scholarly journals Evaluation of Posaconazole Dosing in Children and Young Adults: A Single-Center Review

2021 ◽  
Vol 26 (8) ◽  
pp. 834-840
Author(s):  
Lauren M. Garner ◽  
Susan Ngo ◽  
Jenna Bognaski Kaplan ◽  
William S. Wilson ◽  
Cameron J. McKinzie
Keyword(s):  
Pediatric Patients ◽  
Liver Function Tests ◽  
Current Data ◽  
Dosing Regimen ◽  
Drug Concentrations ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
Trough Concentrations ◽  
Dosing Strategy ◽  
Dose Modifications

OBJECTIVE Initial posaconazole dosing regimens in children often do not achieve target concentrations, and data continue to support the need for higher initial dosing regimens. The objective of this study is to contribute to the current data regarding suboptimal posaconazole dosing in pediatric patients by retrospectively observing dosing strategies and subsequent drug concentrations. METHODS This study was conducted at a single institution in 27 patients aged 1 to 21 years. Patients who were initiated on any formulation of posaconazole for prophylaxis or treatment while admitted to the hospital were included. The primary outcome was to determine the percentage of pediatric patients who achieved the targeted trough concentration using their initial posaconazole dosing regimen. Secondary outcomes included percentage of patients who experienced a breakthrough invasive fungal infection (IFI), percentage of patients with elevated liver function tests (LFTs), and discontinuation for any reason. RESULTS There were 15 patients (55.5%) who reached desired trough serum concentration after the initial dosing regimen. The number of dose modifications to achieve the desired trough ranged from 1 to 3. Most patients received delayed-release tablets (n = 17), and the average doses for reaching prophylactic and treatment trough concentrations were 6.1 mg/kg/day and 11 mg/kg/day, respectively. There were 2 patients (7.4%) who experienced breakthrough IFI. Overall, 5 patients developed elevated LFTs and 7 patients discontinued treatment early. CONCLUSIONS The results describe a single population of pediatric patients, of whom 55% were able to achieve target trough concentrations of posaconazole with the initial dosing strategy used.

scholarly journals Use of Body Surface Area for Dosing of Vancomycin

2019 ◽  
Vol 24 (4) ◽  
pp. 296-303
Author(s):  
Elizabeth L. Sawrey ◽  
Mary W. Subramanian ◽  
Kacy A. Ramirez ◽  
Brandy S. Snyder ◽  
Brittany B. Logston ◽  
...  
Keyword(s):  
Serum Concentration ◽  
Surface Area ◽  
Body Surface ◽  
Pediatric Patients ◽  
Obese Patients ◽  
Dosing Regimen ◽  
Trough Serum ◽  
Dosing Regimens ◽  
Vancomycin Trough ◽  
Trough Concentrations

OBJECTIVES Vancomycin weight-based dosing regimens often fail to achieve therapeutic trough serum concentration in children ≤12 years of age and rigorous studies evaluating efficacy and safety of body surface area (BSA)–based dosing regimens have not been performed. We compared vancomycin trough serum concentrations in pediatric patients receiving a weight- or BSA-based dosing regimen. METHODS This was a single-center, retrospective study evaluating pediatric patients, ages 1 to 12 years, who received vancomycin from September 2012 to October 2015. Patients received a minimum of 3 consecutive doses at the same scheduled interval within a dosing regimen prior to a measured vancomycin serum trough concentration. The primary outcome was percentage of initial vancomycin trough concentrations ≥10 mg/L. The secondary outcomes were percentage of supratherapeutic, therapeutic, and subtherapeutic vancomycin serum concentration for all patients, including a subset of overweight and obese patients, and number of nephrotoxic occurrences. RESULTS BSA-based dosing regimens resulted in 50% of the initial vancomycin trough concentrations ≥ 10 mg/L compared with 17% for the weight-based dosing regimens (p < 0.0001). No statistically significant differences were noted between the 2 dosing regimens for supratherapeutic, therapeutic, or subtherapeutic trough concentrations for all patients, and for the subset of overweight and obese patients. Nephrotoxic occurrences were noted in 7% of the weight-based dosing regimens compared with none in the BSA-based dosing regimens. CONCLUSIONS A BSA-based vancomycin dosing regimen resulted in significantly more initial vancomycin trough concentrations ≥10 mg/L and trended towards higher initial vancomycin trough concentrations without observable nephrotoxicity.

