scholarly journals Possibly Appropriate Maintenance dose of Voriconazole in pediatric patients: a single center observational study

2021 ◽  
Author(s):  
Yi-Chang Zhao ◽  
Yang Zou ◽  
Dan Tang ◽  
Chen-Lin Xiao ◽  
Yi-Wen Xiao ◽  
...  
Keyword(s):  
Trough Concentration ◽  
Maintenance Dose ◽  
Pediatric Patients ◽  
Initial Dosage ◽  
Individual Variability ◽  
Maintenance Dosage ◽  
Lower Percentage ◽  
Target Range ◽  
Therapeutic Level ◽  
Concentration Data

Abstract Background: Voriconazole is a triazole antifungal agent and a commonly used first-line treatment for invasive aspergillosis (IA). The study was performed to explore the factors affecting voriconazole trough concentration and maintenance dose to optimize voriconazole dosage in pediatric patients. Method: The demographic information, concentration data, CYP2C19 genotypes, and clinical outcomes of eligible pediatric patients from January 1th, 2016 to December 31th, 2018 were collected retrospective . Result: The study finally included 145 voriconazole trough concentrations from 94 pediatric patients. Steady trough concentration ranged from 0.04 to 16.11 μg/mL. Morerover, the distinction between the maximum and the minimum corrected concentration of per kilogram maintenance dosage is as high as 907 folds and children ≤2 years old showed the minimum variation compared to other individuals (P<0.001). A high inter- and intra-individual variability of voriconazole in pediatric patients were observed. Only 54.5% of the pediatric patients achieved the target range (1.0 to 5.5 μg/mL) at unadjusted initial dosage, while 35.9% of children were subtherapeutic, only 9.6% of children were supratherapeutic at unadjusted initial dosing. The younger children (≤12 years) seem to have a lower trough concentration (P=0.0096) and lower percentage of target achievements (P=0.004). And 98.97% of the maintenance dosage was below 9.0 mg/kg. For pediatric patients of different ages, it was found that most of them was underdosed. While, to achieve targeted therapeutic level for different age groups of ≤2, 2-6, 6-12, and 12-18 years, the median voriconazole maintenance doses were 5.7, 6.7, 5.0, and 3.3 mg-1kg/12h, respectively had been required in order to achieve therapeutic level (P<0.001). Conclusion: Pediatric patients especially those ≤12 years old might need a higher dosage regime to achieve therapeutic trough concentration. Importantly, early and repeat monitoring of voriconazole is essential to ensure the effectiveness and safety of voriconazole in children.

scholarly journals Optimized Administration of Voriconazole and Therapeutic Drug Monitoring in Children and Adolescents: A Single-Centre Retrospective Experience from China

2021 ◽  
Author(s):  
Yi-Chang Zhao ◽  
Yang Zou ◽  
Dan Tang ◽  
Chen-Lin Xiao ◽  
Yi-Wen Xiao ◽  
...  
Keyword(s):  
Trough Concentration ◽  
Therapeutic Drug ◽  
Demographic Information ◽  
Therapeutic Level ◽  
Multiple Dosing ◽  
Concentration Data ◽  
Factors Affecting ◽  
Dosage Regime ◽  
Trough Concentrations ◽  
Anti Fungal

Abstract Background Voriconazole (VRC) is a triazole anti-fungal agent and a first-line treatment for invasive fungal infection (IFI) generally. The purpose of our study was performed to explore the factors affecting voriconazole trough concentration (Ctrough) and to show VRC dose adjustment experience in children. Methods The demographic information, concentration data, CYP2C19 genotypes and clinical outcomes of eligible children from January 1th, 2016 to December 31th, 2018 were collected. Factors affecting the voriconazole trough concentration were statistically analyzed. Results A total of 145 trough concentrations in 94 patients were included in this study, 54.5% of which achieved the target concentrations; however, 35.9% and 9.6% of which were sub-therapeutic and super-therapeutic post-multiple dosing. For children ≤ 2, 2–6, 6–12, and 12–18 years, the median VRC maintenance doses of 5.7, 6.7, 5.0 and 3.3 mg/kg twice daily respectively had been required in order to achieve therapeutic level (P < 0.001). Co-administration of proton pump inhibitors affected VRC target trough concentration significantly (P = 0.001). Conclusion Younger pediatric patients might need a higher dosage regime to achieve therapeutic trough concentration. In order to ensure the effectiveness and safety of voriconazole in children, early and repeat monitoring of voriconazole is a powerful tool.

