Association between genetic variants of transmembrane transporters and susceptibility to anthracycline-induced cardiotoxicity: Current understanding and existing evidence.

Anthracyclines remain the cornerstone of numerous chemotherapeutic protocols, with beneficial effects against haematological malignancies and solid tumours. Unfortunately, the clinical usefulness of anthracyclines is compromised by the development of cardiotoxic side effects, leading to dose limitations or treatment discontinuation. There is no absolute linear correlation between the incidence of cardiotoxicity and the threshold dose, suggesting that genetic factors may modify the association between anthracyclines and cardiotoxicity risk. And the majority of single nucleotide polymorphisms (SNPs) associated with anthracycline pharmacogenomics were identified in the ATP-binding cassette (ABC) and solute carrier (SLC) transporters, generating increasing interest in the pharmacogenetic implications of their genetic variations for anthracycline-induced cardiotoxicity (AIC). This review focuses on the influence of SLC and ABC polymorphisms on AIC and highlights the prospects and clinical significance of pharmacogenetics for individualised preventive approaches.

Efficacy and safety of bisphosphonates on childhood osteoporosis secondary to chronic illness or its treatment: a meta-analysis.

Background: Bisphosphonates are a type of medication that prevents the loss of bone density. Secondary childhood osteoporosis reduces bone strength and results in an increased risk of fragility fracture. This meta-analysis aims to explore the efficacy and safety of bisphosphonates on secondary childhood osteoporosis. Methods: We performed a systematic search of PubMed, Cochrane library, and Web of Science databases up to 31 July 2022 to screen for random clinical trials (RCTs) on bisphosphonate treatment for childhood secondary osteoporosis. Data from selected studies, mainly changes in lumbar spine (LS) bone mineral density (BMD), changes in LS BMD Z-scores, fracture events, and adverse events (AEs), were extracted and analyzed. Results: Nine RCTs (n = 429 in total) were included in our meta-analysis. The meta-analysis indicated that bisphosphonates improved the changes in LS BMD [mean difference (MD) = 0.04, 95% confidence intervals (CIs) = 0.01-0.07, p < 0.01] and LS BMD Z-scores [MD = 0.52, 95% CI = 0.23-0.81, p < 0.01]. Use of bisphosphonates did not increase the risk of AEs [odds ratio (OR) = 1.61, 95% CI = 0.87-2.99, p = 0.13]. Subgroup analysis showed that routes of administration, but not causes of secondary osteoporosis, might influence the efficacy of bisphosphonates. IV bisphosphonates close to significantly improved the incidence of fracture (OR = 0.34, 95% CI: 0.11-1.08, p = 0.07). Conclusions: The use of bisphosphonates improves LS BMD without increasing AE rates, which supports the clinical use of bisphosphonates in secondary childhood osteoporosis. Further large RCTs are still warranted, especially for their long-term effects on fracture rates.

Corrigendum: Impact of sampling time variability on tacrolimus dosage regimen in pediatric primary nephrotic syndrome: Single-center, prospective, observational study.

[This corrects the article DOI: 10.3389/fphar.2021.726667.].

Tigecycline-Induced Tooth Discoloration in Children Younger than Eight Years.

Tetracycline may cause tooth discoloration when used in young children during tooth development. Whether tigecycline, a tetracycline derivative, has either a similar adverse event or not remains unclear. We assessed the discoloration of the permanent teeth of patients <8 years old after tigecycline exposure. These patients were identified through a retrospective chart review in a Chinese children's hospital. Those who had at least one erupted permanent tooth after tigecycline exposure were interviewed, examined, and photographed by an experienced pediatric dentist and independently assessed by another senior dentist to detect tetracycline-like tooth discoloration. We identified 101 patients who were exposed to tigecycline, 12 of whom were included. The mean daily dose of tigecycline was 2.3 mg/kg of body weight (standard deviation, 0.6), and the median duration was 12.5 days (interquartile range [IQR], 8.0 to 19.3). The median age of exposure was 5.2 years (IQR, 4.5 to 7.4), and the median age of dental examination was 9.1 years (IQR, 9.0 to 10.3). Two patients (16.7%) developed yellow discoloration: a girl having yellow discoloration with white-to-yellow opacities in the upper lateral incisors and lower incisors and a boy with a suspicious buccal yellow discoloration and enamel dysplasia in the second molars. The incidence and extent of tigecycline-associated dental adverse events remain unclear due to the small sample size and inadequate follow-up period.

