Identification of biomarkers that predict renal flare in childhood-onset lupus nephritis with mycophenolate acid.

BACKGROUND: Children-onset lupus nephritis (cLN) occurs > 50 % of patients with systemic lupus erythematosus. Mycophenolic acid (MPA) is the first-line agent for the induction and maintenance treatment of LN. This study was to explore the predictors of renal flare in cLN. METHODS: Data from 90 patients were included in population pharmacokinetic (PK) models to predict MPA exposure. Cox regression models and restricted cubic spline were performed in 61 patients to identify the risk factors for renal flare, baseline clinical characteristics and MPA exposures as potential covariates. RESULTS: PK best fitted a two-compartment model of first-order absorption and linear elimination, with delayed absorption. Clearance increased with weight and immunoglobulin G (IgG), but decreased with albumin and serum creatinine. During follow-up of 1040 (658-1359) days, 18 patients experienced a renal flare, after a median time of 932.5 (663.5-1316) days. Each 1-mg·h/L increase of MPA-AUC was associated with a 6 % decreased risk of an event (HR = 0.94; 95 % CI: 0.90-0.98), while IgG significantly increased this risk (HR = 1.17; 95 % CI: 1.08-1.26). ROC analysis showed that MPA-AUC0-12h < 35 mg·h/L and IgG > 17.6 g/L had a good prediction of renal flare. Of restricted cubic spline, the risk of renal flares decreased with higher MPA exposure but reached a plateau when AUC0-12h > 55 mg·h/L, while substantially increases when IgG is > 18.2 g/L. CONCLUSIONS: Monitoring MPA exposure together with IgG could be very useful during clinical practice to identify patients with a potential high risk of renal flare. This early risk assessment would allow for the treat-to-target and tailored medicine.

Population Pharmacokinetics of Enteric-Coated Mycophenolate Sodium in Children after Renal Transplantation and Initial Dosage Recommendation Based on Body Surface Area.

Objective: Enteric-coated mycophenolate sodium (EC-MPS) is widely used in renal transplant recipients. There is a lack of study on the pharmacokinetics of this drug in children. This study is aimed at developing a population pharmacokinetic model of mycophenolic acid in children who were treated with EC-MPS after renal transplantation and to recommend initial dosage. Methods: Pediatric patients who had undergone renal transplantation and received EC-MPS were included. Data on demographic characteristics, biochemical tests, blood routine examinations, mycophenolic acid plasma concentrations, dosing amount and frequency of EC-MPS, and coadministered medications were retrospective collected from June 2018 to August 2019. Nonlinear mixed effect modeling methods were adopted to develop a population pharmacokinetic model with the data above. Additional data from September 2019 to July 2020 were used to validate the model. Simulations under different dosage regimen were conducted to evaluate the percentage of target attainment (PTA, AUC0-12h 30-60 mg·h/L). Results: A total of 96 pediatric patients aged at 13.3 (range 4.3-18.0) years were included in the modeling group. Data from 32 patients aged at 13.0 (range 3.6-18.3) years were used to validate the model. A one-compartment model with a double extravascular absorption was developed. Body surface area (BSA) was added as a covariate. Simulations showed that for different dosing regimens, the highest percentage of target attainment is around 50%. The best dosing regimen is 180 mg every 48 hours for patients with BSA of 0.22-0.46 m2, 180 mg every 24 hours with BSA of 0.47-0.67 m2, 180 mg every 24 hours with BSA of 0.68-0.96 m2, 360 mg every 24 hours with BSA of 0.97-1.18 m2, 540 mg every 24 hours with BSA of 1.19-1.58 m2, and 360 mg every 12 hours with BSA of 1.59-2.03 m2. Conclusion: BSA could affect the area under curve of mycophenolic acid with the administration of EC-MPS. Considering the inflexibility of the dosage form, future development of smaller amount per tablet suitable for younger children with BSA < 1.19 m2 is warranted.

Intercepting Medication Errors in Pediatric In-patients Using a Prescription Pre-audit Intelligent Decision System: A Single-center Study.

