scholarly journals P49 A pharmacokinetic evaluation of oral clavulanic acid in term newborns

2019 ◽  
Vol 104 (6) ◽  
pp. e37.2-e37
Author(s):  
FM Keij ◽  
RF Kornelisse ◽  
NG Hartwig ◽  
J van der Sluijs ◽  
A van Driel ◽  
...  
Keyword(s):  
Clavulanic Acid ◽  
Intervention Group ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Time Interval ◽  
Antibiotic Administration ◽  
List Type ◽  
Beta Lactam ◽  
Multicenter Rct ◽  
Term Newborns

BackgroundClavulanic acid is an irreversible beta-lactamase inhibitor which has a weak antibacterial action. When combined with a beta-lactam antibiotic such as amoxicillin, it is effective against a broad range of bacteria. Despite its widespread use, little is known on the mechanism of action and target levels. A few studies on oral clavulanic acid in adults are available reporting great variance (AUC median 4.99 mg·h/L [0.44–8.31])1 and a short elimination half-time (1.08h).2 Observations in neonates are currently lacking. We therefore evaluated the pharmacokinetics of oral clavulanic acid co-administered with amoxicillin in term newborns.MethodsAs part of a multicenter RCT (Clinicaltrials.gov:NCT03247920) evaluating neonatal intravenous-to-oral switch therapy in probable bacterial infection, we measured serum levels in patients allocated to the intervention group. They switched to amoxicillin/clavulanic acid suspension (25/6.25 mg/kg tid), after 48 hours of intravenous penicillin/gentamicin. Two blood samples from different dosing intervals, were obtained and directly stored at -80°C. Initially, and to ensure that amoxicillin levels were attained as safety marker, levels in the second part of the timeframe (4–8 h after administration) were collected. For the second batch, peak levels (1–2 h after administration) were collected. Analysis was performed using Liquid Chromatography and Mass Spectrometry.ResultsAt submission, samples of the first 15 patients were analysed (first batch). Samples were collected 6.0 ± 1.3 h (mean,S.D.) after antibiotic administration. Clavulanic acid levels were detected in all patients but a great variance was observed (median: 1.4 mg/L; range: 0.20–4.82 mg/L). Extrapolation would lead to an AUC of at least 8.4 mg·h/L.ConclusionsOral clavulanic acid is absorbed in term newborns, but great variance is seen in trough levels (4–8 h after administration). Extrapolation predicts at least an AUC comparable to those of adults. Peak levels in the first part of the time interval (0–4h) are needed to further build confidence on this conclusion.ReferencesDe Velde F, De Winter BCM, Koch BCP, Van Gelder T, Mouton JW, Consortium C-N. Highly variable absorption of clavulanic acid during the day: a population pharmacokinetic analysis. J Antimicrob Chemother. 2018;73(2):469–76.Vree TB, Dammers E, Exler PS. Identical pattern of highly variable absorption of clavulanic acid from four different oral formulations of co-amoxiclav in healthy subjects. J Antimicrob Chemother 2003;51(2):373–8.Disclosure(s)Nothing to disclose

scholarly journals Population Pharmacokinetics of Ceftizoxime Administered by Continuous Infusion in Clinically Ill Adult Patients

1998 ◽  
Vol 42 (7) ◽  
pp. 1783-1787 ◽  
Author(s):  
Bryan Facca ◽  
Bill Frame ◽  
Steve Triesenberg
Keyword(s):  
Serum Creatinine ◽  
Continuous Infusion ◽  
Population Pharmacokinetics ◽  
Bacterial Infections ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Beta Lactam ◽  
Serum Samples ◽  
Mixed Effect

ABSTRACT Ceftizoxime is a widely used beta-lactam antimicrobial agent, but pharmacokinetic data for use with clinically ill patients are lacking. We studied the population pharmacokinetics of ceftizoxime in 72 clinically ill patients at a community-based, university-affiliated hospital. A population pharmacokinetic model for ceftizoxime was created by using a prospective observational design. Ceftizoxime was administered by continuous infusion to treat patients with proven or suspected bacterial infections. While the patients were receiving infusions of ceftizoxime, serum samples were collected for pharmacokinetic analysis with the nonlinear mixed-effect modeling program NONMEM. In addition to clearance and volume of distribution, various comorbidities were examined for their influence on the kinetics. All 72 subjects completed the study, and 114 serum samples were collected. Several demographic and comorbidity variables, namely, age, weight, serum creatinine levels, congestive heart failure, and long-term ventilator dependency, had a significant impact on the estimate for ceftizoxime clearance. A mixture model, or two populations for estimation of ceftizoxime clearance, was discovered. One population presented with an additive clearance component of 1.6 liters per h. In addition, a maximizer function for serum creatinine levels was found. In summary, two models for ceftizoxime clearance, mixture and nonmixture, were found and are presented. Clearance for ceftizoxime can be estimated with commonly available clinical information and the models presented. From the clearance estimates, the dose of ceftizoxime to maintain the desired concentration in serum can be determined. Work is needed to validate the model for drug clearance and to evaluate its predictive performance.