Impact of Sampling Time Variability on Tacrolimus Dosage Regimen in Pediatric Primary Nephrotic Syndrome: Single-Center, Prospective, Observational Study.

Background: Tacrolimus (TAC) is an important immunosuppressant for children with primary nephrotic syndrome (PNS). The relationship between sampling time variability in TAC therapeutic drug monitoring and dosage regimen in such children is unknown. Methods: In this single-center, prospective, observational study, we evaluated the sampling time variability, concentration error (CE), relative CE (RCE), and the impact of the sampling time on TAC dosage regimens in 112 PNS children with 188 blood samples. Nominal concentration (Cnom) at 12-h after last TAC dose was simulated based on observed concentration (Cobs) via previously published pharmacokinetic models, then CE and RCE were calculated. Inappropriate dosing adjustments resulting from deviated sampling time were evaluated based on a target Cnom of 5-10 ng/ml. Results: We found that 32 and 68% of samples were respectively collected early (2-180 min) and delayed (4-315 min). Furthermore, 24, 22, 22, and 32% of blood samples were drawn within deviations of ≤0.5, 0.5-1, 1-2, and >2 h, respectively, and 0.3 ng/ml of CE and 6% RCE per hour of deviation occurred. Within a deviation of >2 h, 25% of Cobs might result in inappropriate dosing adjustments. Early and delayed sampling might result in inappropriate dose holding or unnecessary dose increments, respectively, in patients with Cobs ∼ 5 ng/ml. Conclusions: Variable sampling time might lead to inappropriate dosing adjustment in a minority of children with PNS, particularly those with TAC Cobs ∼ 5 ng/ml collected with a deviation of >2 h.

Diltiazem on tacrolimus exposure and dose sparing in Chinese pediatric primary nephrotic syndrome: impact of CYP3A4, CYP3A5, ABCB1, and SLCO1B3 polymorphisms.

PURPOSE: To evaluate the role of diltiazem on tacrolimus sparing in pediatric primary nephrotic syndrome (PNS) and its relation to CYP3A4, CYP3A5, ABCB1, and SLCO1B3 polymorphisms. METHODS: The PNS children treated with tacrolimus and with steady-state trough concentration (C0) were retrospectively collected. The impacts of diltiazem on tacrolimus dose-adjusted C0 (C0/D), target concentration achievement, and required dose were evaluated. Meanwhile, the relationship between the polymorphisms (including CYP3A4*1G, CYP3A5*3, ABCB1-C3435T, and SCLO1B3) and dose-sparing effect were investigated. RESULTS: A total of 71 children with 535 concentrations, including 16 children with concomitant diltiazem, were involved. Significantly increased C0/D (94.0 vs 83.8 ng/mL per mg/kg, p = 0.038) and lower required daily dose of tacrolimus (0.056 vs 0.064 mg/kg, p = 0.003) were observed in patients co-administered with diltiazem. Subpopulation carrying CYP3A4*1G, CYP3A5*1, ABCB1-3435TT, or SLCO1B3-699AA was presented with enhanced increment in tacrolimus C0/D by 38.8-102.9%. CONCLUSION: Moderate effect of diltiazem on tacrolimus sparing, which might relate to the polymorphisms of CYP3A4, CYP3A5, ABCB1, and SLCO1B3, was documented.

Population Pharmacokinetic Study of Vancomycin in Chinese Pediatric Patients with Hematological Malignancies.

STUDY OBJECTIVES: Vancomycin is a primary antibiotic for the treatment of severe infections in children with malignant hematological disease. However, precise dosing of vancomycin is difficult in children because of high interindividual variability and limited data of pharmacokinetic profiles. The present study aims to develop a population pharmacokinetic (PPK) model for vancomycin in Chinese pediatric patients with hematological malignancies. DESIGN: This was a retrospective pharmacokinetic study. SETTING: The setting for this study was a tertiary-care children's hospital. PATIENTS: This study included 92 pediatric patients with hematological malignancies who received vancomycin and experienced therapeutic drug monitoring from February 2017 to December 2018. MEASUREMENTS AND MAIN RESULTS: A PPK model was generated with a nonlinear mixed effects model. In addition, required doses to achieve target therapeutic concentrations were simulated based on the final model. A one-compartment model with first-order elimination fit the concentration data best. Actual body weight (BW) and glomerular filtration rate (GFR) were the significant influential factors on the clearance (CL) of vancomycin. The final PPK model for CL was CL (L/h) = 4.18  ×GFR/1450.741×BW/25K , K =  BW-0.856/BW-0.856+6.53-0.856 , and the volume of distribution was 22.3 L. The model proved to be robust and reliable. Reference dosing regimens were proposed based on the final model. CONCLUSIONS: A PPK model of vancomycin was established for Chinese pediatric patients with hematological malignancies using a nonlinear mixed effects model, which provided a reference for the clinical application of vancomycin.

