Introducing VancoCalc: A Free Open-Source Bayesian Vancomycin Dosing Tool for Adults (Preprint)

2021 ◽  
Author(s):  
Thomas Oommen ◽  
Anirudh Thommandram ◽  
Adam Palanica ◽  
Yan Fossat
Keyword(s):  
Patient Outcomes ◽  
Therapeutic Monitoring ◽  
Therapeutic Window ◽  
Pharmacokinetic Parameters ◽  
Proof Of Concept ◽  
Intravenous Antibiotic ◽  
Optimal Dosing ◽  
Starting Dose ◽  
Trough Concentrations ◽  
Free Open Source

UNSTRUCTURED Vancomycin is an intravenous antibiotic with a narrow therapeutic window where concentrations must be monitored for safety and efficacy. Traditional methods of dosing vancomycin use a weight-based starting dose with interval based on renal function. Dose adjustments are often based on trough concentrations measurements and heuristics or nomograms. It has been suggested that vancomycin dose adjustments using Bayesian methods is optimal. Unfortunately, many of these Bayesian tools are costly. In the hopes of democratizing Bayesian vancomycin dosing, we created VancoCalc, a free website, as a proof of concept vancomycin dosing tool which leverages Bayesian inference. It uses individual concentrations to estimate pharmacokinetic parameters and suggest optimal dosing options based on these concentrations and estimated pharmacokinetic parameters. To gain confidence in the Bayesian process and evaluate the tool, it was used to predict vancomycin concentrations using retrospective clinical data from 52 patients. Our hope is to increase awareness of this tool and further improve on vancomycin dosing with this freely available instrument, which may have beneficial implications for therapeutic monitoring and improving patient outcomes.

scholarly journals Challenges of Vancomycin Dosing and Therapeutic Monitoring in Neonates

2020 ◽  
Vol 25 (6) ◽  
pp. 476-484
Author(s):  
Jennifer T. Pham
Keyword(s):  
Pediatric Patients ◽  
Late Onset ◽  
Therapeutic Monitoring ◽  
Pharmacokinetic Parameters ◽  
Coagulase Negative Staphylococci ◽  
Optimal Dosing ◽  
Increased Risk ◽  
Dosing Regimens ◽  
Vancomycin Trough ◽  
Trough Concentrations

Late-onset sepsis in neonates can lead to significant morbidity and mortality, especially in preterm infants. Vancomycin is commonly prescribed for the treatment of Gram-positive organisms, particularly methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci, and ampicillin-resistant Enterococcus species in adult and pediatric patients. Currently, there is no consensus on optimal dosing and monitoring of vancomycin in neonates. Different vancomycin dosing regimens exist for neonates, but with many of these regimens, obtaining therapeutic trough concentrations can be difficult. In 2011, the Infectious Diseases Society of America recommended vancomycin trough concentrations of 15 to 20 mg/L or an AUC/MIC ratio of ≥400 for severe invasive diseases (e.g., MRSA) in adult and pediatric patients. Owing to recent reports of increased risk of nephrotoxicity associated with vancomycin trough concentrations of 15 to 20 mg/L and AUC/MIC of ≥400, a revised consensus guideline, recently published in 2020, no longer recommends monitoring vancomycin trough concentrations in adult patients. The guideline recommends an AUC/MIC of 400 to 600, which has been found to achieve clinical efficacy while reducing nephrotoxicity. However, these recommendations were derived solely from adult literature, as there are limited clinical outcomes data in pediatric and neonatal patients. Furthermore, owing to the variation of vancomycin pharmacokinetic parameters among the neonatal population, these recommendations for achieving vancomycin AUC/MIC of 400 to 600 in neonates require further investigation. This review will discuss the challenges of achieving optimal vancomycin dosing and monitoring in neonatal patients.

Is There a Relationship Between the Intensity of Heparin Treatment and Recurrent Thomboembolism?

