK) in plasma and/or subcutaneous adipose tissue (SCT) in critically ill patients receiving extracorporeal membrane oxygenation (ECMO) treatment and to develop a population PK model to simulate alternative dosing regimens and modes of administration. We conducted a prospective observational study. Ten patients on ECMO treatment received meropenem (1 or 2 g) intravenously over 5 min every 8 h. Serial SCT concentrations were determined using microdialysis and compared with plasma concentrations. A population PK model of SCT and plasma data was developed using NONMEM. Time above clinical breakpoint MIC forPseudomonas aeruginosa(8 mg/liter) was predicted for each patient. The following targets were evaluated: time for which the free (unbound) concentration is maintained above the MIC of at least 40% (40%fT>MIC), 100%fT>MIC, and 100%fT>4×MIC. For all dosing regimens simulated in both plasma and SCT, 40%fT>MIC was attained. However, prolonged meropenem infusion would be needed for 100%fT>MIC and 100%fT>4×MIC to be obtained. Meropenem plasma and SCT concentrations were associated with estimated creatinine clearance (eCLCr). Simulations showed that in patients with increased eCLCr, dose increment or continuous infusion may be needed to obtain therapeutic meropenem concentrations. In conclusion, our results show that using traditional targets of 40%fT>MIC for standard meropenem dosing of 1 g intravenously every 8 h is likely to provide sufficient meropenem concentration to treat the problematic pathogenP. aeruginosafor patients receiving ECMO treatment. However, for patients with an increased eCLCr, or if more aggressive targets, like 100%fT>MIC or 100%fT>4×MIC, are adopted, incremental dosing or continuous infusion may be needed.

Download Full-text

Population Pharmacokinetics and Dose Optimization of Teicoplanin during Venoarterial Extracorporeal Membrane Oxygenation

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01015-17 ◽

2017 ◽

Vol 61 (9) ◽

Cited By ~ 3

Author(s):

Jin Wi ◽

Hayeon Noh ◽

Kyoung Lok Min ◽

Seungwon Yang ◽

Byung Hak Jin ◽

...

Keyword(s):

Extracorporeal Membrane Oxygenation ◽

Trough Concentration ◽

Optimal Dose ◽

Volume Of Distribution ◽

Membrane Oxygenation ◽

Venoarterial Extracorporeal Membrane Oxygenation ◽

Optimal Dosing ◽

Population Pk ◽

Severe Infections ◽

Central Volume

ABSTRACT The pharmacokinetics (PK) of drugs are known to be significantly altered in patients receiving extracorporeal membrane oxygenation (ECMO). However, clinical studies of the PK of drugs administered during ECMO are scarce, and the proper dosing adjustment has yet to be established. We developed a population PK model for teicoplanin, investigated covariates influencing teicoplanin exposure, and suggested an optimal dosing regimen for ECMO patients. Samples for PK analysis were collected from 10 adult patients, and a population PK analysis and simulations were performed to identify an optimal teicoplanin dose needed to provide a >50% probability of target attainment at 72 h using a trough concentration target of >10 μg/ml for mild to moderate infections and a trough concentration target of >15 μg/ml for severe infections. Teicoplanin was well described by a two-compartment PK model with first-order elimination. The presence of ECMO was associated with a lower central volume of distribution, and continuous renal replacement therapy (CRRT) was associated with a higher peripheral volume of distribution. For mild to moderate infections, an optimal dose was a loading dose (LD) of 600 mg and a maintenance dose (MD) of 400 mg for ECMO patients not receiving CRRT and an LD of 800 mg and an MD of 600 mg for those receiving CRRT. For severe infections, an optimal dose was an LD of 1,000 mg and an MD of 800 mg for ECMO patients not receiving CRRT and an LD of 1,200 mg and an MD of 1,000 mg for those receiving CRRT. In conclusion, doses higher than the standard doses are needed to achieve fast and appropriate teicoplanin exposure during ECMO. (This study has been registered at ClinicalTrials.gov under identifier NCT02581280.)

Download Full-text