scholarly journals Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Amedeo De Nicolò ◽  
Michele Pinon ◽  
Alice Palermiti ◽  
Antonello Nonnato ◽  
Alessandra Manca ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Whole Blood ◽  
Peripheral Blood ◽  
Pediatric Patients ◽  
Mononuclear Cells ◽  
Individual Variability ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Intracellular Concentrations ◽  
The One

Tacrolimus (TAC) is a first-choice immunosuppressant for solid organ transplantation, characterized by high potential for drug-drug interactions, significant inter- and intra-patient variability, and narrow therapeutic index. Therapeutic drug monitoring (TDM) of TAC concentrations in whole blood (WB) is capable of reducing the incidence of adverse events. Since TAC acts within lymphocytes, its monitoring in peripheral blood mononuclear cells (PBMC) may represent a valid future alternative for TDM. Nevertheless, TAC intracellular concentrations and their variability are poorly described, particularly in the pediatric context. Therefore, our aim was describing TAC concentrations in WB and PBMC and their variability in a cohort of pediatric patients undergoing constant immunosuppressive maintenance therapy, after liver transplantation. TAC intra-PBMCs quantification was performed through a validated UHPLC–MS/MS assay over a period of 2–3 months. There were 27 patients included in this study. No significant TAC changes in intracellular concentrations were observed (p = 0.710), with a median percent change of −0.1% (IQR −22.4%–+46.9%) between timings: this intra-individual variability was similar to the one in WB, −2.9% (IQR −29.4–+42.1; p = 0.902). Among different patients, TAC weight-adjusted dose and age appeared to be significant predictors of TAC concentrations in WB and PBMC. Intra-individual seasonal variation of TAC concentrations in WB, but not in PBMC, have been observed. These data show that the intra-individual variability in TAC intracellular exposure is comparable to the one observed in WB. This opens the way for further studies aiming at the identification of therapeutic ranges for TAC intra-PBMC concentrations.

scholarly journals Influence of NQO1 Polymorphisms on Warfarin Maintenance Dose: A Systematic Review and Meta-Analysis (rs1800566 and rs10517)

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Lihong Tian ◽  
Pingping Xiao ◽  
Bingrong Zhou ◽  
Yishan Chen ◽  
Lijuan Kang ◽  
...  
Keyword(s):  
Maintenance Dose ◽  
Meta Analysis ◽  
Warfarin Dose ◽  
Maintenance Dosage ◽  
Sensitivity Analyses ◽  
Cochrane Library ◽  
The Cochrane Library ◽  
The Relationship ◽  
Review Manager ◽  
Warfarin Maintenance Dose

This meta-analysis was conducted to analyze the effect of NQO1 polymorphism on the warfarin maintenance dosage. Using strict inclusion and exclusion criteria, we searched PubMed, EMBASE, and the Cochrane Library for eligible studies published prior to July 7, 2021. The required data were extracted, and experts were consulted when necessary. Review Manager Version 5.4 software was used to analyze the relationship between NQO1 polymorphisms and the warfarin maintenance dosage. Four articles involving 757 patients were included in the meta-analysis. Patients who were NQO1 rs10517 G carriers (AG carriers or GG carriers) required a 48% higher warfarin maintenance dose than those who were AA carriers. Patients with NQO1 rs1800566 CT carriers required a 13% higher warfarin dose than those who were CC carriers, with no associations observed with the other comparisons of the NQO1 rs1800566 genotypes. However, the results obtained by comparing the NQO1 rs1800566 genotypes require confirmation, as significant changes in the results were found in sensitivity analyses. Our meta-analysis suggests that the NQO1 rs10517and NQO1 rs1800566 variant statuses affect the required warfarin maintenance dose.