1997 ◽  
Vol 3 (1_suppl) ◽  
pp. S64-S67
Author(s):  
Sonia Anand ◽  
Jeffrey S. Ginsberg ◽  
Jack Hirsh
Keyword(s):  
Venous Thromboembolism ◽  
Therapeutic Range ◽  
Activated Partial Thromboplastin Time ◽  
Therapeutic Window ◽  
Heparin Treatment ◽  
Optimal Dosing ◽  
Intravenous Heparin ◽  
Starting Dose ◽  
Dosing Regimens ◽  
Anticoagulant Response

Continuous intravenous heparin is widely used in the initial treatment of patients with venous thromboembolism. However, because it has a narrow therapeutic window and because the anticoagulant response to it varies among patients, it is standard practice to adjust the dose of heparin to achieve a predefined anticoagulant effect (therapeutic range) using the activated partial thromboplastin time (APTT). There is evidence to suggest that the efficacy of heparin is critically dependent on the starting dose used and that failure to maintain APTT results above the lower limit of the therapeutic range leads to increased rates of recurrence. We review the evidence for a rel~tic~nship between the intensity of heparin treatment and recurrence and provide recommendations for optimal dosing regimens.

scholarly journals Vancomycin Dosing in Healthy-Weight, Overweight, and Obese Pediatric Patients

2014 ◽  
Vol 19 (3) ◽  
pp. 182-188
Author(s):  
Lea S. Eiland ◽  
Kalyani B. Sonawane
Keyword(s):  
Serum Concentration ◽  
Pediatric Patients ◽  
Therapeutic Monitoring ◽  
Pharmacokinetic Parameters ◽  
Obese Patients ◽  
Healthy Weight ◽  
Serum Concentrations ◽  
Trough Serum Concentration ◽  
Trough Serum ◽  
Dosing Regimens

OBJECTIVES: With an increase in vancomycin resistance and the prevalence of obesity in children, alterations of vancomycin dosing regimens may be necessary to achieve target serum concentrations. The primary objective of this study was to describe initial vancomycin dosing with resulting serum concentrations in healthy-weight and overweight/obese children. Secondary objectives include comparing vancomycin dosing regimens of healthy-weight and overweight/obese patients that produced target trough serum concentrations and evaluating the likelihood of attaining target concentrations by patient characteristics. METHODS: This retrospective review evaluated healthy-weight and overweight/obese patients, aged 2 to 18 years, who had vancomycin trough serum concentrations obtained between 2005 and 2010. Vancomycin dosing, initial trough serum concentrations, pharmacokinetic parameters, and patient demographics were collected for analysis. Target trough serum concentrations were defined as 10 to 20 mg/L. RESULTS: The study included 98 patients (48 healthy weight, 50 overweight/obese) of which only 14 patients (14.2%, 6 healthy weight, 8 obese) reached a target trough serum concentration with empiric dosing. No difference was found between the mean daily dosing of vancomycin that produced target trough serum concentrations in healthy-weight or overweight/obese patients (53.63 mg/kg/day vs 51.6 mg/kg/day, respectively). Demographic or clinical characteristics were not found to be associated with the likelihood of target trough serum concentration attainment. CONCLUSIONS: Vancomycin dosing in healthy-weight and overweight/obese pediatric patients did not reach target trough serum concentrations most of the time. In obtaining initial target serum concentrations, no dosing difference was identified for overweight/obese patients compared with healthy-weight patients. Alternate dosing strategies, therapeutic monitoring, and clinical outcomes should continue to be evaluated in this population.

Accuracy of predicting the vancomycin concentration in Japanese cancer patients by the Sawchuk–Zaske method or Bayesian method

2019 ◽  
Vol 26 (3) ◽  
pp. 543-548
Author(s):  
Toshihisa Nakashima ◽  
Takayuki Ohno ◽  
Keiichi Koido ◽  
Hironobu Hashimoto ◽  
Hiroyuki Terakado
Keyword(s):  
Cancer Patients ◽  
Prediction Error ◽  
Bayesian Method ◽  
Predictive Accuracy ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Squared Prediction Error ◽  
Trough Concentrations ◽  
The Mean ◽  
Mean Prediction Error

Background In cancer patients treated with vancomycin, therapeutic drug monitoring is currently performed by the Bayesian method that involves estimating individual pharmacokinetics from population pharmacokinetic parameters and trough concentrations rather than the Sawchuk–Zaske method using peak and trough concentrations. Although the presence of malignancy influences the pharmacokinetic parameters of vancomycin, it is unclear whether cancer patients were included in the Japanese patient populations employed to estimate population pharmacokinetic parameters for this drug. The difference of predictive accuracy between the Sawchuk–Zaske and Bayesian methods in Japanese cancer patients is not completely understood. Objective To retrospectively compare the accuracy of predicting vancomycin concentrations between the Sawchuk–Zaske method and the Bayesian method in Japanese cancer patients. Methods Using data from 48 patients with various malignancies, the predictive accuracy (bias) and precision of the two methods were assessed by calculating the mean prediction error, the mean absolute prediction error, and the root mean squared prediction error. Results Prediction of the trough and peak vancomycin concentrations by the Sawchuk–Zaske method and the peak concentration by the Bayesian method showed a bias toward low values according to the mean prediction error. However, there were no significant differences between the two methods with regard to the changes of the mean prediction error, mean absolute prediction error, and root mean squared prediction error. Conclusion The Sawchuk–Zaske method and Bayesian method showed similar accuracy for predicting vancomycin concentrations in Japanese cancer patients.

