Using Population Pharmacokinetic Modeling and Monte Carlo Simulations To Determine whether Standard Doses of Piperacillin in Piperacillin-Tazobactam Regimens Are Adequate for the Management of Febrile Neutropenia

ABSTRACT Changes in the pharmacokinetics of piperacillin in febrile neutropenic patients have been reported to result in suboptimal exposures. This study aimed to develop a population pharmacokinetic model for piperacillin and perform dosing simulation to describe optimal dosing regimens for hematological malignancy patients with febrile neutropenia. Concentration-time data were obtained from previous prospective observational pharmacokinetic and interventional therapeutic drug monitoring studies. Nonparametric population pharmacokinetic analysis and Monte Carlo dosing simulations were performed with the Pmetrics package for R. A two-compartment model, with between-subject variability for clearance (CL), adequately described the data from 37 patients (21 males, age of 59 ± 12 years [means ± standard deviations] and weight of 77 ± 16 kg). Parameter estimates were CL of 18.0 ± 4.8 liters/h, volume of distribution of the central compartment of 14.3 ± 7.3 liters, rate constant for piperacillin distribution from the central to peripheral compartment of 1.40 ± 1.35 h−1, and rate constant for piperacillin distribution from the peripheral to central compartment of 4.99 ± 7.81 h−1. High creatinine clearance (CLCR) was associated with reduced probability of target attainment (PTA). Extended and continuous infusion regimens achieved a high PTA of >90% for an unbound concentration of piperacillin remaining above the MIC (fT >MIC) of 50%. Only continuous regimens achieved >90% PTA for 100% fT >MIC when CLCR was high. The cumulative fraction of response (FTA, for fractional target attainment) was suboptimal (<85%) for conventional regimens for both empirical and directed therapy considering 50% and 100% fT >MIC. FTA was maximized with prolonged infusions. Overall, changes in piperacillin pharmacokinetics and the consequences on therapeutic dosing requirements appear similar to those observed in intensive care patients. Guidelines should address the altered dosing needs of febrile neutropenic patients exhibiting high CLCR or with known/presumed infections from high-MIC bacteria.

Download Full-text

Population Pharmacokinetics of Continuous-Infusion Meropenem in Febrile Neutropenic Patients with Hematologic Malignancies: Dosing Strategies for Optimizing Empirical Treatment against Enterobacterales and P. aeruginosa

Pharmaceutics ◽

10.3390/pharmaceutics12090785 ◽

2020 ◽

Vol 12 (9) ◽

pp. 785

Author(s):

Pier Giorgio Cojutti ◽

Anna Candoni ◽

Davide Lazzarotto ◽

Carla Filì ◽

Maria Zannier ◽

...

Keyword(s):

Monte Carlo ◽

Monte Carlo Simulations ◽

Continuous Infusion ◽

Hematologic Malignancies ◽

Population Pharmacokinetic Analysis ◽

Empirical Treatment ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Dosing Strategies ◽

Neutropenic Patients

A population pharmacokinetic analysis of continuous infusion (CI) meropenem was conducted in a prospective cohort of febrile neutropenic (FN) patients with hematologic malignancies. A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations were performed for identifying the most appropriate dosages for empirical treatment against common Enterobacterales and P. aeruginosa. The probability of target attainment (PTA) of steady-state meropenem concentration (Css)-to-minimum inhibitory concentration (MIC) ratio (Css/MIC) ≥1 and ≥4 at the European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoint of 2 mg/L were calculated. Cumulative fraction of response (CFR) against Enterobacterales and P. aeruginosa were assessed as well. PTAs and CFRs ≥ 90% were considered optimal. A total of 61 patients with 178 meropenem Css were included. Creatinine clearance (CLCR) was the only covariate associated with meropenem clearance. Monte Carlo simulations showed that dosages of meropenem ranging between 1 g q8h and 1.25 g q6h by CI may grant optimal PTAs of Css/MIC ≥4 at the EUCAST clinical breakpoint. Optimal CFRs may be granted with these dosages against the Enterobacterales at Css/MIC ≥ 4 and against P. aeruginosa at Css/MIC ≥ 1. When dealing against P. aeruginosa at Css/MIC ≥ 4, only a dosage of 1.5 g q6h by CI may grant quasi-optimal CFR (around 80–87%). In conclusion, our findings suggest that dosages of meropenem ranging between 1 g q8h and 1.25 g q6h by CI may maximize empirical treatment against Enterobacterales and P. aeruginosa among FN patients with hematologic malignancies having different degree of renal function.