Anticoagulation with Warfarin in Infants and Children

1996 ◽  
Vol 30 (11) ◽  
pp. 1316-1322 ◽  
Author(s):  
Marcia L Buck
Keyword(s):  
Clinical Trials ◽  
Adverse Effects ◽  
Case Reports ◽  
Initial Dosage ◽  
Case Series ◽  
Infants And Children ◽  
Target Range ◽  
Search Term ◽  
Cardiac Valves ◽  
In Infants And Children

OBJECTIVE: TO provide a comprehensive review of warfarin use in infants and children, including recommendations for appropriate dosage and monitoring parameters. DATA SOURCES: A MEDLINE search (1966-1995) was used to identify pertinent English-language articles in the medical literature. The key search term was warfarin. Additional material was obtained from references cited in articles retrieved through MEDLINE. STUDY SELECTION: All articles involving children younger than 18 years were evaluated. In addition, articles on the pharmacokinetics and pharmacodynamics in adults, adverse effects, and drug interactions were included. DATA EXTRACTION: Material selected for review included clinical trials, case reports, and surveys of practice. DATA SYNTHESIS: Warfarin has been used as prophylactic therapy in children with prosthetic cardiac valves as well as for prevention of thromboembolic complications associated with autoimmune disorders and protein C or protein S deficiency. Warfarin also has been used to prevent embolization in children with deep-vein thrombosis or clots in central venous catheters. According to the literature, an initial dosage of 0.1 mg/kg/d should provide anticoagulation without significant adverse effects. As in adults, dosing should be adjusted to achieve a target international normalized ratio (INR). Although the target range in children is not well established, INR values of 1.5–3 are recommended for most patients. Higher values have been used in children with prosthetic cardiac valves and hereditary clotting disorders. CONCLUSIONS: Due to its infrequent use, there is limited information on the effects of warfarin in children. Basic guidelines for initiating and monitoring warfarin were developed by using data gathered from clinical trials, retrospective reviews, case series, and surveys of practice.

UNDERSTANDING REAL-WORLD BIOLOGIC MAINTENANCE DOSING PATTERNS AMONG PEDIATRIC ULCERATIVE COLITIS AND CROHN’S DISEASE PATIENTS

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S23-S23
Author(s):  
Wallace Crandall ◽  
Richard Colletti ◽  
Wendy Komocsar ◽  
Chunyan Liu ◽  
Jennifer Dotson ◽  
...  
Keyword(s):  
Maintenance Dose ◽  
Pediatric Patients ◽  
Descriptive Statistics ◽  
Patient Demographics ◽  
Baseline Visit ◽  
The Us ◽  
Inflammatory Bowel ◽  
Using Data ◽  
Term Maintenance