scholarly journals 1535. Pharmacokinetic (PK) and Pharmacodynamic (PD) Evaluation of Cefepime (CPM) in Obese and Non-Obese Patients

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S559-S559
Author(s):  
Taylor Morrisette ◽  
Nichole Neville ◽  
Scott W Mueller ◽  
Abbie Britton ◽  
Gabrielle Jacknin ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
High Performance ◽  
Reversed Phase ◽  
Simulated Patients ◽  
Obese Patients ◽  
Target Attainment ◽  
Optimal Dosing ◽  
Significant Difference ◽  
Chi Squared ◽  
Dosing Strategies

Abstract Background Appropriate application of antimicrobial PK/PD properties is crucial to optimizing patient outcomes. Although β-lactams are among the most utilized and effective antibiotics, optimal dosing strategies in obese populations are largely unknown. The objective of this study was to compare PK/PD of CPM in non-obese (NO, weight 80–100 kg) and obese (O, weight > 100 kg) patients. Methods A prospective comparative PK/PD analysis was conducted in NO and O patients receiving CPM. Blood samples were obtained at 30, 60, 120, 240, 360, and 480 minutes after CPM infusion. CPM concentrations were determined by reversed-phase high-performance liquid chromatography. Non-compartmental PK analyses were performed, followed by Monte Carlo simulations (Oracle Crystal Ball®, 5,000 simulated patients) to estimate probability of target attainment (PTA) against common Gram-negative pathogens. The desired PD target for CPM was % time above MIC of unbound drug (%fT > MIC) ≥ 60%. Chi-squared and Mann–Whitney U tests were used for analysis. Results Seventeen patients were enrolled and most (94%) received CPM 2 g q8h. A significant difference in actual body weight and body mass index was observed (P < 0.001). There were no differences in other baseline or PK characteristics between the two groups. Utilizing CPM 2 g q8h, PTA ≥ 90% was not observed for organisms with an MIC of 8 μg/mL, the current CLSI breakpoint for P. aeruginosa and A. baumannii (PTA = 88% vs. 81% in NO and O groups, respectively). With a 6 g continuous infusion (CI), however, ≥ 90% PTA was achieved in both groups (PTA = 100%) for organisms with an MIC of 8 μg/mL, while a regimen of 2 g q8h (infused over 3 hours [EI]) also provided PTA of ≥ 90% in both groups (PTA = 98% vs. 92% in NO and O groups, respectively). Goal PTA was not obtained in either group for organisms with an MIC of 4 μg/mL with CPM 1 g q8h or 2 g q12h (i.e., CLSI recommended dosing for organisms with MICs of 4 μg/mL). Conclusion Optimizing PK/PD parameters through novel dosing strategies are essential in both the NO and O populations for optimal CPM exposure in susceptible pathogens with higher MICs. CPM 6 grams/day by either CI or EI provides more optimal PK/PD characteristics in obese patients for pathogens with MICs at or near the current CLSI-recommended breakpoint. Disclosures All authors: No reported disclosures.

scholarly journals Effects of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults

2004 ◽  
Vol 48 (11) ◽  
pp. 4328-4331 ◽  
Author(s):  
Robert DiCenzo ◽  
Derick Peterson ◽  
Kim Cruttenden ◽  
Gene Morse ◽  
Garret Riggs ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Valproic Acid ◽  
Geometric Mean ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Blood Samples ◽  
Immunodeficiency Virus ◽  
Before And After ◽  
Trough Concentrations ◽  
Hiv 1