Underlying Mechanism of Insulin Resistance: A Bioinformatics Analysis Based on Validated Related-Genes from Public Disease Databases.

BACKGROUND The underlying mechanism of insulin resistance is complex; bioinformatics analysis is used to explore the mechanism based differential expression genes (DEGs) obtained from omics analysis. However, the expression and role of most DEGs involved in bioinformatics analysis are invalidated. This study aimed to disclose the mechanism of insulin resistance via bioinformatics analysis based on validated insulin resistance-related genes (IRRGs) collected from public disease-gene databases. MATERIAL AND METHODS IRRGs were collected from 4 disease databases including NCBI-Gene, CTD, RGD, and Phenopedia. GO and KEGG analysis of IRRGs were performed by DAVID. Then, the STRING database was employed to construct a protein-protein interaction (PPI) network of IRRGs. The module analysis and hub genes identification were carried out by MCODE and cytoHubba plugin of Cytoscape based on the primary PPI network, respectively. RESULTS A total of 1195 IRRGs were identified. Response to drug, hypoxia, insulin, positive regulation of transcription from RNA polymerase II promoter, cell proliferation, inflammatory response, negative regulation of apoptotic process, glucose homeostasis, cellular response to insulin stimulus, and aging were proposed as the crucial functions related to insulin resistance. Ten insulin resistance-related pathways included the pathways of insulin resistance, pathways in cancer, adipocytokine, prostate cancer, PI3K-Akt, insulin, AMPK, HIF-1, prolactin, and pancreatic cancer signaling pathway were revealed. INS, AKT1, IL-6, TP53, TNF, VEGFA, MAPK3, EGFR, EGF, and SRC were identified as the top 10 hub genes. CONCLUSIONS The current study presented a landscape view of possible underlying mechanism of insulin resistance by bioinformatics analysis based on validated IRRGs.

PEGylated versus non-PEGylated drugs: A cross-sectional analysis of adverse events in the FDA Adverse Event Reporting System (FAERS) Database
.

OBJECTIVE: PEGylation is commonly used to optimize pharmacological properties and improve the clinical response of drugs. Due to the inherent toxicity of polyethylene glycol (PEG) and pharmacological changes induced by PEGylation, the safety may be altered and required to be explored. This study explored the adverse events (AEs) associated with PEGylation by comparing pharmacovigilance data of PEGylated and parent drugs. MATERIALS AND METHODS: We conducted a disproportionality analysis of spontaneous reports associated with PEGylated and corresponding parent medications from the FDA Adverse Event Reporting System database recorded between the 1st quarter of 2004 and the 4th quarter of 2018 at the level of preferred terms (PTs) and standard MedDRA queries (SMQs), respectively. The AEs probably different in risk due to changed pharmacological effects and inherent toxicity of PEG were analyzed. RESULTS: A total of 259,428 cases associated to six drug pairs (filgrastim, asparaginase, interferon α-2a, interferon α-2b,interferon ß-1a, and liposomal doxorubicin) were collected. Although 95% of PTs were comparable between the two groups, PTs of deep vein thrombosis, pancreatitis acute, diabetes mellitus, liver disorder, disorientation, aphasia and infection, and SMQ of embolic and thrombotic events were significantly alleviated by PEGylation. No PT was significantly enhanced by PEGylation. CONCLUSION: The pharmacovigilance profiles of PEGylated and non-PEGylated agents were similar. Further clinical assessment is required to validate the pharmacovigilance data.

Evaluation of Concentration Errors and Inappropriate Dose Tailoring of Tacrolimus Caused by Sampling-Time Deviations in Pediatric Patients With Primary Nephrotic Syndrome.