Abstract Objectives To assess the initial and long-term maintenance dosing of biologic medications in pediatric UC and CD patients, using data in the ICN registry. Methods Pediatric patients (2–17 years) in the US who were diagnosed with UC or CD between June 1, 2013 and December 31, 2019, who, after enrollment in the ICN registry, initiated a biologic (adalimumab, infliximab, certolizumab, golimumab, ustekinumab, vedolizumab, and natalizumab) and were actively followed for at least 12 months after first maintenance dose were included in this study. Descriptive statistics of baseline patient demographics were summarized for the overall Inflammatory Bowel Disease (IBD) patient population and separately for UC and CD. Biologic maintenance dosage was calculated for UC and CD patients who had data for both dose and weight for each biologic at the baseline visit (first maintenance dose), 1-year and 3-year time points. Results A total of 1,887 pediatric IBD patients (UC=350; CD=1,537) were included in this study. Patients had a mean age at diagnosis of 12.9 years (UC=13.1; CD=12.9), 57.1% were male (UC=48.9%; CD=59.0%), and 80.6% were White (UC=79.8%; CD=80.8%) (Table 1). Infliximab (77.0%) was the most commonly prescribed biologic for UC, followed by adalimumab (12.4%), vedolizumab (10.1%), certolizumab (0.3%), and ustekinumab (0.3%). Similarly, infliximab (80.6%) was the most commonly prescribed biologic for CD, followed by adalimumab (16.5%), vedolizumab (1.6%), ustekinumab (1.2%), and certolizumab (0.1%) (Table 2). At first maintenance dose, UC patients on infliximab were receiving a mean dose of 10.5mg/kg/8wk, patients on adalimumab (weight &lt;40kg) were receiving a mean dose of 1.3mg/kg/2wk, patients on adalimumab (weight≥40kg) were receiving a mean dose of 0.8mg/kg/2wk, and patients on vedolizumab were receiving a mean dose of 6.9mg/kg/8wks. Mean dose of infliximab among UC patients increased from 10.5mg/kg/8wk at first maintenance dose to 11.8mg/kg/8wk at 1-year from first maintenance dose. At the first maintenance dose, CD patients on infliximab were receiving a mean dose of 8.1mg/kg/8wk, patients on adalimumab (weight &lt;40kg) were receiving a mean dose of 1.1mg/kg/2wk, patients on adalimumab (weight ≥40kg) were receiving a mean dose of 0.8mg/kg/2wk, patients receiving vedolizumab were receiving a mean dose of 10.5mg/kg/8wks. Mean dose of infliximab among CD patients increased from 8.1mg/kg/8wk at first maintenance dose to 9.6mg/kg/8wk at 1-year from first maintenance dose. Conclusion These results highlight the biologic maintenance dose changes among pediatric UC and CD patients. TNF inhibitors remain the most commonly used class of biologic, but the doses being used are double the standard dosing guidelines. There is little evidence of dose reduction over time among pediatric UC and CD patients in the ICN registry.

Comparison of Three Methods to Assess Therapeutic Quality Control of Treatment with Vitamin K Antagonists

1999 ◽  
Vol 82 (10) ◽  
pp. 1260-1263 ◽  
Author(s):  
Martin Prins ◽  
W. Ken Redekop ◽  
Jan Tijssen ◽  
Siem Heisterkamp ◽  
Harry Büller ◽  
...  
Keyword(s):  
Quality Control ◽  
Vitamin K ◽  
Hybrid Method ◽  
Vitamin K Antagonists ◽  
Linear Interpolation ◽  
Target Range ◽  
Therapeutic Level

SummaryDuring treatment with vitamin K antagonists, International Normalized Ratios (INR) are determined periodically to maintain a therapeutic level of anticoagulation. We evaluated two existing methods for therapeutic quality control (linear interpolation and equidivision), with regard to their validity and reproducibility. In addition, we proposed and evaluated a (hybrid) method that takes into account potential effects of dosage modifications when INRs are far out of the target range. Validity was assessed by deleting intermediary INR results and estimating this INR based on the two surrounding INRs with each of the three methods. The estimated INRs were then compared with the observed INR.Reproducibility of time spent in an INR range was evaluated for each of the three methods by deleting at random increasing proportions of INRs and comparing these estimates with the situation without deletions. We found that estimates of time spent in INR categories obtained with equidivision were most reproducible, but least valid. The hybrid method showed slightly higher validity and reproducibility in comparison with linear interpolation. Since these differences were small, linear interpolation is preferable to the hybrid method, since the calculations involved are easier.