ABSTRACT Valproic acid (VPA) has the potential to benefit patients suffering from human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine if VPA affects the plasma concentration of efavirenz (EFV) or lopinavir. HIV type 1 (HIV-1)-infected patients receiving EFV or lopinavir-ritonavir (LPV/r) had 9 or 10 blood samples drawn over 8 to 24 h of a dosing interval at steady state before and after receiving 250 mg of VPA twice daily for 7 days. VPA blood samples drawn before (C 0) and 8 h after the morning dose (8 h) were compared to blood samples from a group of HIV-1-infected subjects who were taking either combined nucleoside reverse transcriptase inhibitors alone or had discontinued antiretroviral therapy. Pharmacokinetic parameters were calculated by noncompartmental analysis, and tests of bioequivalence were based on 90% confidence intervals (CIs) for ratios or differences. The geometric mean ratio (GMR) (90% CI) of the areas under the concentration-time curve from 0 to 24 h (AUC0-24s) of EFV (n = 11) with and without VPA was 1.00 (0.85, 1.17). The GMR (90% CI) of the AUC0-8s of LPV (n = 8) with and without VPA was 1.38 (0.98, 1.94). The differences (90% CI) in mean C 0 and 8-h VPA concentrations versus the control (n = 11) were −1.0 (−9.4, 7.4) μg/ml and −2.1 (−11.1, 6.9) μg/ml for EFV (n = 10) and −5.0 (−13.2, 3.3) μg/ml and −6.7 (−17.6, 4.2) μg/ml for LPV/r (n = 11), respectively. EFV administration alone is bioequivalent to EFV and VPA coadministration. LPV concentrations tended to be higher when the drug was combined with VPA. Results of VPA comparisons fail to raise concern that coadministration with EFV or LPV/r will significantly influence trough concentrations of VPA.

scholarly journals Use of a rapid HPLC assay for determination of pharmacokinetic parameters of ibuprofen in patients with cystic fibrosis

1996 ◽  
Vol 42 (11) ◽  
pp. 1812-1816 ◽  
Author(s):  
N Rifai ◽  
M Sakamoto ◽  
T Law ◽  
V Galpchian ◽  
N Harris ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Adverse Effects ◽  
Peak Concentration ◽  
Therapeutic Monitoring ◽  
Pharmacokinetic Parameters ◽  
Hplc Assay ◽  
Average Recovery ◽  
Time To Peak ◽  
High Doses

Abstract High doses of ibuprofen have been shown to delay the progression of lung disease without serious adverse effects in patients with cystic fibrosis. To be effective, peak ibuprofen concentration of 50 to 100 mg/L has to be achieved. We developed an HPLC assay to rapidly determine plasma ibuprofen concentration. We used this assay to determine the pharmacokinetics of ibuprofen in patients with cystic fibrosis. The assay possessed linearity up to 500 mg/L, sensitivity to 1 mg/L, average recovery of 98%, and run-to-run precision (n = 23) of 3%. Furthermore, the assay proved to be free of interference from 51 medications. Observed time to peak concentration varied significantly between those receiving ibuprofen tablets (mean + SD, 94 +/- 29 min, n = 16) and syrup (30 +/- 0 min, n = 4) (P &lt; 0.0001). We conclude that the method described here is ideal for therapeutic monitoring of ibuprofen.

scholarly journals 1552. Correlation Between Vancomycin Serum Trough Concentrations and Area Under the Curve in Pediatric Patients

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S566-S567
Author(s):  
Krista Weaver ◽  
Madan Kumar ◽  
Allison Nelson ◽  
Palak Bhagat
Keyword(s):  
Pediatric Patients ◽  
Retrospective Chart Review ◽  
Primary Study ◽  
Pharmacokinetic Parameters ◽  
Optimal Method ◽  
Study Objective ◽  
Serum Trough ◽  
Trough Concentrations ◽  
Group 2 ◽  
Group 1