OBJECTIVES: Medication errors can happen at any phase of the medication process at health care settings. The objective of this study is to identify the characteristics of severe prescribing errors at a pediatric hospital in the inpatient setting and to provide recommendations to improve medication safety and rational drug use. METHODS: This descriptive retrospective study was conducted at a tertiary pediatric hospital using data collected from Jan. 1st, 2019 to Dec. 31st, 2020. During this period, the Prescription Pre-audit Intelligent Decision System was implemented. Medication orders with potential severe errors would trigger a Level 7 alert and would be intercepted before it reached the pharmacy. Trained pharmacists maintained the system and facilitated decision making when necessary. For each order intercepted by the system the following patient details were recorded and analyzed: patient age, patient's department, drug classification, dosage forms, route of administration, and the type of error. RESULTS: A total of 2176 Level 7 medication orders were intercepted. The most common errors were associated with drug dosage, administration route, and dose frequency, accounting for 35.2%, 32.8% and 13.2%, respectively. Of all the intercepted oerrors. 53.6% occurred in infants aged < 1 year. Administration routes involved were mainly intravenous, oral and external use drugs. Most alerts came from the neonatology department and constituted 40.5% of the total alerts, followed by the nephrology department 15.9% and pediatric intensive care unit (PICU) 11.3%. As to dosage forms, injections accounted for 50.4% of alerts, with 21.3% attributable to topical solutions, 9.1% to tablets, and 5.7% to inhalation. Anti-infective agents were the most common therapeutic drugs prescribed with errors. CONCLUSIONS: The Prescription Pre-audit Intelligent Decision System, with the supervision of trained pharmacists can validate prescriptions, increase prescription accuracy, and improve drug safety for hospitalized children. It is a medical service model worthy of consideration.

Effects of Posaconazole on Tacrolimus Population Pharmacokinetics and Initial Dose in Children With Crohn's Disease Undergoing Hematopoietic Stem Cell Transplantation.

The present study explored the effects of posaconazole on tacrolimus population pharmacokinetics (PPK) in children with Crohn's disease (CD) undergoing hematopoietic stem cell transplantation (HSCT). Tacrolimus concentrations, physiological and biochemical factors, and concomitant medications from 51 CD children undergoing HSCT were used to establish a PPK model based on a nonlinear mixed-effect model. Steady-state concentrations of tacrolimus for children weighing less than 20 kg treated with different dose regimens were simulated by the Monte Carlo method. Weight and concomitant medications were included as covariates. At the same weight, the relative tacrolimus clearance was 1:0.43 in children without or with posaconazole. Compared to children not receiving posaconazole, the simulated tacrolimus steady-state concentrations at different doses for different body weights were all higher in children receiving posaconazole (p < 0.01). Furthermore, in children not receiving posaconazole, the dosage regimen with the best probability of achieving the target concentration was 0.6 mg/kg/day for children weighing 5-8.2 kg and 0.5 mg/kg/day for children weighing 8.2-20 kg, while for children receiving posaconazole, the best probability of reaching the target concentration of tacrolimus was a dosage regimen of 0.5 mg/kg/day for children weighing 5-20 kg. In conclusion, the PPK for tacrolimus was determined in children with CD undergoing HSCT for the first time. Co-treatment with posaconazole significantly increased tacrolimus concentrations, and we recommend a specific initial dose regimen for tacrolimus.

Population pharmacokinetic and dose optimization of mycophenolic acid in children with anti-neutrophilic cytoplasmic antibody-associated nephritis.

PURPOSE: Anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis is a rare autoimmune disease. Mycophenolic acid (MPA) is widely used for ANCA-associated nephritis (AAN) but with large pharmacokinetic variability. This study aims to investigate clinical factors impacting MPA disposition in pediatric AAN. METHODS: We retrospectively collected 391 MPA concentrations from 25 children diagnosed with AAN. A population pharmacokinetic model was developed to explore the potential effects of demographics and biochemical covariates on MPA. Monte Carlo simulations were performed to optimize dosage regimen. RESULTS: MPA pharmacokinetics best fitted a two-compartment model with first-order absorption and linear elimination. The pharmacokinetic parameters for Ka, CL/F, Vc/F, Vp/F, and Q/F were 0.45 h-1, 9.86 L/h, 19.69 L, 408.32 L, and 23.01 L/h. Dosage form significantly affected drug absorption. CL/F significantly decreased with increasing cystatin C, while decreasing with myeloperoxidase. Cystatin C was superior to serum creatinine in predicting apparent clearance of MPA. A dose regimen of 650 mg/m2 twice daily was required to achieve target exposure in children with normal renal function and no inflammation. The combined effects of myeloperoxidase concentration and renal function resulted in a sixfold range of MPA dose. CONCLUSION: This was the first study of MPA population pharmacokinetic model in children with AAN. Myeloperoxidase was not only a biomarker of AAN, but also an inflammatory factor to impact drug CL. The influence of renal function and underlying diseases on drug metabolism should be fully considered in personalized medication for AAN.