Download Full-text

Micafungin population PK analysis in plasma and peritoneal fluid in septic patients with intra-abdominal infections: a prospective cohort study

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02307-20 ◽

2021 ◽

Author(s):

Nicolas Garbez ◽

Litaty Mbatchi ◽

Steven C. Wallis ◽

Laurent Muller ◽

Jeffrey Lipman ◽

...

Keyword(s):

Peritoneal Fluid ◽

Central Compartment ◽

Population Pharmacokinetic Analysis ◽

Peritoneal Exudate ◽

Fat Free Mass ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

The Mean ◽

Abdominal Infections

Objectives: To describe the pharmacokinetics (PK) of micafungin in plasma and peritoneal fluid in septic patients with intra-abdominal infections. Methods: Twelve patients with secondary peritonitis in septic shock receiving 100 mg micafungin once daily were included. Total micafungin plasma and peritoneal fluid were subject to a population pharmacokinetic analysis using Pmetrics®. Monte Carlo simulations were performed considering total AUC0-24h/MIC ratios in plasma. Results: Micafungin concentrations in both plasma and peritoneal exudate were best described by a three-compartmental PK model with the fat free mass (FFM) as a covariate of clearance (CL) and volume of the central compartment (Vc). The mean parameter estimates (standard deviation, SD) were 1.18 (0.40) L/h for CL and 12.85 (4.78) L for Vc. The mean peritoneal exudate/plasma ratio (SD) of micafungin was 25% (5%) on day 1 and 40% (8%) between day 3-5. Dosing simulations supported the use of standard 100 mg daily dosing for C. albicans (FFM < 60 kg), C. glabrata (FFM < 50 kg) and C. tropicalis (FFM < 30 kg) on the second day of therapy. Conclusions: There is a moderate penetration of micafungin into peritoneal cavity (25 to 40%). For empirical treatment, a dose escalation of at least a loading dose of 150 mg depending on the FFM of patients and Candida species is suggested to be effective from the first day of therapy.

Download Full-text

Pharmacodynamic Profiling of Piperacillin in the Presence of Tazobactam in Patients through the Use of Population Pharmacokinetic Models and Monte Carlo Simulation

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.12.4718-4724.2004 ◽

2004 ◽

Vol 48 (12) ◽

pp. 4718-4724 ◽

Cited By ~ 89

Author(s):

Thomas P. Lodise ◽

Ben Lomaestro ◽

Keith A. Rodvold ◽

Larry H. Danziger ◽

George L. Drusano

Keyword(s):

Monte Carlo Simulation ◽

Monte Carlo ◽

Linear Model ◽

Pharmacokinetic Model ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Target Attainment ◽

Raw Data ◽

Dosing Interval ◽

Pharmacodynamic Profile

ABSTRACT The primary objectives of this analysis were to determine which pharmacokinetic model most accurately describes the elimination pathways for piperacillin in the presence of tazobactam through population pharmacokinetic modeling and to characterize its pharmacodynamic profile. Once the optimal pharmacokinetic model was identified, Monte Carlo simulation of 10,000 subjects with ADAPT II was performed to estimate the probability of attaining a target free-piperacillin concentration greater than the MIC for 50% of the dosing interval for 3.375 g every 6 h or every 4 h given as a 0.5-h infusion at each MIC between 0.25 and 32 μg/ml. In the population pharmacokinetic analysis, measurements of bias and precision, observed-predicted plots, and r 2 values were highly acceptable for all three models and all three models were appropriate candidates for the Monte Carlo simulation evaluation. Visual comparison of the distribution of the piperacillin concentrations at the pharmacodynamic endpoint—h 3 concentrations of a 6-h dosing interval—between the simulated populations and raw data revealed that the linear model was most reflective of the raw data at the pharmacodynamic endpoint, and the linear model was therefore selected for the target attainment analysis. In the target attainment analysis, administration of 3 g of piperacillin every 6 h resulted in a robust target attainment rate that exceeded 95% for MICs of ≤8 mg/liter. The 4-h piperacillin administration interval had a superior pharmacodynamic profile and provided target attainment rates exceeding 95% for MICs of ≤16 mg/liter. This study indicates that piperacillin-tazobactam should have utility for empirical therapy of hospital-onset infections.