scholarly journals Bone Penetration of Amoxicillin and Clavulanic Acid Evaluated by Population Pharmacokinetics and Monte Carlo Simulation

2009 ◽  
Vol 53 (6) ◽  
pp. 2569-2578 ◽  
Author(s):  
Cornelia B. Landersdorfer ◽  
Martina Kinzig ◽  
Jürgen B. Bulitta ◽  
Friedrich F. Hennig ◽  
Ulrike Holzgrabe ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Cortical Bone ◽  
Population Pharmacokinetics ◽  
Clavulanic Acid ◽  
Cancellous Bone ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Bone Infections ◽  
Drug Concentrations ◽  
Amoxicillin Clavulanic Acid

ABSTRACT Amoxicillin (amoxicilline)-clavulanic acid has promising activity against pathogens that cause bone infections. We present the first evaluation of the bone penetration of a beta-lactam by population pharmacokinetics and pharmacodynamic profiling via Monte Carlo simulations. Twenty uninfected patients undergoing total hip replacement received a single intravenous infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid before surgery. Blood and bone specimens were collected. Bone samples were pulverized under liquid nitrogen with a cryogenic mill, including an internal standard. The drug concentrations in serum and total bone were analyzed by liquid chromatography-tandem mass spectrometry. We used NONMEM and S-ADAPT for population pharmacokinetic analysis and a target time of the non-protein-bound drug concentration above the MIC for ≥50% of the dosing interval for near-maximal bactericidal activity in serum. The median of the ratio of the area under the curve (AUC) for bone/AUC for serum was 20% (10th to 90th percentile for between-subject variability [variability], 16 to 25%) in cortical bone and 18% (variability, 11 to 29%) in cancellous bone for amoxicillin and 15% (variability, 11 to 21%) in cortical bone and 10% (variability, 5.1 to 21%) in cancellous bone for clavulanic acid. Analysis in S-ADAPT yielded similar results. The equilibration half-lives between serum and bone were 12 min for amoxicillin and 14 min for clavulanic acid. For a 30-min infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid every 4 h, amoxicillin achieved robust (≥90%) probabilities of target attainment (PTAs) for MICs of ≤12 mg/liter in serum and 2 to 3 mg/liter in bone and population PTAs above 95% against methicillin-susceptible Staphylococcus aureus in bone and serum. The AUC of amoxicillin-clavulanic acid was 5 to 10 times lower in bone than in serum, and amoxicillin-clavulanic acid achieved a rapid equilibrium and favorable population PTAs against pathogens commonly encountered in bone infections.

scholarly journals Assessment of two penicillins plus beta-lactamase inhibitors versus cefotaxime in treatment of murine Klebsiella pneumoniae infections.

1996 ◽  
Vol 40 (2) ◽  
pp. 325-330 ◽  
Author(s):  
J L Fournier ◽  
F Ramisse ◽  
A C Jacolot ◽  
M Szatanik ◽  
O J Petitjean ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Clavulanic Acid ◽  
Survival Rates ◽  
Dose Effect ◽  
Pharmacokinetic Analysis ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Bacterial Killing ◽  
Bacterial Counts