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.

scholarly journals P072 Evaluation of dosing strategies of anti-TNFα monoclonal antibodies using pharmacokinetic modelling and simulation

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S171-S172
Author(s):  
A Démaris ◽  
A M Grišić ◽  
W Huisinga ◽  
R Walter ◽  
C Kloft
Keyword(s):  
Monoclonal Antibodies ◽  
Body Size ◽  
Fixed Dose ◽  
Dosing Regimen ◽  
Target Concentration ◽  
Concentration Time ◽  
Dosing Strategies ◽  
Dosing Strategy ◽  
The Impact ◽  
Size Descriptor

Abstract Background Anti-TNFα monoclonal antibodies (mAbs) are a well-established treatment for patients with Crohn’s disease (CD). However, subtherapeutic concentrations of mAbs have been related to a loss of response during the first year of therapy1. Therefore, an appropriate dosing strategy is crucial to prevent the underexposure of mAbs for those patients. The aim of our study was to assess the impact of different dosing strategies (fixed dose or body size descriptor adapted) on drug exposure and the target concentration attainment for two different anti-TNFα mAbs: infliximab (IFX, body weight (BW)-based dosing) and certolizumab pegol (CZP, fixed dosing). For this purpose, a comprehensive pharmacokinetic (PK) simulation study was performed. Methods A virtual population of 1000 clinically representative CD patients was generated based on the distribution of CD patient characteristics from an in-house clinical database (n = 116). Seven dosing regimens were investigated: fixed dose and per BW, lean BW (LBW), body surface area, height, body mass index and fat-free mass. The individual body size-adjusted doses were calculated from patient generated body size descriptor values. Then, using published PK models for IFX and CZP in CD patients2,3, for each patient, 1000 concentration–time profiles were simulated to consider the typical profile of a specific patient as well as the range of possible individual profiles due to unexplained PK variability across patients. For each dosing strategy, the variability in maximum and minimum mAb concentrations (Cmax and Cmin, respectively), area under the concentration-time curve (AUC) and the per cent of patients reaching target concentration were assessed during maintenance therapy. Results For IFX and CZP, Cmin showed the highest variability between patients (CV ≈110% and CV ≈80%, respectively) with a similar extent across all dosing strategies. For IFX, the per cent of patients reaching the target (Cmin = 5 µg/ml) was similar across all dosing strategies (~15%). For CZP, the per cent of patients reaching the target average concentration of 17 µg/ml ranged substantially (52–71%), being the highest for LBW-adjusted dosing. Conclusion By using a PK simulation approach, different dosing regimen of IFX and CZP revealed the highest variability for Cmin, the most commonly used PK parameter guiding treatment decisions, independent upon dosing regimen. Our results demonstrate similar target attainment with fixed dosing of IFX compared with currently recommended BW-based dosing. For CZP, the current fixed dosing strategy leads to comparable percentage of patients reaching target as the best performing body size-adjusted dosing (66% vs. 71%, respectively). References

Pharmacokinetic/Pharmacodynamic Evaluation of Hydrocortisone Therapy in Pediatric Patients with Congenital Adrenal Hyperplasia

2020 ◽  
Vol 105 (4) ◽  
pp. e1729-e1740 ◽  
Author(s):  
Johanna Melin ◽  
Zinnia P Parra-Guillen ◽  
Robin Michelet ◽  
Thi Truong ◽  
Wilhelm Huisinga ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Congenital Adrenal Hyperplasia ◽  
Replacement Therapy ◽  
Pediatric Patients ◽  
Compartment Model ◽  
Cortisol Concentration ◽  
Healthy Children ◽  
Adrenal Hyperplasia ◽  
Dosing Regimen ◽  
Dosing Regimens

