Population Pharmacokinetics and Dose Optimization of Piperacillin/tazobactam in Critically Ill Patients During Extracorporeal Membrane Oxygenation (ECMO) and Weaned from ECMO

2021 ◽  
Author(s):  
Jongsung Hahn ◽  
Kyoung Lok Min ◽  
Soyoung Kang ◽  
Seungwon Yang ◽  
Byung Hak Jin ◽  
...  
Keyword(s):  
Critical Illness ◽  
Extracorporeal Membrane Oxygenation ◽  
Volume Overload ◽  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Optimal Dosage ◽  
Close Monitoring ◽  
Membrane Oxygenation ◽  
Extended Infusion

Abstract Background: Piperacillin/tazobactam is commonly used for empirical or directed treatment of infections during extracorporeal membrane oxygenation therapy (ECMO). Critical illness and extracorporeal circulation, such as ECMO and continuous renal replacement therapy may alter the pharmacokinetic parameters. We aimed to develop a population pharmacokinetic model of piperacillin/tazobactam in ECMO patients and investigate the optimal dosage regimen to achieve a pharmacodynamics target.Methods: This was a prospective observational study of 26 ECMO patients who received piperacillin/tazobactam. A population PK model was developed using non-linear mixed-effects models and simulations were performed to evaluate patient variables, MIC levels, and dosage regimens in relation to the probability of target attainment (PTA). The acceptable piperacillin PTA was set at ≥90% for 50%ƒT >16 mg/L.Results: A total of 244 samples were collected (163 during ECMO and 81 weaned from ECMO). Thirteen patients (50%) underwent continuous venovenous hemodiafiltration (CVVHDF). In a 2-compartment model, clearance increased by 10.1% when patients weaned from ECMO. Because patients on CVVHDF had a significant residual renal function, CVVHDF was found non-relevant to clearance. Instead, volume overload which was main cause of CVVHDF and membrane adsorption might contribute to the increased volume of distribution. Creatinine clearance (CrCL) calculated by Cockcroft-Gault equation had a significant impact on clearance. Simulation demonstrated that extended infusion should be considered in ECMO patients with CrCL >60 mL/min. Our proposed regimen was extended infusion of 2/0.25 g q8h, 2/0.25 g 6h, 3/0.375 g q 6h, and 4/0.5g q6h for CrCL ≤40, 40–60, 60–130, and >130 mL/min, respectively. Furthermore, even a higher dose would be required when patients did not receive CVVHDF after weaning from ECMO, which was 4/0.5g q6h for CrCL >110 mL/minConclusions: Piperacillin/tazobactam PK changes observed in ECMO patients were associated with critical illness rather than ECMO itself. A recent guideline dose may result in underexposure against P.aeruginosa when ECMO patients have CrCL > 110 mL/min; therefore, close monitoring of renal clearance is crucial in ECMO patients who received piperacillin/tazobactam regardless of CVVHDF use to provide effective treatment of infections and promote recovery. Overall, this study provides preliminary insights into the incremental effects of critical illness, ECMO and CVVHDF on piperacillin/tazobactam PK.Trial Registration: Clinicaltrials.gov NCT02581280, December 1st, 2014.

scholarly journals 1540. A Population Pharmacokinetic Model for Vancomycin in Korean Patients Receiving Extracorporeal Membrane Oxygenation Therapy: A Prospective Study

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S562-S562
Author(s):  
Younghee Jung ◽  
Dong-Hwan Lee ◽  
Hyoung Soo Kim
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Creatinine Clearance ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Test Model ◽  
Mixed Effect ◽  
Korean Patients ◽  
Membrane Oxygenation ◽  
Population Pk