The in vivo efficacies of piperacillin, piperacillin plus tazobactam, ticarcillin, ticarcillin plus clavulanic acid, piperacillin plus clavulanic acid, and cefotaxime were compared in a mouse model of pneumonia induced by the SHV-1 beta-lactamase-producer Klebsiella pneumoniae. Each antibiotic was injected either once intraperitoneally at 24 h postinfection or at repeated times during 24 h. The efficacies of the drugs and therapeutic protocols were assessed by counting viable bacteria recovered from the lungs of mice sacrificed at selected times. No emergence of beta-lactam-resistant organisms was detected. Ticarcillin at 300 mg/kg was ineffective. Repeated injections of piperacillin at 300 mg/kg, either alone or in combination with tazobactam (8:1), led to a significant decrease in bacterial counts, but this was followed by bacterial regrowth. The pharmacokinetic analysis demonstrated that this short-lasting antibacterial effect was not due to a failure of piperacillin and/or tazobactam to penetrate the lungs. The combinations of ticarcillin at 300 mg/kg plus clavulanic acid (15:1) and piperacillin at 300 mg/kg plus tazobactam (4:1) were proven to be effective in that they decreased the bacterial burden in the lungs from 10(5) to < 10(3) CFU. This dose effect of tazobactam can be explained by its dose-dependent penetration in the lungs. Cefotaxime at 100 mg/kg and the combination of piperacillin (slightly hydrolyzed by SHV-1) at 300 mg/kg plus clavulanic acid (15:1) led to the best efficacy. Both of these treatments induced a decrease in bacterial counts of nearly 4 log10 units. The survival rates correlated with the quantitative measurements of in vivo bacterial killing. These experimental results obtained from the restricted animal model used here may help in the design of further protocols for clinical trials.

scholarly journals P61 Population pharmacokinetics of vancomycin in chinese ICU neonates: initial dosage recommendations

2019 ◽  
Vol 104 (6) ◽  
pp. e42.2-e42
Author(s):  
Z Li ◽  
Z Jiao
Keyword(s):  
Body Weight ◽  
Population Pharmacokinetics ◽  
Pharmacokinetic Model ◽  
Preterm Neonates ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
List Type ◽  
Current Guideline ◽  
Mixed Effect ◽  
Pediatric Cancer Patients

The main goal of our study was to characterize the population pharmacokinetics of vancomycin in critically ill Chinese neonates to develop a pharmacokinetic model and investigate factors that have significant influences on the pharmacokinetics of vancomycin in this population.1 2 The study population consisted of 80neonates in the neonatal intensive care unit (ICU)from which 165 trough and peak concentrations of vancomycin were obtained.Nonlinear mixed effect modeling was used to develop a population pharmacokinetic model for vancomycin.4 The stability and predictive ability of the final model were evaluated based on diagnostic plots, normalized prediction distribution errorsandthe bootstrap method.Serum creatinine (Scr) and body weight were significant covariates on the clearance of vancomycin.5 6 The average clearance was 0.309L/h for a neonate with Scr of 23.3mmol/L and body weight of 2.9 kg. No obvious ethnic differences in the clearance of vancomycin were found relative to the earlier studies of Caucasian neonates. Moreover, the established model indicated that in patients with a greater renal clearance status, especially Scr < 15mmol/L,current guideline recommendationswould likely not achieve therapeuticarea under the concentration-time curve over24 h/minimum inhibitoryconcentration (AUC24h/MIC) ≥ 400.3 The exceptions to this areBritish National Formulary (2016–2017), Blue Book (2016) and Neofax (2017). Recommended dose regimensfor neonates with differentScrlevelsandpostmenstrual ageswere estimatedbased on Monte Carlo simulations andthe established model.These findings will be valuable for developing individualized dosage regimens in the neonatal ICU setting.ReferencesAbdel HO, Al OS, Nazer LH., Mubarak S, Le, J. Vancomycin pharmacokinetics and predicted dosage requirements in pediatric cancer patients. Journal of Oncology Pharmacy Practice 2015;22(3):448–453doi: 10.1177/1078155215591386Anderson, B. J., Allegaert, K., Jn, V. D. A., Cossey, V., &amp;Holford, N. H. ( 2007). Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance. British Journal of Clinical Pharmacolog;63(1):75–84. doi: 10.1111/j.1365-2125.2006.02725.xAllegaert K, Anderson BJ, Jn, VDA, Vanhaesebrouck, S., & De, Z. F. ( 2007). Renal drug clearance in preterm neonates: relation to prenatal growth. Therapeutic Drug Monitoring, 29(3), 284–291. doi: 10.1097/FTD.0b013e31806db3f5Byon, W., Smith, M. K., Chan, P., Tortorici, M. A., Riley, S., & Dai, H., et al. ( 2013). Establishing best practices and guidance in population modeling: an experience with an internal population pharmacokinetic analysis guidance. CptPharmacometrics & Systems Pharmacology,2(7), e51. doi: 10.1016/j.cmpb.2010.04.018Capparelli, E. V., Lane, F. R., Romanowski, G. L., Pharm, M. F., Murray, W., & Sousa, P., et al. ( 2001). The influences of renal function and maturation on vancomycin elimination in newborns and infants. Journal of Clinical Pharmacology, 41(9), 927–934.Centers for Disease Control and Prevention. ( 2009). WHO Child Growth Standards. http://www.who.int/childgrowth/en. [EB/OL] 2017-09-12Disclosure(s)Nothing to disclose

scholarly journals Highly variable absorption of clavulanic acid during the day: a population pharmacokinetic analysis