Download Full-text

Monte Carlo Simulations Based on Phase 1 Studies Predict Target Attainment of Ceftobiprole in Nosocomial Pneumonia Patients: a Validation Study

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02292-12 ◽

2013 ◽

Vol 57 (5) ◽

pp. 2047-2053 ◽

Cited By ~ 18

Author(s):

Anouk E. Muller ◽

Anne H. Schmitt-Hoffmann ◽

Nieko Punt ◽

Johan W. Mouton

Keyword(s):

Monte Carlo ◽

Healthy Volunteers ◽

Nosocomial Pneumonia ◽

Extreme Values ◽

Phase 1 ◽

Optimal Dose ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Target Attainment ◽

Phase 3

ABSTRACTMonte Carlo simulation (MCS) of antimicrobial dosage regimens during drug development to derive predicted target attainment values is frequently used to choose the optimal dose for the treatment of patients in phase 2 and 3 studies. A criticism is that pharmacokinetic (PK) parameter estimates and variability in healthy volunteers are smaller than those in patients. In this study, the initial estimates of exposure from MCS were compared with actual exposure data in patients treated with ceftobiprole in a phase 3 nosocomial-pneumonia (NP) study (NTC00210964). Results of MCS using population PK data from ceftobiprole derived from 12 healthy volunteers were used (J. W. Mouton, A. Schmitt-Hoffmann, S. Shapiro, N. Nashed, N. C. Punt, Antimicrob. Agents Chemother. 48:1713–1718, 2004). Actual individual exposures in patients were derived after building a population pharmacokinetic model and were used to calculate the individual exposure to ceftobiprole (the percentage of time the unbound concentration exceeds the MIC [percentfT> MIC]) for a range of MIC values. For the ranges of percentfT> MIC used to determine the dosage schedule in the phase 3 NP study, the MCS using data from a single phase 1 study in healthy volunteers accurately predicted the actual clinical exposure to ceftobiprole. The difference at 50%fT> MIC at an MIC of 4 mg/liter was 3.5% for PK-sampled patients. For higher values of percentfT> MIC and MICs, the MCS slightly underestimated the target attainment, probably due to extreme values in the PK profile distribution used in the simulations. The probability of target attainment based on MCS in healthy volunteers adequately predicted the actual exposures in a patient population, including severely ill patients.

Download Full-text

DOSAGE INDIVIDUALIZATION OF LINEZOLID: PRECISION DOSING OF LINEZOLID TO OPTIMISE EFFICACY AND MINIMISE TOXICITY

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02490-20 ◽

2021 ◽

Author(s):

S Luque ◽

W Hope ◽

L Sorli ◽

R Muñoz-Bermudez ◽

N Campillo ◽

...

Keyword(s):

High Performance ◽

Compartment Model ◽

Central Compartment ◽

Pharmacokinetic Analysis ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

High Interindividual Variability ◽

Using Data ◽

Toxic Concentrations ◽

High Degree

High interindividual variability in the pharmacokinetics (PK) of linezolid has been described, which results in an unacceptably high proportion of patients with either suboptimal or potentially toxic concentrations following the administration of a fixed regimen. The aim of this study was to develop a population pharmacokinetic model of linezolid and use this to build and validate alogorithms for individualised dosing. A retrospective pharmacokinetic analysis was performed using data from 338 hospitalized patients (65.4% male, 65.5(14.6) years) who underwent routine therapeutic drug monitoring TDM for linezolid. Linezolid concentrations were analysed by using high-performance liquid chromatography. Population pharmacokinetic modelling was performed using a nonparametric methodology with Pmetrics and Monte Carlo simulations were employed to calculate the 100% time >MIC after the administration of a fixed regimen of 600 mg q12h i.v. The dose of linezolid needed to achieve a PTA ≥ 90% for all susceptible isolates classified according to EUCAST was estimated to be as high as 2400mg/12h, which is 4 times higher than the maximum licensed linezolid dose. The final pk model was then used to construct software for dosage individualisation and the performance of the software was assessed using 10 new patients not used to construct the original population PK model. A three-compartment model with an absorptive compartment with zero-order i.v. input and first-order clearance from the central compartment best described the data. The dose optimization software tracked patients with a high degree of accuracy. The software may be a clinically useful tool to adjust linezolid dosages in real-time to achieve prespecified drug exposures targets. A further prospective study is needed to examine the potential clinical utility of individualised therapy.