Abstract Background Despite years of experience with vancomycin (VAN), the optimal method to monitor VAN therapy in pediatric patients is still unknown. Recent pediatric data indicate serum trough concentrations lower than 10–20 mg/L or 15–20 mg/L based on indication may achieve an AUC24> 400 mg hours/L. The primary study objective was to compare AUC24 to goal VAN serum trough concentrations (STC). Methods A retrospective chart review of pediatric patients who received intravenous VAN June 1, 2018 to December 31, 2018 was completed. AUC24 was calculated using a trapezoidal method with 2 steady-state serum concentrations. A serum peak concentration was drawn 1 hour and 15 minutes following the end of infusion and an STC was drawn 30 minutes prior to infusion. Results During 25 admissions, 12 patients had a first AUC24 at goal and 13 patients had a first AUC24 below goal. Of 41 AUC24 calculations, 27 AUC24s were ≥400 mg hours/L (group 1), and 14 AUC24s were <400 mg hours/L (group 2). Median AUC24 was 561 mg hours/L for group 1 vs. 344.5 mg hours/L for group 2 (P < 0.001). Correlating Cmin and Ctrough (Ctr) for group 1 and group 2 were 12 mg/L and 13.5 mg/L vs. 6.4 mg/L and 7.3 mg/L, respectively (P < 0.001). Figure 1 shows the pharmacokinetic parameters for each group. Spearman correlation between AUC24 and Cmin was 0.87. Of the 35 subtherapeutic VAN STCs, 20 (57.1%) achieved an AUC24 ≥400 mg hours/L (P = 0.08). Subgroup analysis of AUC24 400–600 mg hours/L showed a median AUC24 of 519 mg hours/L with correlating Cmin and Ctr of 10.6 mg/L and 11.9 mg/L, respectively. The MIC was <1 in 90.9% of cases (Figure 2). The mean VAN dose required to achieve an AUC24 ≥400 mg hours/L was 77.7 mg/kg/day; dosing frequency did not appear to affect AUC24 outcome. Time to culture clearance was 2 days in group 1 and 6.5 days in group 2 (P = 0.24). No cases of nephrotoxicity were identified despite AUC24 values ranging from 265–1294 mg hours/L. Conclusion AUC24 monitoring using a 2-sample trapezoidal method was successfully implemented at this institution. The results of this study align with previous pediatric studies, supporting the use of lower serum trough concentration goals of 10–15 mg/L. Disclosures All authors: No reported disclosures.

Impact of Donor and Recipient CYP3A5*3 Genotype on Tacrolimus Population Pharmacokinetics in Chinese Adult Liver Transplant Recipients

2019 ◽  
Vol 54 (7) ◽  
pp. 652-661 ◽  
Author(s):  
Jia Shao ◽  
Chenyu Wang ◽  
Peng Fu ◽  
Fan Chen ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Liver Transplant ◽  
Distribution Volume ◽  
Therapeutic Window ◽  
Population Pharmacokinetic ◽  
Transplant Recipients ◽  
Adult Liver ◽  
Chinese Adult ◽  
Starting Dose ◽  
Liver Transplant Recipients

Background: Tacrolimus (TAC) is widely used after liver transplantation, but the therapeutic window is narrow. Objective: The purpose was to study both donor and recipient CYP3A5*3 genotypes affecting TAC apparent clearance rate (CL/F) and investigate a TAC population pharmacokinetic (PPK) model in Chinese liver transplant recipients for potential starting-dose individualized medication. Methods: A data set of 721 TAC concentrations was obtained from 43 adult liver transplant recipients. The TAC PPK model was analyzed using nonlinear mixed-effects modeling. Potential covariates, including demographic characteristics, physiological and pathological data, concomitant medications, and CYP3A5*3 genotype, were evaluated. The final model was validated using normalized prediction distribution errors and bootstrapping. Results: A 2-compartment model with first-order absorption and elimination was used to describe TAC disposition. Population estimates of TAC, CL/F, apparent central distribution volume (V2/F), rate of absorption (Ka), and apparent peripheral distribution volume (V3/F) were 18.1 L/h (12%), 72.7 L (34%), 0.163 h−1 (17%), and 412 L (21%), respectively. The model and estimated parameters were found to be stable. Other covariates did not influence TAC CL/F. Both donor and recipient CYP3A5*1 genotypes were significantly correlated with TAC clearance, and CL/F was 1.70-fold higher in both donor and recipient CYP3A5*1 carriers than in noncarriers among Chinese liver transplant recipients. Conclusion and Relevance: A PPK model of TAC was established in Chinese adult liver transplantation recipients for starting-dose individualized medication, which can be expanded to optimize clinical efficacy and minimize toxicity with therapeutic drug monitoring.

Reiterated Therapeutic Drug Monitoring (TDM) Dosing to Significantly Improve the Control of Exposure to IV Busulfan in Infants and Older Children Undergoing Hematopoietic Stem-Cell Transplantation (HSCT)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4326-4326
Author(s):  
Alexandre Amin ◽  
Philippe Bourget ◽  
Benedicte Neven ◽  
Marie-Louise Fremond ◽  
Martin Castelle ◽  
...  
Keyword(s):  
Medical Staff ◽  
Therapeutic Monitoring ◽  
Therapeutic Window ◽  
Rank Test ◽  
Therapeutic Drug ◽  
Metabolic Clearance ◽  
Time Data ◽  
Study Objective ◽  
Hematopoietic Stem ◽  
The Mean