2017 ◽  
Vol 73 (2) ◽  
pp. 469-476 ◽  
Author(s):  
Femke De Velde ◽  
Brenda C M De Winter ◽  
Birgit C P Koch ◽  
Teun Van Gelder ◽  
Johan W Mouton ◽  
...  
Keyword(s):  
Clavulanic Acid ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic

scholarly journals 465 Bintrafusp alfa in combination with chemotherapy in patients with stage IV NSCLC: safety and pharmacokinetic results of the INTR@PID LUNG 024 study

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A494-A494
Author(s):  
Christian Rolfo ◽  
Laurent Greillier ◽  
Remi Veillon ◽  
Firas Badin ◽  
Francois Ghiringhelli ◽  
...  
Keyword(s):  
Safety Data ◽  
Stage Iv ◽  
Population Pharmacokinetic Analysis ◽  
Skin Lesions ◽  
Primary Objective ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
List Type ◽  
Poppk Model ◽  
Study Teams

BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β ”trap”) fused to a human IgG1 mAb blocking PD-L1. Here we report cumulative safety and pharmacokinetic (PK) results from the global, phase 1b/2 INTR@PID LUNG 024 study (NCT03840915), which evaluated bintrafusp alfa in combination with chemotherapy (CT) in patients with stage IV NSCLC.MethodsAdult patients with stage IV nonsquamous or squamous NSCLC and an ECOG PS ≤1 were included. Cohorts A, B, and C included patients with no prior systemic therapy; patients in cohort D had disease that progressed with previous anti–PD-(L)1 therapy. Cohorts received bintrafusp alfa 2400 mg every 3 weeks intravenously in combination with CT for 4 cycles (A [nonsquamous only]: cisplatin or carboplatin + pemetrexed; B: carboplatin + nab-paclitaxel or paclitaxel; C: cisplatin or carboplatin + gemcitabine; D: docetaxel) followed by bintrafusp alfa maintenance (monotherapy or in combination with pemetrexed in cohort A) for up to 31 cycles. The primary objective of this study was to evaluate the safety of bintrafusp alfa in combination with CT. Dose-limiting toxicities (DLTs) were assessed during a 3-week observation period. Serial samples were drawn to assess serum concentration and calculate PK parameters by noncompartmental analysis.ResultsAs of the May 5, 2021, data cutoff, 70 patients received bintrafusp alfa in combination with CT. Of 35 patients included in the DLT analysis, 4 experienced 1 DLT according to a safety monitoring committee (data cutoff May 5, 2021; A: n=1/8; B: n=1/8; C: n=0/8; D: n=2/11). Cumulative safety data are reported in table 1. PK data were available for 67 patients (A: n=38; B: n=9; C: n=8; D: n=12). PK profiles were similar across cohorts and between patients who did and did not experience a DLT. Observed bintrafusp alfa first-cycle exposures (Cmax, AUC, and Ctrough) were consistent with the published population PK (popPK) model.1Abstract 465 Table 1Safety results from the INTR@PID LUNG 024 studyConclusionsThe safety profile of bintrafusp alfa in combination with CT was manageable and similar to that reported for ICIs in combination with CT, with the exception of TGF-β–related skin lesions known to occur with TGF-β inhibition. No new safety signals were identified and there were no treatment-related deaths. The PK profile was consistent with the predicted monotherapy popPK model, suggesting no victim DDI potential for bintrafusp alfa with CT.AcknowledgementsThe authors thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers, at the healthcare business of Merck KGaA, Darmstadt, Germany, and at EMD Serono, Billerica, Massachusetts, USA.Trial RegistrationNCT03840915ReferenceWilkins JJ, Vugmeyster Y, Dussault I. Population pharmacokinetic analysis of bintrafusp alfa in different cancer types. Adv Ther 2019;36:2414–2433.Ethics ApprovalThe trial was approved by each site’s independent ethics committee.

scholarly journals Development of population and Bayesian models for applied use in patients receiving cefepime