Optimization of Initial Dose Regimen for Sirolimus in Pediatric Patients With Lymphangioma.

Sirolimus is an effective oral treatment for pediatric patients with lymphangioma. The present clinical study in 15 children (0.12-16.39 years of age) examines the effects of underlying factors on sirolimus concentrations through application of a population pharmacokinetic model. Using Monte Carlo simulation, an initial dose regimen for sirolimus in pediatric patients with lymphangioma is presented. It is found that the lower the body weight, the higher the clearance rate and sirolimus clearances are 0.31-0.17 L/h/kg in pediatric patients with lymphangioma whose weights are 5-60 kg, respectively. The doses of sirolimus, 0.07, 0.06, 0.05 mg/kg/day are recommended for weights of 5-10, 10-24.5 and 24.5-60 kg in children with lymphangioma. This study is the first to establish a population pharmacokinetic model for sirolimus and to recommend initial doses in pediatric patients with lymphangioma. Large scale, prospective studies are needed in the future.

Factors associated with the time to return negative RT-PCR from COVID-19 in paediatric patients: a retrospective cohort study.

OBJECTIVE: This study aimed to describe the epidemiological and clinical features and potential factors related to the time to return negative reverse transcriptase (RT)-PCR in discharged paediatric patients with COVID-19. DESIGN: Retrospective cohort study. SETTING: Unscheduled admissions to 12 tertiary hospitals in China. PARTICIPANTS: Two hundred and thirty-three clinical charts of paediatric patients with confirmed diagnosis of COVID-19 admitted from 1 January 2020 to 17 April 2020. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome measures: factors associated with the time to return negative RT-PCR from COVID-19 in paediatric patients. SECONDARY OUTCOME MEASURES: epidemiological and clinical features and laboratory results in paediatric patients. RESULTS: The median age of patients in our cohort was 7.50 (IQR: 2.92-12.17) years, and 133 (57.1%) patients were male. 42 (18.0%) patients were evaluated as asymptomatic, while 162 (69.5%) and 25 (10.7%) patients were classified as mild or moderate, respectively. In Cox regression analysis, longer time to negative RT-PCR was associated with the presence of confirmed infection in family members (HR (95% CI): 0.56 (0.41 to 0.79)). Paediatric patients with emesis symptom had a longer time to return negative (HR (95% CI): 0.33 (0.14 to 0.78)). During hospitalisation, the use of traditional Chinese medicine (TCM) and antiviral drugs at the same time is less conducive to return negative than antiviral drugs alone (HR (95% CI): 0.85 (0.64 to 1.13)). CONCLUSIONS: The mode of transmission might be a critical factor determining the disease severity of COVID-19. Patients with emesis symptom, complications or confirmed infection in family members may have longer healing time than others. However, there were no significant favourable effects from TCM when the patients have received antiviral treatment.

Optimized Dosing Regimens of Meropenem in Septic Children Receiving Extracorporeal Life Support.