Download Full-text

Use of Population Pharmacokinetic Modeling and Monte Carlo Simulation To Describe the Pharmacodynamic Profile of Cefditoren in Plasma and Epithelial Lining Fluid

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00736-06 ◽

2007 ◽

Vol 52 (6) ◽

pp. 1945-1951 ◽

Cited By ~ 13

Author(s):

Thomas P. Lodise ◽

Martina Kinzig-Schippers ◽

George L. Drusano ◽

Ulrich Loos ◽

Friedrich Vogel ◽

...

Keyword(s):

Monte Carlo Simulation ◽

Monte Carlo ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Epithelial Lining ◽

Target Attainment ◽

Epithelial Lining Fluid ◽

Dosing Interval ◽

Pharmacodynamic Profile

ABSTRACT Cefditoren is a broad-spectrum, oral cephalosporin that is highly active against clinically relevant respiratory tract pathogens, including multidrug-resistant Streptococcus pneumoniae. This study described its pharmacodynamic profile in plasma and epithelial lining fluid (ELF). Plasma and ELF pharmacokinetic data were obtained from 24 patients under fasting conditions. Cefditoren and urea concentrations were determined in plasma and bronchoalveolar lavage fluid by liquid chromatography-tandem mass spectrometry. Concentration-time profiles in plasma and ELF were modeled using a model with three disposition compartments and first-order absorption, elimination, and transfer. Pharmacokinetic parameters were identified in a population pharmacokinetic analysis (big nonparametric adaptive grid with adaptive γ). Monte Carlo simulation (9,999 subjects) was performed with the ADAPT II program to estimate the probability of target attainment at which the free-cefditoren plasma concentrations (88%) protein binding and total ELF concentrations exceeded the MIC for 33% of the dosing interval for 400 mg cefditoren given orally every 12 h. After the Bayesian step, the overall fits of the model to the data were good, and plots of predicted versus observed concentrations for plasma and ELF showed slopes and intercepts very close to the ideal values of 1.0 and 0.0, respectively. In the plasma probability of target attainment analysis, the probability of achieving a time for which free, or unbound, plasma concentration exceeds the MIC of the organism for 33% of the dosing interval was <80% for a MIC of >0.06 mg/liter. Similar to plasma, the probability of achieving a time above the MIC of 33% was <80% for MIC of >0.06 mg/liter in ELF. Cefditoren was found to have a low probability of achieving a bacteriostatic effect against MICs of >0.06 mg/liter, which includes most S. pneumoniae isolates with intermediate susceptibility to penicillin, when given in the fasting state in both plasma and ELF.

Download Full-text

1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1501 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S670-S671

Author(s):

Ronald G Hall ◽

Jotam Pasipanodya ◽

William C Putnam ◽

John Griswold ◽

Sharmila Dissanaike ◽

...

Keyword(s):

Human Plasma ◽

Kidney Injury ◽

Compartment Model ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Population Parameter ◽