Abstract Background There is no literature on population pharmacokinetics (PK) of vancomycin in Korean patients receiving extracorporeal membrane oxygenation (ECMO) therapy. The aim of this study was to develop a population PK model for vancomycin in Korean ECMO patients. Methods We prospectively enrolled adult patients who were undergoing ECMO and receiving vancomycin from July 2018 to April 2019. After initial dose of vancomycin was administrated, serial blood samples (seven to nine times per patient) were drawn before the next dose. A population PK model for vancomycin was developed using a nonlinear mixed-effect modeling. Age, sex, creatinine clearance, and body weight were tested as potential covariates in the model. Model selection was based on log-likelihood test, model diagnostic plots, and clinical plausibility. Results Fourteen patients were included over the period. Ten received venovenous, three venoarterial, and one both type ECMO. Eleven were men and the median age was 54 (interquartile range 45–66.3). Mean estimated glomerular filtration rate (eGFR) was 69 ± 46 mL/minute/1.73m2 by the modification of diet in renal disease equation. A total of 123 vancomycin concentrations from the patients were included in the analysis. The population PK of vancomycin was best described by a two-compartment model with a proportional residual error model. The typical value (%between-subject variability) for total clearance was estimated to be 4.33 L/h (21.6%), central volume of distribution was 9.22 L, the intercompartmental clearance was 10.75 L/hr (34.9%) and the peripheral volume of distribution was 19.6 L (26.6%). The proportional residual variability was 8.81%. Creatinine clearance significantly influenced vancomycin clearance (CL). The proposed equation to estimate vancomycin clearance in Korean ECMO patients was CL = 4.33 + 0.199 × (eGFR – 56). Conclusion A two-compartment population PK model successfully describes vancomycin PK profiles in Korean ECMO patients. The model could be used to optimize the dosing regimen if more data become available from currently ongoing clinical study. Disclosures All authors: No reported disclosures.

scholarly journals Pharmacokinetics of vancomycin in critically ill infants undergoing extracorporeal membrane oxygenation.

1996 ◽  
Vol 40 (5) ◽  
pp. 1139-1142 ◽  
Author(s):  
R D Amaker ◽  
J T DiPiro ◽  
J Bhatia
Keyword(s):  
Renal Impairment ◽  
Extracorporeal Membrane Oxygenation ◽  
Half Life ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Published Data ◽  
Term Infants ◽  
Circulating Blood Volume ◽  
Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO) is a widely used therapy for neonates with respiratory failure. Because of sepsis, many of these infants require antibiotics like vancomycin during ECMO treatment. ECMO transiently alters renal function and increases the circulating blood volume by 75%. Initial vancomycin pharmacokinetics were determined in 12 infants undergoing ECMO to determine an adequate drug administration regimen. Vancomycin dosage was based on current recommendations for weight and gestational age. Pharmacokinetic parameters were determined by fitting the data to a two compartment model. This study yielded a mean steady-state volume of distribution of 1.1 +/- 0.5 (range, 0.6 to 2.1) liters/kg and a mean vancomycin clearance of 0.78 +/- 0.19 (range, 0.49 to 1.07) ml/min/kg. The mean vancomycin half-life was 16.9 +/- 9.5 (range, 8.8 to 42.9) h. Nomogram-calculated creatinine clearance was a significant predictor of vancomycin terminal rate constant and clearance. These data suggest alterations in the pharmacokinetics of vancomycin in infants on ECMO. With the goal of achieving vancomycin concentrations in serum above the MIC for the offending pathogen while using the least amount of the drug necessary, new administration guidelines for term infants without renal impairment undergoing ECMO should be 20 mg of vancomycin per kg at an interval of 24 h. With significant renal impairment, the interval should be extended on the basis of concentrations in serum. In comparison with previously published data, the neonates undergoing ECMO in our study demonstrated a much larger volume of distribution, a lower clearance, and consequently a longer vancomycin half-life.

scholarly journals Dose Optimization of Cefpirome Based on Population Pharmacokinetics and Target Attainment during Extracorporeal Membrane Oxygenation

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Soyoung Kang ◽  
June Young Jang ◽  
Jongsung Hahn ◽  
Dasohm Kim ◽  
Jun Yeong Lee ◽  
...  
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Population Pharmacokinetics ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Dose Optimization ◽  
Population Pharmacokinetic ◽  
Optimal Dosage ◽  
Target Attainment ◽  
Membrane Oxygenation ◽  
The Impact