Objectives: To develop a population pharmacokinetic model of meropenem in children with sepsis receiving extracorporeal life support (ECLS) and optimize the dosage regimen based on investigating the probability of target attainment (PTA). Methods: The children with sepsis were prospectively enrolled in a pediatric intensive care unit from January 2018 to December 2019. The concentration-time data were fitted using nonlinear mixed effect model approach by NONMEM program. The stochastic simulation considering various scenarios based on proposed population pharmacokinetics model were conducted, and the PTAs were calculated to optimize the dosage regimens. Results: A total of 25 children with sepsis were enrolled, of whom13 received ECMO, 9 received CRRT, and 4 received ECMO combined with CRRT. 12 children received a two-step 3-h infusion and 13 children received 1-h infusion. Bodyweight and creatinine clearance had significant impacts on the PK parameters. ECMO intervention was not related to the PK properties. If 100%T > MIC was chosen as target, children receiving 40 mg/kg q8h over a 3 h-infusion only reached the PTA up to 77.4%. If bacteria with MIC 2 mg/L were to be treated with meropenem and the PTA target was 50%T > MIC, a dose of 40 mg/kg q8h for 1 h infusion would be necessary. Conclusions: The PK properties of meropenem in septic children receiving extracorporeal life support were best described. We recommended the opitimized dosing regimens for septic children receiving ECLS depending on the PTA of PK target 50%T > MIC and 100%T > MIC, for children with sepsis during ECLS with different body weight, estimated creatinine clearance (eCRCL) and MIC of bacteria.

Exposure levels of mycophenolic acid are associated with comorbidities in children with systemic lupus erythematosus.

INTRODUCTION: Little is known about the relationship between exposure levels of mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and comorbidities of systemic lupus erythematosus (SLE) in children. This study aims to explore this association. METHODS: Longitudinal data from SLE children, who were taking MMF for immunosuppression and under therapeutic drug monitoring (TDM), were retrospectively collected. Area under the concentration-time curve of mycophenolic acid (MPA) over 24 hours (AUC0-24h) was estimated with Bayesian methods. Logistic regression and random forest models were used to explore the association between comorbidities and MPA exposure levels. RESULTS: This study included 107 children with 358 times of follow-up (median age 169.02 months). The incidence of diabetes, acute kidney injury (AKI), or pneumonia was significantly associated with AUC0-24h (odds ratio [OR] 0.991, 95% confidence interval [CI] 0.982-0.999), SLE duration (OR 1.012, 95% CI 1.002-1.022), lymphocyte percentage (OR 0.959, 95% CI 0.925-0.991), plasma albumin levels (OR 0.891, 95% CI 0.843-0.940), use of aspirin (OR 0.292, 95% CI 0.126-0.633) and hydroxychloroquine (OR 0.407, 95% CI 0.184-0.906). The random forest model showed that albumin and AUC0-24h were two important predictors. The case group (with the three comorbidities) had a mean AUC0-24h of 73.63 mg · h/L, while the control group had a mean AUC0-24h of 100.39 mg · h/L. CONCLUSIONS: Increased levels of MPA exposure are associated with decreased incidence odds of diabetes, AKI or pneumonia in SLE children. An AUC0-24h of 100.39 mg · h/L or an AUC0-12h of 50.20 mg · h/L could be used as the targeted exposure level for clinical practice.

Mycophenolic Acid Exposure Optimization Based on Vitamin D Status in Children with Systemic Lupus Erythematosus: A Single-Center Retrospective Study.

INTRODUCTION: Systemic lupus erythematosus (SLE) can affect bone metabolism and homeostasis of serum electrolytes that are associated with abnormal levels of vitamin D. Mycophenolate mofetil (MMF) is a commonly used immunosuppressant with the active metabolite mycophenolic acid (MPA). The area under the plasma concentration-time curve (AUC) of MPA is often monitored during the treatment to assess the exposure levels. This study aims to explore the association between exposure levels of MPA and 25-hydroxyvitamin D [25(OH)D] levels in children with SLE. METHODS: Repeated measured data of children with SLE who were treated with MMF and under therapeutic drug monitoring (TDM) were retrospectively collected from the electronic medical records. MPA exposure levels were reflected by the area under the concentration-time curve over 24 h (AUC0-24h). Univariate and multivariate linear regression models were employed to analyze factors associated with 25(OH)D levels. Hierarchical linear models were developed to analyze the intra- and inter-individual effects of AUC0-24h on the variance of 25(OH)D levels. RESULTS: Data from 184 children with SLE (142 female and 42 male) with 518 follow-ups were collected. The median age was 14 years (range 3-18 years) at TDM. Children with normal 25(OH)D levels had significantly higher AUC0-24h than children with low 25(OH)D levels (98.71 vs. 84.05 mg·h/L, P = 0.004). Intra- and inter-individual effects of AUC0-24h on 25(OH)D levels were similar ([Formula: see text] = 0.034 vs. [Formula: see text] = 0.037) but only the intra-individual effect was significant (P = 0.001) in hierarchical models. Other associated factors include age, sex, season at measurement, glucocorticoid daily dose, and external vitamin D3 supplements. CONCLUSION: 25(OH)D levels are associated with MPA exposure levels, and may serve as a potential indicator to optimize the exposure level of MPA during treatment. AUC0-24h of 98.71 mg·h/L or AUC0-12h of 49.36 mg·h/L could be the targeted exposure level for children with SLE.