2019 ◽  
Author(s):  
Jiajun Liu ◽  
Michael Neely ◽  
Jeffrey Lipman ◽  
Fekade Sime ◽  
Jason Roberts ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Drug Exposure ◽  
Model Performance ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
List Type ◽  
Beta Lactam ◽  
Lactam Antibiotic

AbstractUnderstanding exposures of cefepime, a β-lactam antibiotic, is crucial for developing regimens to achieve optimal exposure and improved clinical outcomes. This study sought to develop and evaluate a unified population pharmacokinetic model in both pediatric and adult patients receiving cefepime treatment. Multiple physiologically relevant models were fit to pediatric and adult subject data. To evaluate the final model performance, a withheld group of twelve pediatric and two separate adult populations were assessed. Seventy subjects with a total of 604 cefepime concentrations were included in this study. All adults (n=34) on average weighed 82.7 kg and displayed a mean creatinine clearance (CrCL) of 106.7 mL/min. All pediatric subjects (n=36) had mean weight and CrCL of 16.0 kg and 195.64 mL/min, respectively. A covariate-adjusted two compartment model described the observed concentrations well (population model R2, 87.0%; Bayesian model R2, 96.5%). In the evaluation subsets, the model performed similarly well (population R2, 84.0%; Bayesian R2, 90.2%). The identified model serves well for population dosing and as a Bayesian prior for precision dosing.Key pointsA unified cefepime population pharmacokinetic model has been developed from adult and pediatric patients and evaluates well in independent populations.When paired with real time beta-lactam assays, precision dosing approach will optimize drug exposure and improve clinical outcomes.

scholarly journals P103 Target attainment of amikacin therapy in critically ill children

2019 ◽  
Vol 104 (6) ◽  
pp. e60.2-e61
Author(s):  
J Verbruggen ◽  
K Jakipbayeva ◽  
T Van Der Heggen ◽  
E Dhont ◽  
L Dhondt ◽  
...  
Keyword(s):  
Steady State ◽  
Pilot Study ◽  
Critically Ill ◽  
Critically Ill Children ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
List Type ◽  
Dosing Regimen ◽  
Target Attainment ◽  
Clinical Pharmacokinetics

BackgroundResearch regarding the optimal amikacin (AMI) dosing regimen in critically ill children is scarce.1 Optimal AMI efficacy has been observed with plasma peak over minimal inhibitory concentration of the suspected pathogen (peak/MIC) ratios of 8 to 10. Plasma trough levels (Cmin) >5mcg/ml are related to its toxicity.The objectives of this pilot study were to: (1) evaluate target attainment rate and occurrence of supratherapeutic concentrations in early and assumed steady-state dose conditions, and (2) investigate the correlation between AMI clearance and estimated glomerular filtration (eGFR).MethodsChildren admitted to the ICU receiving intravenous AMI (20 mg/kg once daily) were included. Serial blood samples were obtained from early (1st/2nd) and assumed steady-state (SS) doses. The evaluated target peak concentration range was 54–64 mcg/ml, assuming a Pseudomonas aeruginosa infection with Eucast MIC breakpoint of 8 mg/L, and a Cmin threshold of 5 mcg/L. eGFR was estimated using the modified Schwartz formula. AMI clearance was calculated using noncompartmental PK analysis. Correlation was assessed by means of a scatter plot and Pearson Correlation Coefficient (r).ResultsTwenty-one patients (median age1,5 years; range:0,5 months-14 year, median eGFR 162 ml/min/1,73m2 (range:107–475 ml/min/1,73m2) were included. In early dose conditions, 69% of patients had therapeutic peak concentrations (median: 60 mcg/ml; range:26–73 mcg/ml). In SS conditions, 60% of patients had therapeutic peak concentrations (median: 59 mcg/ml; range:35–83 mcg/ml). Only one supratherapeutic Cmin was observed. AMI clearance (median 0.08L/h/kg; range: 0.05–0.91 L/h/kg) was comparable to what has been previously reported but showed no correlation with eGFR (r=0.1; p=0,66) [1].ConclusionThis pilot study suggest that the current AMI dosing regimen may lead to subtherapeutic concentrations in patients infected with less susceptible pathogens. Supratherapeutic Cmin were far less of a concern. Dose adjustments of renally cleared drugs based on eGFR may not be reliable in this patient population.ReferencesIllamola SM, Sherwin CM, van Hasselt JGC. Clinical Pharmacokinetics of Amikacin in Pediatric Patients: A Comprehensive review of Population Pharmacokinetic Analysis. Clin Pharmacokinet ( 2018) 57:1217.Disclosure(s)Nothing to disclose

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