Abstract Objectives Patients with congenital adrenal hyperplasia (CAH) require lifelong replacement therapy with glucocorticoids. Optimizing hydrocortisone therapy is challenging, since there are no established cortisol concentration targets other than the cortisol circadian rhythm profile. 17-hydroxyprogesterone (17-OHP) concentrations are elevated in these patients and commonly used to monitor therapy. This study aimed to characterize the pharmacokinetics/pharmacodynamics (PK/PD) of cortisol using 17-OHP as a biomarker in pediatric patients with CAH and to assess different hydrocortisone dosing regimens. Methods Cortisol and 17-OHP concentrations from 30 CAH patients (7–17 years of age) receiving standard hydrocortisone replacement therapy (5–20 mg) twice (n = 17) or 3 times (n = 13) daily were used to develop a PK/PD model. Sequentially, simulated cortisol concentrations for clinically relevant 3- and 4-times daily dosing regimens were compared with cortisol and 17-OHP target ranges and to concentrations in healthy children. Results Cortisol concentration-time profiles were accurately described by a 2-compartment model with first-order absorption and expected high bioavailability (82.6%). A time-delayed model with cortisol-mediated inhibition of 17-OHP synthesis accurately described 17-OHP concentrations. The cortisol concentration inhibiting 50% of 17-OHP synthesis was 48.6 nmol/L. A 4-times-daily dosing better attained the target ranges and mimicked the cortisol concentrations throughout the 24-hour period than 3-times-daily. Conclusions A PK/PD model following hydrocortisone administration has been established. An improved dosing regimen of 38% at 06:00, 22% at 12:00, 17% at 18:00, and 22% at 24:00 of the daily hydrocortisone dose was suggested. The 4-times-daily dosing regimen was superior, avoiding subtherapeutic cortisol concentrations and better resembling the circadian rhythm of cortisol.

scholarly journals Remedial dosing recommendation for delayed or missed rivaroxaban doses for patients with non-valvular atrial fibrillation based on Monte Carlo simulation

2020 ◽  
Author(s):  
Xiao-qin Liu ◽  
Yin-wei Yin ◽  
Chen-yu Wang ◽  
Zi-ran Li ◽  
Xiao Zhu ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Factor Xa ◽  
Heart Rhythm ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Drug Concentrations ◽  
Simulation Based ◽  
Dosing Regimens

Background Rivaroxaban is a non-vitamin K oral anticoagulant used widely for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). During long-term anticoagulant therapy, delayed or missed doses are common. However, a lack of practical instructions on remedial methods has created a barrier for patients to maximise the benefit of their medications. This study aimed to explore appropriate remedial dosing regimens for rivaroxaban-treated patients with NVAF. Methods Monte Carlo simulation based on a previously established rivaroxaban population pharmacokinetic/pharmacodynamic model for patients with NVAF was employed to design remedial dosing regimens. Both the European Heart Rhythm Association (EHRA) recommendations and the model were used to establish remedial dosing regimens, which were assessed considering the on-therapy range of drug concentration, factor Xa activity, and prothrombin time under various scenarios of non-adherence. Results Recommendations of EHRA guide may not be optimal. Our findings suggested that a missed dose is taken immediately when the delay is less than or equal to 6 h; a half dose is advisable when the delay exceeds 6 h but is less than 4 h before the next dose. It is recommended to skip a dose when there are less than 4 h before the next dose. Age or renal function do not significantly influence the remedial dosing regimen. Conclusion A remedial dosing regimen based on model-based Monte Carlo simulation was systematically developed for rivaroxaban-treated patients with NVAF with poor adherence to quickly restore drug concentrations to the on-therapy range and to reduce the risk of bleeding and thromboembolism.

scholarly journals Population Pharmacokinetics and Dosage Optimization of Linezolid in Critically Ill Pediatric Patients

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
Mei Yang ◽  
Libo Zhao ◽  
Xiaohui Wang ◽  
Chen Sun ◽  
Hengmiao Gao ◽  
...  
Keyword(s):  
Body Weight ◽  
Critically Ill ◽  
Pediatric Patients ◽  
Pediatric Population ◽  
Treatment Success ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
Optimal Dosage ◽  
Dosing Regimen ◽  
Dosing Regimens