ABSTRACT To obtain the optimal dosage regimen in patients receiving extracorporeal membrane oxygenation (ECMO), we developed a population pharmacokinetics model for cefpirome and performed pharmacodynamic analyses. This prospective study included 15 patients treated with cefpirome during ECMO. Blood samples were collected during ECMO (ECMO-ON) and after ECMO (ECMO-OFF) at predose and 0.5 to 1, 2 to 3, 4 to 6, 8 to 10, and 12 h after cefpirome administration. The population pharmacokinetic model was developed using nonlinear mixed effects modeling and stepwise covariate modeling. Monte Carlo simulation was used to assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) according to the MIC distribution. Cefpirome pharmacokinetics were best described by a two-compartment model. Covariate analysis indicated that serum creatinine concentration (SCr) was negatively correlated with clearance, and the presence of ECMO increased clearance and the central volume of distribution. The simulations showed that patients with low SCr during ECMO-ON had lower PTA than patients with high SCr during ECMO-OFF; so, a higher dosage of cefpirome was required. Cefpirome of 2 g every 8 h for intravenous bolus injection or 2 g every 12 h for extended infusion over 4 h was recommended with normal kidney function receiving ECMO. We established a population pharmacokinetic model for cefpirome in patients with ECMO, and appropriate cefpirome dosage regimens were recommended. The impact of ECMO could be due to the change in patient status on consideration of the small population and uncertainty in covariate relationships. Dose optimization of cefpirome may improve treatment success and survival in patients receiving ECMO. (This study has been registered at ClinicalTrials.gov under identifier NCT02581280.)

scholarly journals 1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns

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)

scholarly journals Evaluation of the Adequacy of WHO Revised Dosages of the First-Line Antituberculosis Drugs in Children with Tuberculosis Using Population Pharmacokinetic Modeling and Simulations

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Yasuhiro Horita ◽  
Abdullah Alsultan ◽  
Awewura Kwara ◽  
Sampson Antwi ◽  
Antony Enimil ◽  
...  
Keyword(s):  
Compartment Model ◽  
World Health ◽  
Population Pharmacokinetic ◽  
Optimal Dosage ◽  
Nonlinear Mixed Effects Models ◽  
First Line ◽  
Time Curve ◽  
Drug Concentrations ◽  
Target Values ◽  
Population Pk

ABSTRACTOptimal doses for antituberculosis (anti-TB) drugs in children have yet to be established. In 2010, the World Health Organization (WHO) recommended revised dosages of the first-line anti-TB drugs for children. Pharmacokinetic (PK) studies that investigated the adequacy of the WHO revised dosages to date have yielded conflicting results. We performed population PK modeling using data from one of these studies to identify optimal dosage ranges. Ghanaian children with tuberculosis on recommended therapy with rifampin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods. Nonlinear mixed-effects models were applied to describe the population PK of those drugs using MonolixSuite2016R1 (Lixoft, France). Bayesian estimation was performed, the correlation coefficient, bias, and precision between the observed and predicted areas under the concentration-time curve (AUCs) were calculated, and Bland-Altman plots were analyzed. The population PK of RIF and PZA was described by a one-compartment model and that for INH and EMB by a two-compartment model. Plasma maximum concentration (Cmax) and AUC targets were based on published results for children from India. The lowest target values for pediatric TB patients were attainable at the WHO-recommended dosage schedule for RIF and INH, except forN-acetyltransferase 2 non-slow acetylators (rapid and intermediate acetylators) in the lower-weight bands. However, higher published adult targets were not attainable for RIF and INH. The targets were not achieved for PZA and EMB. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.)

scholarly journals Joint Population Pharmacokinetic Analysis of Zidovudine, Lamivudine, and Their Active Intracellular Metabolites in HIV Patients

2011 ◽  
Vol 55 (7) ◽  
pp. 3423-3431 ◽  
Author(s):  
C. Bazzoli ◽  
H. Bénech ◽  
E. Rey ◽  
S. Retout ◽  
D. Salmon ◽  
...  
Keyword(s):  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Intracellular Metabolites ◽  
Drug Concentrations ◽  
The Mean ◽  
Intracellular Concentrations ◽  
Apparent Bioavailability

ABSTRACTThe population pharmacokinetic parameters of zidovudine (AZT), lamivudine (3TC), and their active intracellular metabolites in 75 naïve HIV-infected patients receiving an oral combination of AZT and 3TC twice daily as part of their multitherapy treatment in the COPHAR2-ANRS 111 trial are described. Four blood samples per patient were taken after 2 weeks of treatment to measure drug concentrations at steady state. Plasma AZT and 3TC concentrations were measured in 73 patients, and among those, 62 patients had measurable intracellular AZT-TP and 3TC-TP concentrations. For each drug, a joint population pharmacokinetic model was developed and we investigated the influence of different covariates. We then studied correlations between the mean plasma and intracellular concentrations of each drug. A one-compartment model with first-order absorption and elimination best described the plasma AZT concentration, with an additional compartment for intracellular AZT-TP. A similar model but with zero-order absorption was found to adequately described concentrations of 3TC and its metabolite 3TC-TP. The half-lives of AZT and 3TC were 0.81 h (94.8%) and 2.97 h (39.2%), respectively, whereas the intracellular half-lives of AZT-TP and 3TC-TP were 10.73 h (69%) and 21.16 h (44%), respectively. We found particularly a gender effect on the apparent bioavailability of AZT, as well as on the mean plasma and intracellular concentrations of AZT, which were significantly higher in females than in males. Relationships between mean plasma drug and intracellular metabolite concentrations were also highlighted both for AZT and for 3TC. Simulation with the model of plasma and intracellular concentrations for once- versus twice-daily regimens suggested that a daily dosing regimen with double doses could be appropriate.