Full Thickness ◽

Severe Burns

Abstract Background Antimicrobial dosing in moderate/severe burns patients is complicated due to the potential unpredictable hyperdynamic pathophysiologic states including 1) hypoproteinemia, 2) acute kidney injury and 3) onset of septicemia. Therefore, distribution assumptions about the population pharmacokinetic (PopPK) profiles of either endogenous or xenobiotic pharmacophores in this patient population can lead to biased parameter estimates. In order to prevent potential bias an agnostic nonparametric adaptive grid approach to describe ceftolozane/tazobactam (C/T) PopPK profiles in patients with partial- and full-thickness burns was employed. Methods A human clinical PK study in burn patients was conducted using the standard approved dose of C/T (2 grams/1 gram). A single intravenous dose was administered over 60 minutes. Whole blood was obtained pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours following the start of infusion. LC-MS/MS bioanalytical methods were developed, validated and employed to determine C/T concentrations in human plasma. PopPK were modeled using Pmetrics package for R. One-, two- and three-compartment models were examined and compared. The influence of several parameters, including %body surface area burns, creatinine clearance (CrCL), weight, albumin and age were tested. Results The bioanalytical method for determination of C/T in human plasma met all recommended criteria of the LC-MS/MS. Five males and one female (ages 24 to 66 years), contributed 148 plasma PK samples. The female had 35% partial-thickness burns. The males had full-thickness burns ranging from 27 to 66%. The median CrCL was 104 mL/min (range 73-148 mL/min). Two-compartment model with absorption (Ka) from compartment 1 to 2 and elimination from compartment 2 (Ke), with nonlinear interactions between C/T elimination and CrCL best described the data. Figure A show that bias was minimal. Importantly, both drugs exhibited marked variability for both volume and elimination (Table), since volume was bimodally distributed (Figure B). A) Observation-versus-Prediction; B) Estimated Ke, V and Ka population parameter densities Summary of pharmacokinetic parameters Conclusion C/T exhibited high variability surpassing that observed with severe infections, suggesting that dose adjustment and/or may be therapeutic drug monitoring may be needed to balance target attainment from dose-related toxicities. Disclosures Ronald G. Hall, II, PharmD, MSCS, Medical Titan Group (Grant/Research Support)Merck (Research Grant or Support)

Download Full-text

Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02808-13 ◽

2014 ◽

Vol 58 (8) ◽

pp. 4718-4726 ◽

Cited By ~ 28

Author(s):

Ping Liu ◽

Diane R. Mould

Keyword(s):

Invasive Aspergillosis ◽

Area Under The Curve ◽

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Institutional Review Boards ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

First Order ◽

Two Compartment Model

ABSTRACTTo assess the pharmacokinetics (PK) of voriconazole and anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or anidulafungin. PK parameter estimates of voriconazole and anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC0–12] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on ClinicalTrials.gov (NCT00531479).

Download Full-text

Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Simulation of Piperacillin/Tazobactam for Dosing Optimization in Late Elderly Patients with Pneumonia

Antibiotics ◽

10.3390/antibiotics9030113 ◽

2020 ◽

Vol 9 (3) ◽

pp. 113 ◽

Cited By ~ 1

Author(s):

Noriyuki Ishihara ◽

Nobuhiro Nishimura ◽

Kazuro Ikawa ◽

Fumi Karino ◽

Kiyotaka Miura ◽

...

Keyword(s):

Plasma Concentration ◽

Elderly Patients ◽

Distribution Volume ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Target Attainment ◽

Old Patients ◽

Final Model ◽

Concentration Time ◽

Population Pk

The aim of this study was to develop a population pharmacokinetic model for piperacillin (PIPC)/tazobactam (TAZ) in late elderly patients with pneumonia and to optimize the administration planning by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. PIPC/TAZ (total dose of 2.25 or 4.5 g) was infused intravenously three times daily to Japanese patients over 75 years old. The plasma concentrations of PIPC and TAZ were determined using high-performance liquid chromatography and modeled using the NONMEM program. PK/PD analysis with a random simulation was conducted using the final population PK model to estimate the probability of target attainment (PTA) profiles for various PIPC/TAZ-regimen–minimum-inhibitory-concentration (MIC) combinations. The PTAs for PIPC and TAZ were determined as the fraction that achieved at least 50% free time > MIC and area under the free-plasma-concentration–time curve over 24 h ≥ 96 μg h/mL, respectively. A total of 18 cases, the mean age of which was 86.5 ± 6.0 (75–101) years, were investigated. The plasma-concentration–time profiles of PIPC and TAZ were characterized by a two-compartment model. The parameter estimates for the final model, namely the total clearance, central distribution volume, peripheral distribution volume, and intercompartmental clearance, were 4.58 + 0.061 × (CLcr − 37.4) L/h, 5.39 L, 6.96 L, and 20.7 L/h for PIPC, and 5.00 + 0.059 × (CLcr − 37.4) L/h, 6.29 L, 7.73 L, and 24.0 L/h for TAZ, respectively, where CLcr is the creatinine clearance. PK/PD analysis using the final model showed that in drug-resistant strains with a MIC > 8 μg/mL, 4.5 g of PIPC/TAZ every 6 h was required, even for the patients with a CLcr of 50–60 mL/min. The population PK model developed in this study, together with MIC value, can be useful for optimizing the PIPC/TAZ dosage in the over-75-year-old patients, when they are administered PIPC/TAZ. Therefore, the findings of present study may contribute to improving the efficacy and safety of the administration of PIPC/TAZ therapy in late elderly patients with pneumonia.