ABSTRACT Linezolid is an oxazolidinone antibiotic exhibiting efficacy against multidrug-resistant (MDR) Gram-positive-related infections. However, its population pharmacokinetic (PopPK) profile in critically ill Chinese children has not been characterized. Optimal dosing regimens should be established according to the population pharmacokinetic (PopPK)/pharmacodynamic (PD) properties of linezolid in the specific population. This work aims to describe the pharmacokinetic (PK) properties of linezolid, assess the factors affecting interpatient variability, and establish an optimized regimen for children in pediatric intensive care units (PICU). A single-center, prospective, open-labeled PK study was performed. Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was applied to measure the plasma levels during linezolid treatment. PopPK analysis was conducted using Phoenix NLME software. A total of 63 critically ill pediatric patients were included. The data showed good fit for a two-compartment model with linear elimination. Body weight and aspartate aminotransferase (AST) were the most significant covariates explaining variabilities in linezolid PK for the pediatric population. The therapeutic target was defined as the ratio of the area under the drug plasma concentration-time curve over 24 h to a MIC (AUC/MIC) of >80. Different dosing regimens were evaluated using Monte Carlo simulation to determine the optimal dosage strategy for linezolid. Although the probability of target attainment (PTA) was high (>96%) for 10 mg/kg body weight every 8 h at a MIC of ≤1 mg/liter, it was lower than 70% at a MIC of >1 mg/liter. Thus, the dosing regimen required adjustment. When the dosing regimen was adjusted to 15 mg/kg every 6 h, the PTA increased from 63.6% to 94.6% at a MIC of 2 mg/liter, thereby indicating a higher degree of treatment success. Children with AST of >40 U/liter had a significantly higher AUC than those with AST of ≤40 U/liter (205.45 versus 159.96). Therefore, dosage adjustment was required according to the AST levels. The PopPK characteristics of linezolid in critically ill children were evaluated, and an optimal dosage regimen was constructed based on developmental PopPK/PD model and simulation. (This study has been registered in the Chinese Clinical Trial Registry under no. ChiCTR1900021386).

scholarly journals Identification of Optimal Renal Dosage Adjustments for Traditional and Extended-Infusion Piperacillin-Tazobactam Dosing Regimens in Hospitalized Patients

2009 ◽  
Vol 54 (1) ◽  
pp. 460-465 ◽  
Author(s):  
N. Patel ◽  
M. H. Scheetz ◽  
G. L. Drusano ◽  
T. P. Lodise
Keyword(s):  
Monte Carlo Simulation ◽  
Free Drug ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Population Pharmacokinetic Modeling ◽  
Dosing Interval ◽  
Drug Concentrations ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
Extended Infusion

ABSTRACT This study examined the effect of various levels of renal impairment on the probability of achieving free drug concentrations that exceed the MIC for 50% of the dosing interval (50% fT > MIC) for traditional and extended-infusion piperacillin-tazobactam (TZP) dosing strategies. It also identified optimal renal dosage adjustments for traditional and extended-infusion dosing schemes that yielded probability of target attainment (PTA) and exposure profiles that were isometric to those of the parent regimens. Data from 105 patients were analyzed using the population pharmacokinetic modeling program BigNPAG. To assess the effect of creatinine clearance (CLCR) on overall clearance, TZP clearance was made proportional to the estimated CLCR. A Monte Carlo simulation (9,999 subjects) was performed for the traditional dosing scheme (4.5 g infused during 30 min every 6 h) and the extended-infusion TZP dosing scheme (3.375 g infused during 4 h every 8 h). The fraction of simulated subjects who achieved 50% fT > MIC was calculated for the range of piperacillin MICs from 0.25 to 32 mg/liter and stratified by CLCR. The traditional TZP regimen displayed the greatest variability in PTA across MIC values, especially for MIC values exceeding 4 mg/liter, when stratified by CLCR. In contrast, the PTA for the extended-infusion TZP regimen exceeded ≥80% for MIC values of ≤8 mg/liter across all CLCR strata. All regimens were associated with suboptimal PTA for MIC values of ≥32 mg/liter irrespective of the CLCR. The CLCR adjustments for traditional and extended-infusion TZP dosing regimens should be considered at a CLCR of ≤20 ml/min.