Analysis of Warfarin Therapy in Pediatric Patients: A Prospective Cohort Study of 319 Patients

Blood ◽  
1999 ◽  
Vol 94 (9) ◽  
pp. 3007-3014 ◽  
Author(s):  
W. Streif ◽  
M. Andrew ◽  
V. Marzinotto ◽  
P. Massicotte ◽  
A.K.C. Chan ◽  
...  
Keyword(s):  
Enteral Nutrition ◽  
Warfarin Therapy ◽  
Pediatric Patients ◽  
Pediatric Population ◽  
International Normalized Ratio ◽  
Target Range ◽  
Age Group ◽  
Older Children ◽  
Effect Of Age ◽  
Fontan Patients

Abstract This study details warfarin use in a large pediatric population followed in a central anticoagulation clinic. A prospective, consecutive cohort of nonselected children were studied. Patients were divided into groups by age, target international normalized ratio (INR) range, disease, medications, and vitamin K supplemented enteral nutrition use. Groups were analyzed on multiple aspects of warfarin therapy using multivariate methods. A total of 319 patients received 352 warfarin courses representing 391 treatment years. Age independently influenced all aspects of therapy. When compared with all older children, the ≤1 year of age group required increased warfarin doses, longer overlap with heparin, longer time to achieve target INR ranges, more frequent INR testing and dose adjustments, and fewer INR values in the target range. Although significantly different than children ≤1 year, children 1 to 6 years of age showed the same findings when compared with 7- to 18-year-olds. Fontan patients required 25% decreased dosage as compared with other congenital heart disease patients. Children on corticosteroids had less INRs in the target range and children on phenobarbital/carbamazepine required increased maintenance dosages of warfarin. Also, patients receiving enteral nutrition required increased dosages of warfarin. Serious bleeding occurred in 2 children (0.5% per patient year). Recurrent thromboembolic events (TEs) occurred in 8 children. Two children had recurrences while receiving warfarin (1.3% per patient year). This study outlines the profound effect of age and relative complexity of clinical management of warfarin therapy in children.

scholarly journals Vitamin K antagonists in children with heart disease: height and VKORC1 genotype are the main determinants of the warfarin dose requirement

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 861-867 ◽  
Author(s):  
Caroline Moreau ◽  
Fanny Bajolle ◽  
Virginie Siguret ◽  
Dominique Lasne ◽  
Jean-Louis Golmard ◽  
...  
Keyword(s):  
Vitamin K ◽  
Dose Response ◽  
Maintenance Dose ◽  
Vitamin K Antagonists ◽  
Warfarin Dose ◽  
International Normalized Ratio ◽  
Individual Variability ◽  
Dose Requirement ◽  
Warfarin Dose Requirement ◽  
Main Determinants

Abstract Managing vitamin K antagonist (VKA) therapy is challenging in children because of a narrow therapeutic range and wide inter- and intra-individual variability in dose response. Only a few small studies have investigated the effect of nongenetic and genetic factors on the dose response to VKAs in children. In a cohort study including 118 children (median age 9 years; range, 3 months-18 years) mostly with cardiac disease, we evaluated by multivariate analysis the relative contribution of nongenetic factors and VKORC1/CYP2C9/CYP4F2 genotypes on warfarin (n = 83) or fluindione (n = 35) maintenance dose and the influence of these factors on the time spent within/above/below the range. The results showed that height, target international normalized ratio and VKORC1 and CYP2C9 genotypes were the main determinants of warfarin dose requirement, accounting for 48.1%, 4.4%, 18.2%, and 2.0% of variability, respectively, and explaining 69.7% of the variability. Our model predicted the warfarin dose within 7 mg/wk in 86.7% of patients. None of the covariates was associated with the time spent above or below the international normalized ratio range. Whether this model predicts accurately the effective maintenance dose is currently being investigated.

Clinical Outcomes and Pharmacokinetics of Targeted Intravenous Busulfan in Children Receiving Stem Cell Transplantation for Thalassemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1117-1117 ◽  
Author(s):  
Javi d Gaziev ◽  
Luca Spitaleri ◽  
Alessia Mozzi ◽  
Laurent Nguyen ◽  
Christian Puozzo ◽  
...  
Keyword(s):  
Univariate Analysis ◽  
Iron Concentration ◽  
Conditioning Regimen ◽  
Systemic Exposure ◽  
Thalassemia Major ◽  
Individual Variability ◽  
Target Range ◽  
High Dose ◽  
Liver Iron ◽  
Transplant Outcomes