Population Pharmacokinetics and Initial Dose Optimization of Sirolimus Improving Drug Blood Level for Seizure Control in Pediatric Patients With Tuberous Sclerosis Complex.

The purposes of this study were to explore the population pharmacokinetics and initial dose optimization of sirolimus improving drug blood level for seizure control in pediatric patients with tuberous sclerosis complex (TSC). Eighty pediatric patients diagnosed with TSC-related epilepsy were included for analysis. Sirolimus concentrations, physiological and biochemical indexes, and drug combination were collected to build a nonlinear mixed effect (NONMEM) model. Initial dose optimization was simulated by the Monte Carlo method. The weight and concomitant medication of oxcarbazepine affected sirolimus clearance. Without oxcarbazepine, for once-daily sirolimus regimen, the doses of 0.07, 0.06, 0.05, 0.04, and 0.03 mg/kg/day were recommended for weights of 5-7.5, 7.5-11.5, 11.5-19, 19-40, and 40-70 kg, respectively; for twice-daily sirolimus regimen, the doses of 0.05, 0.04, and 0.03 were recommended for weights of 5-8, 8-20, and 20-70 kg, respectively. With oxcarbazepine, for once-daily sirolimus regimen, the doses of 0.09, 0.08, 0.07, 0.06, 0.05, and 0.04 mg/kg/day were recommended for weights of 5-7.5, 7.5-10, 10-13.5, 13.5-20, 20-35, and 35-70 kg, respectively; for twice-daily sirolimus regimen, the doses of 0.06, 0.05, 0.04, and 0.03 were recommended for weights of 5-7, 7-14.5, 14.5-38, and 38-70 kg, respectively. The present study was the first to establish a population pharmacokinetic model of sirolimus improving drug blood level for seizure control in pediatric patients with TSC and recommend the initial dosage regimen.

Safety survey by clinical pharmacists on COVID-19 vaccination from a single center in China.

This study explored the safety of COVID-19 vaccine (Aikewei) and the role of clinical pharmacists in the implementation of COVID-19 vaccination. A total of 2305 hospital employees in Children's Hospital of Fudan University in Shanghai, China received the COVID-19 vaccine. The whole process of vaccination was monitored by clinical pharmacists, and the occurrence, types, severity of adverse reactions were recorded in detail. Through the investigation and analysis on the safety of COVID-19 vaccination of the 2305 people, the important role and value of clinical pharmacists in the vaccination process was elaborated. Common adverse reactions included local pain, dizziness and fatigue, with the incidence rates of 2.09%, 0.67% and 0.49%, respectively. Others such as headache, nausea, skin itching, cough, palpitation, dry mouth, hand anesthesia, local induration, muscle soreness, local rash, and chill had incidence rates of less than 0.30%. Three cases of serious adverse events that occurred in this vaccination returned to normal after treatment, with no subsequent discomfort. Clinical pharmacists played an important role in the safety monitoring of COVID-19 vaccination. The safety of the inactivated COVID-19 vaccine is good. Most of the common adverse reactions were mild and tolerable, with generally low incidence. The work of clinical pharmacists is important and can be expanded in the future to ensure the safety of vaccination and to provide better health care service.

Low-dose oral hydroxychloroquine led to impaired vision in a child with renal failure: Case report and literature review.

