scholarly journals Dosing Recommendations for Vancomycin in Children and Adolescents with Varying Levels of Obesity and Renal Dysfunction: a Population Pharmacokinetic Study in 1892 Children Aged 1–18 Years

2021 ◽  
Vol 23 (3) ◽  
Author(s):  
Cornelis Smit ◽  
Sebastiaan C. Goulooze ◽  
Roger J. M. Brüggemann ◽  
Catherine M. Sherwin ◽  
Catherijne A. J. Knibbe
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Children And Adolescents ◽  
Pharmacokinetic Study ◽  
Pediatric Population ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Obese Children ◽  
Population Pharmacokinetic Study

AbstractVancomycin is an effective but potentially nephrotoxic antibiotic commonly used for severe infections. Dosing guidelines for vancomycin in obese children and adolescents with or without renal impairment are currently lacking. This study describes the pharmacokinetics of vancomycin in a large pediatric cohort with varying degrees of obesity and renal function to design practical dosing guidelines for this population. A multi-center retrospective population pharmacokinetic study was conducted using data from patients aged 1−18 years who received >1 dose of vancomycin and had ≥1 vancomycin concentration measured between January 2006 and December 2012. Besides pharmacokinetic data, age, gender, body weight, creatinine clearance (CLcr, bedside Schwartz equation), ward, race, and neutropenic status were collected. Population pharmacokinetic analysis and simulations were performed using NONMEM7.4. A total of 1892 patients (5524 samples) were included, with total body weight (TBW) ranging 6−188 kg (1344 normal weight, 247 overweight, and 301 obese patients) and CLcr down to 8.6 mL/min/1.73 m2. The two-compartment model, with clearance (CL) significantly increasing with TBW and CLcr, central and peripheral volume of distribution and inter-compartmental clearance increasing with TBW, performed well for all age, weight, and renal function ranges. A dosing guideline is proposed that integrates body weight and CLcr resulting in effective and safe exposures across all ages, body weight, and renal functions in the pediatric population. We have characterized the full pharmacokinetic profile of vancomycin in obese children and adolescents aged 1−18 years and propose a practical dosing guideline that integrates both body weight and renal function.

scholarly journals Population Pharmacokinetic Study of Ceftriaxone in Elderly Patients, Using Cystatin C-Based Estimates of Renal Function To Account for Frailty

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Shu Jin Tan ◽  
Matthew Cockcroft ◽  
Madhu Page-Sharp ◽  
Glenn Arendts ◽  
Timothy M. E. Davis ◽  
...  
Keyword(s):  
Renal Function ◽  
Elderly Patients ◽  
Cystatin C ◽  
Pharmacokinetic Study ◽  
Severe Renal Impairment ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Total Exposure ◽  
Population Pharmacokinetic Study ◽  
Trough Concentrations

ABSTRACT Ceftriaxone is widely used for respiratory and urinary infections in elderly and frail patients, but there are few pharmacokinetic studies. A prospective population pharmacokinetic study of ceftriaxone in adults over 65 years old was undertaken. Dried blood spots collected at baseline (predose) and 0.5, 1, 4, 8, and 24 h after administration of 1 g of ceftriaxone were assayed using a validated liquid chromatography-mass spectroscopy analytical method. Frailty was classified using the Edmonton frailty scale and grip strength via a hand dynamometer. Estimates of glomerular filtration rate were determined using creatinine-based and cystatin C-based equations. Of 26 patients recruited, 23 (88%) were vulnerable or very frail. Estimates of drug clearance improved significantly with a cystatin C-based estimate of renal function that accounted for frailty. Simulations indicate that the combined effects of ranges of size and renal function resulted in a 6-fold range in peak ceftriaxone concentrations and 9-fold range in total exposure (area under the concentration-time curve [AUC]). For elderly patients with moderate or severe renal impairment, 48-h dosing results in greater trough concentrations and total exposure than the trough concentrations and total exposure in patients with normal renal function receiving 24-h dosing. Cystatin C-based measures of renal function improved predictions of ceftriaxone clearance in elderly patients.