Abstract Background: High dose busulfan (BU) in combination with cyclophosphamide (BUCY) is a preferred conditioning regimen for patients with hemoglobinopathies. Recently introduced intravenous BU (IVBU) has decreased intra-and inter-individual variability of BU systemic exposure (AUC) when compared to oral dosing. There are no data available on IVBU pharmacokinetics (PK) in a large group of patients with thalassemia to date. Purpose: to asses the IVBU PK in relation to patient and disease-related (hepatomegaly, blood transfusion, ferritin, liver iron concentration, hepatitis, liver fibrosis) variables and the relationship of BU exposure to toxicities and transplant outcomes in children and young adults given SCT for thalassemia from HLA-matched related donors. Methods: 57 patients with thalassemia major with median age of 9 years (range, 1.6–24) received IVBU (Busilvex, Pierre Fabre Medicament, France) as a part of conditioning regimen between 2006 and 2008. BU doses were based on actual body weight: &lt;9–16= 1.2 mg/kg (n=10); 16–23= 1.1 mg/kg (n=13); 23–34= 0.95 mg/kg (n=23) and &gt;34=0.8 mg/kg (n=11) and were given every 6 hours for 4 days. Valproic acid (Depakin) was administered before and during BU treatment as anticonvulsant prophylaxis. Most patients had liver disease and moderate to severe iron overload. Class 1 and class 2 patients (n=24) received IVBU in combination with CY200 ± thiotepa as conditioning regimen. Class 3 patients (n=33) before conditioning with IVBU/CY160 ± thiotepa were given cytoreduction/immunosuppression with hydroxyurea, azathioprine and fludarabine between −45 and −12 days pretransplant. GVHD prophylaxis consisted of CSA+ short MTX. Blood samples were drawn just before and 2h, 4h, and 6h after BU administration following the 1st, 5th, 9th, and 13th doses for PK assessment by HPLC-MS. Dose adjustment (DA) was made at the 3rd dose as needed, to target an AUC range of 900–1350 μol/L/min. The influence of patient and disease-related variables on IVBU PK was investigated by a population PK-based approach using the NONMEM program. Results: PK parameters following the 1st dose are reported in Table. Overall, 58% of patients AUC were within, 37% were below and 5% were above the target range following the 1st dose of IVBU. Dose elevations of 5.2–54% (median, 18.8%) were made in 17 patients and dose reductions of 5–34.2% (median,9.2%) in 19 patients. Following DA 79 % of patients after the 5th and 9th doses and 91 % after the 13th dose reached the target range. The inter-patient variability in IV BU clearance was moderate (CV=19%) and the intra-patient variability was low (CV=7%). Only weight or body surface area significantly explained the PK variability. Fifty three patients had sustained engraftment, 4 had primary (n=2) or secondary (n=2) graft failure. Forty eight (89%) of 54 evaluable patients were complete and 6 (11%) mixed chimeras. One patient had moderate hepatic VOD resolved with supportive care. Seventeen patients developed grade 2–4 acute GVHD. None of patients had seizure within 30 days post-transplant. Grade 1 or 2 ALT/AST increases were observed in 19,3% and 44% of patients and stomatitis/diarrhoea in 47% and 19% of patients respectively. Five patients died. There was no relationship between busulfan exposure and toxicities, engraftment time, chimerism, rejection, GVHD and survival in univariate analysis. No association was found between PK parameters and transplant outcomes in a subgroup of patients (n=19) who never needed DA. This study demonstrates that IVBU in children with thalassemia who have important organ damage due to their disease and treatment is well tolerated with no increase in organ system toxicity. IVBU exposure did not predict rejection, liver VOD or death in patients with thalassemia who received HLA-matched related SCT. AUC, μol/min Css, ng/ml Cmax, ng/ml Cmin, ng/ml Cl, ml/min/kg Vd, L T ½, h Mean ± sd 982± 203 672± 139 1071± 207 239± 72 4.23± 0.95 16.8±6.8 1.8±0.2 Range 630–1621 431–1109 735–1614 101–450 2.31–6.43 7.3–43.6 1.2–2.3

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