Abstract Introduction: Busulfan (Bu) is recognized worldwide as the cornerstone for HSCT conditioning regimens (CR). It has a narrow therapeutic window (TW), and graft rejection or toxicity are related to Bu exposure. In very young children, Bu exhibits large pharmacokinetic (PK) variability, and its metabolic clearance is non-linearly related to body weight (BW). In this setting, Bu dosage is stratified according to BW and commonly monitored once after the 1st of 16 total 2-hr infusions and finally, 96-hr exposure to this major alkylating agent. Given the narrow TW of Bu in relation to clinical outcomes and to better understand its PK/PD relationship, it is important to attempt to optimize both the duration and the intensity of exposure to Bu in children undergoing HSCT, whatever their BW and pathologies. Study objective: To optimize Bu duration/intensity exposure in children undergoing HSCT, we studied the possible contribution of double TDM of IV Bu dosing in children receiving Bu-based CR for HSCT, by comparing the expected targeted values of exposure after performing 1 PK (1st dose, PK1) and finally 2 PK (1st dose, PK1, and 9th dose, PK2). Patients and methods: In this single-centre* prospective observational study (05/2012-07/2015), the PK of Bu was performed using the NONMEM® software; a one-compartment PK model suitably fitted the concentrations vs. time data. The PK of Bu was assessed on 6 plasma samples (3 samples/PK) using a validated LC-MS/MS method, with area under the concentration-time curve (AUC) calculation from the 1st and 9th doses. AUC calculated after the 1st dose and extrapolated to the 16th one were compared intraindividually by the non-parametric Wilcoxon signed-rank test to the sum of AUC1-6 with TDM1 applied from the 7th dose with or without TDM2 applied from the 13th or 14th dose; p≤0.025 was considered statistically significant. 63 patients (Pts) undergoing HSCT were included with median follow up of 14 months [1-39]. Median age was 17 months [1-193] and BW 11 kg [3-59]. Most Pts had non-malignant diseases, received allogenic HSCT and Bu-based CR in combination with Flu (morphometric, disease and CR details will be provided). *one of the 14 French Pediatric BMT units, involved in the therapeutic monitoring of IV Bu dosing in children undergoing HSCT. Results: 63 Pts (37 males (59%) and 26 females (41%)) were included. According to the EBMT-ESID recommendations, a median Bu posology of 1 mg/kg 4x/day for 4 days [0.6-1.3 mg/kg] was given. We demonstrate that: (a) estimated total AUC obtained from 2 PK differ significantly from those calculated after none (p=8.6455 E-7) or PK1 alone (p=7.2157 E-8), (b) double TDM allows achieving no difference between the expected AUC [20,706-23,180 mmol/min] desired by the medical staff in view of diseases vs. estimated AUC (p=0.5285). In 2/63 (3.2%) Pts, PK analysis did not lead to change Bu dosage. In 11/63 (18%) and 15/63(24%) Pts, dosage was modified after PK1 (TDM1 Group) or PK2 alone, respectively. In 35/63 (56%) Pts, changes were required twice, after the 2 PK (Double-TDM Group). The mean total dose of Bu were as follows: (a) a theoretical value of 220.80 mg (20.11 mg/kg) would have been given through 16 consecutive infusions without any TDM, (b) 199.35 mg (18.08 mg/kg) were administered in the TDM1 Group (16 doses), (c) 246.00 mg (19.46 mg/kg) were administered in the Double-TDM Group, avoiding the infusion of 24.00 mg of Bu vs. PK1 alone in these Pts. In 16/63 (25%) Pts, a decision of discontinuation of Bu exposure was taken. Indeed, the value that was desired by the medical staff was achieved after 13 (6 Pts) or 14 (10 Pts) doses; the mean total amounts of Bu were 273.22 mg (14.96 mg/kg) and 225.88 mg (16.16 mg/kg), respectively, vs. 336.27 mg (18.45 mg/kg) and 262.56 mg (18.60 mg/kg) theoretically after TDM1 alone. Conclusion: In this large paediatric cohort, the double TDM of Bu is a relevant and feasible option to better control Bu exposure and to potentially minimize the risk of overexposure. Correlations with toxicities (VOD, aGVH), CR, OS are under analysis. Based on these data, the double-TDM procedure is routinely applied in our centre. Disclosures Petain: Laboratoires Pierre Fabre: Employment. Nguyen:Laboratoires Pierre Fabre: Employment.

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