Prospective evaluation of a developed S-1 dosage formula based on renal function.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 86-86
Author(s):  
Takuro Mizukami ◽  
Masashi Takeuchi ◽  
Chiyo K. Imamura ◽  
Eisuke Booka ◽  
HIROYA TAKEUCHI ◽  
...  
Keyword(s):  
Renal Function ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Target Area ◽  
Time Curve ◽  
And Gender ◽  
A Prospective Study ◽  
Clinical Trial Information

86 Background: S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-FU), 5-chloro-2,4-dihydroxypyridine (CDHP, inhibitor of dihydoropyrimidine dehydrogenase) and potassium oxonate. Because CDHP is excreted in urine, renal dysfunction increases incidence of severe adverse drug reactions due to higher exposure of 5-FU. As approved dose of S-1 is determined by body surface area (BSA) for patients with normal renal function, dose of S-1 is practically reduced according to renal function of creatinine clearance (CLcr) estimated by the Cockcroft-Gault equation. In a previous pharmacokinetic study (n = 16), we had developed an S-1 dosage formula based on renal function achieving the target area under the concentration-time curve (AUC) of 5-FU: Dose = target AUC x (21.9 + 0.375 x CLcr) x BSA. We conducted a prospective study to evaluate and refine this formula if necessary. Methods: Thirty patients with various renal function received S-1 at dose determined by our developed formula. A series of blood samples were obtained at predefined times after the first dose to calculate the AUC of 5-FU. Predictability of the formula was evaluated by comparison between the observed and the target AUCs. Results: The observed daily AUC was ranged from 712.6 to 2868.7 ng‧h/mL in 30 patients with BSA in the range of 1.14-1.84 m2 and CLcr in the range of 23.8-96.4 mL/min. Eighteen patients of them achieved the target AUC (1447.8 ± 545.4 ng‧h/mL). Since population pharmacokinetic analysis using combined pharmacokinetic data of 30 patients in this study and 16 patients in the previous study demonstrated that clearance of 5-FU is significantly lower in female than in male, the S-1 dosage formula was refined including gender as an additional factor: Dose = target AUC × (14.5 + 8.23 x GENDER [0 for female and 1 for male] + 0.301 × CLcr) × BSA. Revised nomograms showing recommended daily dose of S-1 were proposed for males and females taking into account tablet strengths. Conclusions: The refined formula for determining S-1 dosage on the basis of renal function, BSA and gender can be applied to clinical practice to ensure efficacy and safety for cancer patients treated with S-1. Clinical trial information: UMIN 000023880.

scholarly journals Ceftolozane-Tazobactam Population Pharmacokinetics and Dose Selection for Further Clinical Evaluation in Pediatric Patients with Complicated Urinary Tract or Complicated Intra-abdominal Infections

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Kajal B. Larson ◽  
Yogesh T. Patel ◽  
Susan Willavize ◽  
John S. Bradley ◽  
Elizabeth G. Rhee ◽  
...  
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Urinary Tract ◽  
Clinical Evaluation ◽  
Pediatric Patients ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Phase 2 ◽  
Tract Infections ◽  
Abdominal Infections

ABSTRACT Ceftolozane-tazobactam, a combination of the novel antipseudomonal cephalosporin ceftolozane and the well-established extended-spectrum β-lactamase inhibitor tazobactam, is approved for treating complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) in adults. To determine doses likely to be safe and efficacious in phase 2 pediatric trials for the same indications, single-dose ceftolozane-tazobactam plasma pharmacokinetic data from a recently completed phase 1 trial in pediatric patients (birth to <18 years old) with proven/suspected Gram-negative bacterial infections, along with pharmacokinetic data from 12 adult studies, were integrated into a population pharmacokinetic (popPK) analysis. Two-compartment linear models with first-order elimination described the concentration-time profiles of ceftolozane and tazobactam in pediatric patients well. Renal function and body weight were identified to be significant predictors of ceftolozane-tazobactam pharmacokinetics. Renal function, as measured by the estimated glomerular filtration rate (eGFR), significantly affected the clearance of both ceftolozane and tazobactam. Body weight significantly affected clearance and the distribution volume, also of both ceftolozane and tazobactam. Patients with infections had a 32.3% lower tazobactam clearance than healthy volunteers. Using the final popPK models, simulations of various dosing regimens were conducted to assess each regimen’s plasma exposure and the probability of pharmacokinetic/pharmacodynamic target attainment. Based on these simulations, the following doses are recommended for further clinical evaluation in phase 2 pediatric trials for cUTI and cIAI (in patients with an eGFR of ≥50 ml/min/1.73 m2 only): for children ≥12 years old, 1.5 g ceftolozane-tazobactam (1 g ceftolozane with 0.5 g tazobactam), and for neonates/very young infants, infants, and children <12 years old, 20/10 mg/kg of body weight ceftolozane-tazobactam, both via a 1-h intravenous infusion every 8 h.

scholarly journals Empirical Likelihood Estimation for Population Pharmacokinetic Study Based on Generalized Linear Model