scholarly journals Fluconazole Population Pharmacokinetics and Dosing for Prevention and Treatment of Invasive Candidiasis in Children Supported with Extracorporeal Membrane Oxygenation

2015 ◽  
Vol 59 (7) ◽  
pp. 3935-3943 ◽  
Author(s):  
Kevin M. Watt ◽  
Daniel Gonzalez ◽  
Daniel K. Benjamin ◽  
Kim L. R. Brouwer ◽  
Kelly C. Wade ◽  
...  
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Mixed Effect ◽  
Final Model ◽  
Content Type ◽  
Membrane Oxygenation ◽  
Nonlinear Mixed Effect ◽  
Nonlinear Mixed Effect Modeling ◽  
Drug Pharmacokinetics

ABSTRACTCandidainfections are a leading cause of infectious disease-related death in children supported by extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK); thus, standard fluconazole dosing may result in suboptimal drug exposures. The objective of our study was to determine the PK of fluconazole in children on ECMO. Forty children with 367 PK samples were included in the analysis. The PK data were analyzed using nonlinear mixed-effect modeling (NONMEM). A one-compartment model best described the data. Weight was included in the base model for clearance (CL) and volume of distribution (V). The final model included the effect of serum creatinine (SCR) level on CL and the effect of ECMO onVas follows: CL (in liters per hour) = 0.019 × weight × (SCR/0.4)−0.29× exp(ηCL) andV(in liters) = 0.93 × weight × 1.4ECMO× exp(ηV). The fluconazoleVwas increased in children supported by ECMO. Consequently, children on ECMO require a higher fluconazole loading dose for prophylaxis (12 mg/kg of body weight) and treatment (35 mg/kg) paired with standard maintenance doses to achieve exposures similar to those of children not on ECMO.

scholarly journals Estimation of Pharmacokinetic Parameters of Continuous Intravenous Flucloxacillin infusion in the Outpatient Settings (PKFLUCLOX)

2018 ◽  
Author(s):  
Nilar Lwin ◽  
Zheng Liu ◽  
Mark Loewenthal ◽  
Pauline Dobson ◽  
Ji Woong Yoo ◽  
...  
Keyword(s):  
Steady State ◽  
Continuous Infusion ◽  
Time Course ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Device Removal ◽  
Standard Dosage

Flucloxacillin, a beta-lactam antibiotic of the penicillin class, is considered first line therapy for methicillin sensitive Staphylococcus aureus (MSSA) in Australia. At our tertiary referral hospital in the home (HITH) program, it has been prescribed in a standard dosage of 8 grams per day by continuous infusion for more than 20 years. The aim of this observational study was to characterize the pharmacokinetic profile of flucloxacillin in patients who receive continuous infusion in the HITH setting, and to undertake population pharmacokinetic analysis performed with NONMEM software by comparing various structural models. This study utilised flucloxacillin concentrations from 44 separate specimens obtained from 23 patients. Twenty-five of these were collected immediately after elastomeric device removal, representing steady-state concentrations, and the remaining 19 were each collected at least 45 minutes after device removal to determine clearance of the drug. Plasma concentrations ranged from 13 to 194 mg/L with median steady-state concentration of 51.5 mg/L and inter-quartile range of 24.6 mg/L. The time-course of flucloxacillin was best described by a 1-compartment model. The best three covariates, CrCL (ΔOFV= -11.7), eGFR (ΔOFV= -5.9) and serum albumin (ΔOFV= -5.8) were found to be equivalent in terms of decreasing the OFV. CrCL was superior in explaining inter individual variability. The best model for flucloxacillin clearance was a one compartment model with CrCL as the sole covariate. The estimated population parameters were 9.5 L for volume of distribution and 8.1 L/h for flucloxacillin clearance.

scholarly journals Population Pharmacokinetic Study of Cefathiamidine in Infants With Augmented Renal Clearance

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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