BACKGROUND: Tacrolimus dosing is routinely tailored based on its trough level (C0) drawn by therapeutic drug monitoring in pediatric patients with primary nephrotic syndrome. However, this concentration is often inaccurate owing to inappropriate practice, such as deviation of sampling time (DST). The quantitative relationship between DST and C0 remains unclear. METHODS: Tacrolimus concentration at nominal sampling times (12 hours after last dose) and 32 deviation scenarios (12 ± 4 hours every 15 minutes) was predicted using a previously validated population pharmacokinetic model based on 162 scenarios of 100 primary nephrotic syndrome patients involved in the population pharmacokinetic model and derived virtual patients. Concentration error (CE) and relative CE (RCE) were evaluated, and the correlation between DST and RCE was evaluated by subgroup analysis using linear regression. Ultimately, the inappropriate dosing possibly misled by incorrect C0 was simulated in a real-patient cohort according to the target range (5-10 ng/mL). RESULTS: Approximately 7% of RCE was caused at every 1-hour of DST. DST was the most major contributor of RCE (r = 0.773-0.804). Patients with early sampling, older age, high body weight, high dose, low aspartate transaminase level, high corticosteroid dose, and without combination of azole antifungal agents were revealed to have high RCE. Approximately 7%-36% and 9%-25% of inappropriate dose tailoring may be caused by early and delayed sampling, respectively. In addition, patients with early sampling or high-dose tacrolimus had a higher risk of inappropriate dosing than patients with delayed sampling [hazard ratio = 1.53, 95% confidence interval (CI): 1.03-2.27, P = 0.048], and low-dose tacrolimus (P < 0.0001). CONCLUSIONS: A moderate bias of concentration and dose tailoring was revealed within 4 hours of DST. In addition, a high risk of bias was found in patients with early sampling and high-dose tacrolimus.

Impact of CYP3A4/5 and ABCB1 polymorphisms on tacrolimus exposure and response in pediatric primary nephrotic syndrome.

Aim: To evaluate the impact of CYP3A4*1G, CYP3A5*3 and ABCB1-C3435T polymorphisms on tacrolimus concentrations, efficacy and tolerance in pediatric primary nephrotic syndrome. Methods: Dose-adjusted concentrations (C0/D), daily dose, frequency and time to relapse, cumulative remission days, and adverse reactions in 65 Chinese patients with various genotypes were retrospectively collected and compared. Results: C0/D increased in CYP3A4*1/*1, CYP3A5*3/*3 and CYP3A4*1/*1-3A5*3/*3 diplotype carriers by 38.4, 69.7 and 40.9% compared with CYP3A4*1/*1G, CYP3A5*1/*3 and noncarriers, respectively. Recurrence risks were decreased in CYP3A4*1/*1 (0.43 of hazard ratio to *1/*1G) and CYP3A5*3/*3 carriers (0.43 of hazard ratio to *1/*3). None of polymorphisms was linked to adverse reactions. Conclusion: The genotypes of CYP3A4*1G and CYP3A5*3 rather than ABCB1-C3435T potentially predicted tacrolimus exposure and clinical response in pediatric primary nephrotic syndrome.

Retrospective analysis of tigecycline shows that it may be an option for children with severe infections.

AIM: This study assessed the efficacy and safety of tigecycline in children with life-threatening infections. METHODS: We retrospectively reviewed the clinical records of patients treated with tigecycline from June 2012 to May 2014 in a Chinese tertiary centre. RESULTS: The study comprised 24 patients (14 male) with a median age of four years (range, 50 days-12 years). The most frequently isolated microorganism, most common isolation site and type of infection were Acinetobacter baumannii, tracheal aspirate fluid and ventilator-associated pneumonia, respectively. Tigecycline was administered at a loading dose of 1.5 or 2.0 mg/kg and 1.0 mg/kg every 12 hours after that. The average duration of treatment was 11.6 ± 5.8 days. The clinical response and microbiological eradication rate were 37.5% and 29.2%, respectively. Six of the patients we studied (25.0%) died, and three of these deaths were considered to be infection related. Adverse drug reactions were identified in four patients (16.7%) during the treatment, including abnormal liver function, prolonged prothrombin time and diarrhoea. CONCLUSION: Our findings suggest that tigecycline may be an option for children with severe infections. However, more prospective, controlled trials are required to objectively evaluate the efficacy and safety of tigecycline in children.