Download Full-text

P99 Clinical validation of published vancomycin population PK models in critically ill neonates

Archives of Disease in Childhood ◽

10.1136/archdischild-2019-esdppp.137 ◽

2019 ◽

Vol 104 (6) ◽

pp. e58.2-e59

Author(s):

A van der Veen ◽

RJ Keizer ◽

W de Boode ◽

A Somers ◽

R Brüggemann ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

A Priori ◽

Predictive Performance ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Suitable Model ◽

List Type ◽

A Posteriori ◽

Target Attainment

BackgroundVancomycin is commonly used for treatment of severe Gram+ neonatal infections. Currently, even with the use of optimized dosing regimens and therapeutic drug monitoring (TDM), target attainment rates are abominable, leaving patients at risk for therapeutic failure and toxicity. Model-informed precision dosing (MIPD) offers a large potential to improve therapy in the individual patient.The aim of this study was to identify a suitable model for bedside MIPD by assessing the predictive performance of published population pharmacokinetic (popPK) models.MethodsA literature search was conducted to identify parametric popPK models. PK vancomycin data were retrospectively collected from NICU patients at the Radboud University Hospital, Nijmegen, The Netherlands. The model predictive performance was assessed by comparison of predictions to observations, calculation of bias (Mean Percentage Errors, MPE) and imprecision (Normalized Root Mean Squared Errors, NRMSE). Evaluations included both a priori (model covariate input) and a posteriori (model covariate and TDM concentration input) scenarios.Results265 TDM measurements from 65 neonates (median postmenstrual age:32 weeks [range:25–45 weeks]; median weight:1281g [range:597–5360g]; median serum creatinine:0,48 mg/dL [range:0,15–1,28 mg/dL]) were used for model evaluation. Six popPK models were evaluated1–6. A posteriori predictions of all models were consistently more accurate and precise compared to the a priori (starting dose) predictions. PopPK models of Frymoyer et al. and Capparelli et al. consistently performed best through all evaluations in both the a priori and a posteriori scenario (MPE ranging from -18 to 6,4% in a priori scenario and -6,5 to -3,8% in a posteriori scenario; NRMSE ranging from 34 to 40% in a priori scenario and 23 to 24% in a posteriori scenario).ConclusionLarge differences in predictive performance of popPK models were observed. Repeated therapeutic drug monitoring remains necessary to increase target attainment rate. Best performing models for bedside MIPD were identified in our patient population.ReferencesZhao W, Lopez E, Biran V, et al. ( 2013). Vancomycin continuous infusion in neonates: Dosing optimisation and therapeutic drug monitoring. Arch Dis Child;98(6):449–453.Capparelli EV, Lane JR, Romanowski GL, et al. ( 2001). The influences of renal function and maturation on vancomycin elimination in newborns and infants. J Clin Pharmacol, 41:927–934.De Cock RFW, Allegaert K, Brussee JM, et al. ( 2014). Simultaneous pharmacokinetic modeling of gentamicin, tobramycin and vancomycin clearance from neonates to adults: towards a semi-physiological function for maturation in glomerular filtration. Pharm Res;31(10):2642–2654.Frymoyer A, Hersh AL, El-Komy MH, et al. ( 2014). Association between vancomycin trough concentration and area under the concentration-time curve in neonates. Antimicrob Agents Chemother, 58(11):6454–6461.Anderson BJ, Allegaert K, Van Den Anker JN, Cossey V, Holford NHG. ( 2006). Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance. Br J Clin Pharmacol;63(1):75–84.Germovsek E, Osborne L, Gunaratnam F, Lounis SA, Busquets FB, Sinha AK. ( 2019). Development and external evaluation of a population pharmacokinetic model for continuous and intermittent administration of vancomycin in neonates and infants using prospectively collected data. J Antimicrob Chemother, 1–9.Disclosure(s)R. Keizer is an employee and stockholder of InsightRX.

Download Full-text