scholarly journals An Evaluation of Initial Vancomycin Dosing in Infants, Children, and Adolescents

2011 ◽  
Vol 2011 ◽  
pp. 1-4 ◽  
Author(s):  
Laura Broome ◽  
Tsz-Yin So
Keyword(s):  
Primary Outcome ◽  
Age Groups ◽  
Pediatric Age ◽  
Serum Trough ◽  
Hospital Patients ◽  
Dosing Regimens ◽  
Dosing Strategies ◽  
Trough Concentrations ◽  
Higher Doses ◽  
Retrospective Database

Background. The pharmacokinetics of many medications change as we age, thus most would assume dosing strategies would adjust for these changes. The objective of this study is to evaluate the initial vancomycin dosing in three pediatric age groups based on measured serum trough concentrations.Methodology. This retrospective database review included patients aged from 1 month to 18 years old admitted to the Moses H. Cone Memorial Hospital. Patients had to have received vancomycin dosed at 15 mg/kg every 8 hours with an appropriately measured trough concentration. The primary outcome was to determine the percentage of patients in 3 pediatric age groups achieving therapeutic trough concentrations with the initial vancomycin dosing regimen.Results. Twenty-five patients were included in the study. None of the patients had therapeutic trough concentrations after receiving vancomycin 15 mg/kg every 8 hours. Only one patient had a supratherapeutic level, while all of the other patients had levels less than 10 mcg/mL.Conclusions. Vancomycin 15 mg/kg every 8 hours did not provide therapeutic serum trough concentrations for any pediatric age groups. Higher doses and/or more frequent dosing regimens need to be evaluated for each age group to determine the most appropriate strategies for producing therapeutic trough concentrations.

scholarly journals Retrospective multicentre matched cohort study comparing safety and efficacy outcomes of intermittent-infusion versus continuous-infusion vancomycin

2020 ◽  
Vol 75 (4) ◽  
pp. 1038-1046
Author(s):  
Nathan H Ma ◽  
Sandra A N Walker ◽  
Marion Elligsen ◽  
Alex Kiss ◽  
Lesley Palmay ◽  
...  
Keyword(s):  
Cohort Study ◽  
Continuous Infusion ◽  
Renal Injury ◽  
Intermittent Infusion ◽  
Matched Cohort ◽  
Lower Odds ◽  
Matched Cohort Study ◽  
Dosing Strategies ◽  
Trough Concentrations ◽  
Dosing Strategy

Abstract Background Patients with good renal function receiving intermittent-infusion vancomycin (IIV) may require total daily doses ≥4 g to achieve trough concentrations of 15–20 mg/L, increasing the risk of vancomycin-associated nephrotoxicity. Continuous-infusion vancomycin (CIV) may be associated with a lower risk of vancomycin-associated nephrotoxicity compared with IIV, but studies comparing safety of both dosing strategies are lacking. Objectives To compare the risk of nephrotoxicity with CIV versus IIV when target concentration ranges were the same with both dosing modalities. Methods A retrospective multicentre matched cohort study of admitted patients between 1 January 2010 and 31 December 2016 was completed. Adult patients who received ≥48 h of vancomycin with at least one steady-state vancomycin concentration were eligible. The primary outcome was to compare the rates of nephrotoxic risk and renal injury, defined by the RIFLE criteria, between CIV and IIV. Results Of 2136 patients who received vancomycin during the study period, 146 CIV patients were eligible and matched to 146 IIV patients. After adjustment of potential confounders, CIV was found to have a lower odds of developing nephrotoxic risk (OR 0.42, 95% CI 0.21–0.98, P = 0.025) and renal injury (OR 0.19, 95% CI 0.05–0.59, P = 0.004). Conclusions CIV is associated with a lower odds of nephrotoxicity compared with IIV when targeting the same concentration range and should be an alternative dosing strategy for patients who will receive prolonged therapy or require >4 g/day to achieve therapeutic levels.

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