INTRODUCTION: Hydroxychloroquine (HCQ) has received much attention in the treatment of coronavirus disease 2019 recently. However, it can cause irreversible vision loss. Few cases have been reported in pediatric patient with HCQ-related adverse reactions. Appropriate administration and early disease recognition are important for reducing the adverse drug reactions of HCQ. PATIENT CONCERNS: We report a case of a 14-year-old Chinese girl who sought treatment for rapidly decreasing vision in the left eye over 3 days. The simulation results of the population pharmacokinetic model of HCQ revealed that the plasma concentration of HCQ abnormally increased before the visual acuity of the eye decreased. DIAGNOSIS: She was diagnosed as HCQ related drug adverse reaction. INTERVENTIONS: The daily dose of HCQ for this patient was adjusted from 100 mg/d to 50 mg/d. OUTCOMES: Follow-up for 6 months showed no more vision loss recurrence. However, the existing decreased visual acuity of the eye did not recover either. CONCLUSION: Although decreased visual acuity is an infrequent symptom, ophthalmologists should be aware of the possibility of HCQ concentration enrichment and consider minimizing HCQ use when a child with renal hypofunction seeks treatment for shortsightedness.

Population pharmacokinetics of mycophenolic acid in pediatric patients with juvenile dermatomyositis and optimization of limited sampling strategy.

Juvenile dermatomyositis (JDM) is a rare systemic autoimmune disease specifically affecting children. Mycophenolate mofetil (MMF) is an immunosuppressant used to treat JDM. Mycophenolic acid (MPA) is an active metabolite of MMF. This study aimed to develop a population pharmacokinetic (PPK) model of MPA in children with JDM and optimize the limited sampling strategy (LSS). Fifteen JDM patients treated with MMF, at a median age of 7.35 (range, 3.09-16.1) years, were included. Blood samples were collected at 30 minutes pre-dose, 20 minutes, 60 minutes and 180 minutes post-dose to measure the MPA concentrations. Data were retrospectively collected from the electronic medical records. A two-compartment model with first-order absorption, lag time in absorption, and first-order elimination was developed. Height and co-administered cotrimoxazole were added as the covariates to the model. Concentrations at different time points were simulated and area under the concentration-time curve (AUC0-12 h) was calculated. By removing one sampling point at a time, AUC0-12 h from three-point sampling strategy was re-calculated via Bayesian approach. AUC0-12 h from the three-point sampling strategy (by removing the point at 20 minutes post-dose) had the strongest correlation with AUC0-12 h from the four-point sampling strategy (Pearson's r = 0.971).

Clinical features and antimicrobial susceptibility profiles of culture-proven neonatal sepsis in a tertiary children's hospital, 2013 to 2017.

Neonatal sepsis (NS) remains a major cause of morbidity and mortality in neonates, but data on the etiology and antibiotic susceptibility patterns of pathogens are limited. The aim of this study was to analyze the clinical characteristics, risk factors, and the antibiotic susceptibility patterns of pathogenic microbes associated with NS at a tertiary children's hospital in Shanghai, China.Episodes of blood culture-proven sepsis in the neonatal intensive care unit (NICU) of Children's Hospital of Fudan University from January 2013 to August 2017 were retrospectively reviewed. Collected data included demographics, perinatal risk factors, clinical symptoms, laboratory values, microbiology results and their antimicrobial susceptibility. Data for early-onset neonatal sepsis (EONS) and late-onset neonatal sepsis (LONS) were compared.The 341 of 976 culture-positive cases were selected, including 161 EONS cases (47.21% of 341) and 180 LONS cases (52.79% of 341). 635 incomplete cases were excluded. There was significant difference in risk factors between the EONS group and LONS group including birth weight, gestational age, 1-minute Apgar score, respiratory support, and the use of peripherally insertion central catheter (PICC). Clinical symptoms such as fever, feeding intolerance, abdominal distension, and neonatal jaundice, and laboratory results such as hemoglobin and lymphocyte counts also showed between-group differences. Staphylococcus epidermidis (22.87%), Escherichia coli (9.68%), Alcaligenes xylosoxidans (9.38%) and Klebsiella pneumoniae (9.09%) remain the principal organisms responsible for neonatal sepsis. Most isolates of Gram-positive bacteria were sensitive to vancomycin, linezolid, minocycline and tigecycline, of which more than 90% were resistant to penicillin. Most isolates of Gram-negative bacteria were sensitive to amikacin and imipenem and resistant to ampicillin. Fungus was sensitive to antifungal agents. Better medical decisions, especially early detection and appropriate initial antimicrobial therapy can be made after understanding the different clinical features and pathogens of EONS and LONS.