2012 ◽  
Vol 2012 ◽  
pp. 1-13
Author(s):  
Fang-rong Yan ◽  
Jin-guan Lin ◽  
Yuan Huang ◽  
Jun-lin Liu ◽  
Tao Lu
Keyword(s):  
Linear Model ◽  
Empirical Likelihood ◽  
Pharmacokinetic Study ◽  
Generalized Linear Model ◽  
Efficient Estimation ◽  
Likelihood Method ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Population Pharmacokinetic Study ◽  
Study Results

To obtain efficient estimation of parameters is a major objective in population pharmacokinetic study. In this paper, we propose an empirical likelihood-based method to analyze the population pharmacokinetic data based on the generalized linear model. A nonparametric version of the Wilk's theorem for the limiting distributions of the empirical likelihood ratio is derived. Simulations are conducted to demonstrate the accuracy and efficiency of empirical likelihood method. An application illustrating our methods and supporting the simulation study results is presented. The results suggest that the proposed method is feasible for population pharmacokinetic data.

scholarly journals Population Pharmacokinetics of Vancomycin in the Pediatric Cardiac Surgical Population

2019 ◽  
Vol 24 (2) ◽  
pp. 107-116 ◽  
Author(s):  
Brady S. Moffett ◽  
Karla Resendiz ◽  
Jennifer Morris ◽  
Ayse Akcan-Arikan ◽  
Paul A. Checchia
Keyword(s):  
Serum Concentration ◽  
Creatinine Clearance ◽  
Cardiac Surgical Procedures ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Population Pharmacokinetic Study ◽  
Postmenstrual Age ◽  
Dosing Strategy

OBJECTIVE Vancomycin is often used in the pediatric cardiac surgical population, but few pharmacokinetic data are available to guide dosing. METHODS A retrospective, population pharmacokinetic study was performed for patients &lt;19 years of age initiated on vancomycin after cardiac surgery in the cardiac intensive care unit from 2011–2016 in our institution. Patient data were summarized by using descriptive statistical methods, and population pharmacokinetic analysis was performed by using NONMEM. Simulation was performed to determine a dosing strategy that most frequently obtained an AUC0–24:MIC (minimum inhibitory concentration) ratio of &gt;400. RESULTS A total of 261 patients (281 cardiac surgical procedures, cardiopulmonary bypass 82.3%) met inclusion criteria (60.1% male, median age 0.31 [IQR, 0.07–0.77] years). Vancomycin (14.5 ± 1.7 mg/kg/dose) was administered at median postoperative day 9 (IQR, 4–14), with a mean serum concentration of 11.5 ± 5.5 mg/L at 8.9 ± 3.8 hours after a dose. Population pharmacokinetic analysis demonstrated that a 1-compartment proportional error model with allometrically scaled weight best fit the data, with creatinine clearance and postmenstrual age as significant covariates. Simulation identified that a dosing regimen of 20 mg/kg/dose every 8 hours was most likely to achieve an AUC0–24:MIC ratio &gt; 400 at a mean trough serum concentration of 12.9 ± 3.2 mg/L. CONCLUSIONS Vancomycin dosing in the postoperative pediatric cardiac surgical population should incorporate postmenstrual age and creatinine clearance. A vancomycin dose of 20 mg/kg every 8 hours is a reasonable empiric strategy.

scholarly journals Population Pharmacokinetic Analysis of Amikacin for Optimal Pharmacotherapy in Korean Patients with Nontuberculous Mycobacterial Pulmonary Disease

Antibiotics ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 784
Author(s):  
Xuanyou Jin ◽  
Jaeseong Oh ◽  
Joo-Youn Cho ◽  
SeungHwan Lee ◽  
Su-jin Rhee
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Pulmonary Disease ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Compartment Model ◽  
The Body ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Properties

Amikacin is used as a therapy for patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) who are resistant to macrolide antibiotics or have severe symptoms. This study aimed to characterize the pharmacokinetic properties of amikacin in patients with NTM-PD by developing a population pharmacokinetic model and to explore the optimal pharmacotherapy in patients with NTM-PD. For this study, all data were retrospectively collected. The amikacin pharmacokinetic properties were best described by a two-compartment model with first-order elimination. The estimated glomerular filtration rate and body weight were identified as significant covariates for clearance and the volume of distribution, respectively. A model-based simulation was conducted to explore the probability of reaching the target therapeutic range when various dose regimens were administered according to the body weight and renal function. The simulation results indicated that the amikacin dosage should be determined based on the body weight, and for patients who weigh over 70 kg, it is necessary to adjust the dose according to renal function. In conclusion, the optimal pharmacotherapy of amikacin for patients with NTM-PD was recommended based on the population pharmacokinetic model, which is expected to enable the personalization of drug therapy and improve the clinical outcomes of amikacin therapy.

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