Pharmacogenetic implementation for CYP2C19 and pharmacokinetics of voriconazole in children with malignancy or inborn errors of immunity.

BACKGROUND: Voriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19; however, such information is limited for the pediatric population. The primary aim of this study is to establish a voriconazole PK model incorporating CYP2C19 phenotypes in Japanese children with malignancy or inborn errors of immunity. METHODS: CYP2C19 genotypes were assessed by whole-genome genotyping and defined as follows: *17/*17: ultrarapid metabolizer (URM), *1/*17: rapid metabolizer (RM), *1/*1:normal metabolizer (NM), *1/*2, *1/*3, *2/*17:intermediate metabolizer (IM), and *2/*2, *2/*3, *3/*3: poor metabolizer (PM). Population PK analysis was performed. The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination. RESULTS: Voriconazole concentration data were available from 60 patients with a median age of 5.3 years. The phenotypes predicted from CYP2C19 genotypes were RM in 1 (2 %), NM in 21 (35 %) patients, IM in 27 (45 %) patients, and PM in 11 (18 %) patients. Underlying diseases included 38 (63%) patients with hematological malignancy and 18 (30 %) patients with inborn errors of immunity. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of Vmax inhibition [Vmax, inh] = 100 %; Vmax = 0). The estimated parameters of Vmax,inh were +0.8 higher in patients with gamma-glutamyl transpeptidase (γ-GTP) Grade 2 or higher and +2.7 higher when C-reactive protein (CRP) levels were 2.0 mg/dL or higher. CONCLUSION: CYP2C19 genetic polymorphisms, γ-GTP, and CRP affect Vmax,inh of voriconazole in children with malignancy or inborn errors of immunity.

Mechanism of Stent Failure in Patients With Eruptive Calcified Nodule Treated With Rotational Atherectomy.

BACKGROUND: Percutaneous coronary intervention (PCI) for lesions with eruptive calcified nodules (CNs) is associated with worse outcomes compared with that for other calcified lesions. We aimed to clarify the relationship between eruptive CNs at index PCI, optical coherence tomography (OCT) findings at the 8-month follow-up, and clinical outcomes using serial OCT. METHODS: This retrospective observational study used data from a prospective, single-centre registry. We conducted consecutive PCI for calcified lesions requiring rotational atherectomy (RA) with OCT guidance. We categorized 51 patients (54 lesions) into those with (16 patients [16 lesions]) and without eruptive CNs (35 patients [38 lesions]). RESULTS: Post-PCI, stent expansion was comparable between the 2 groups, and CN-like protrusion was found in 75% of lesions with eruptive CNs. Follow-up OCT at 8 months revealed in-stent CNs in 54% of treated eruptive CN lesions, whereas lesions without eruptive CNs lacked in-stent CNs. Multivariate linear regression analysis demonstrated that eruptive CN was associated with maximum neointimal tissue (NIT) thickness (regression coefficient 0.303; 95% confidence interval, 0.057-0.549; P = 0.02). Consequently, patients with eruptive CNs exhibited a higher clinically driven target lesion revascularization (TLR) rate than did those without at 1 year (31.3% vs 2.9%, P = 0.009) and 5 years (43.8% vs 11.4%, P = 0.02). TLR primarily occurred in lesions with maximum eruptive CN arc angles > 180°. CONCLUSIONS: Following RA treatment with acceptable stent expansion, eruptive CNs before PCI correlated with greater NIT formation with in-stent CNs, resulting in a higher TLR rate, particularly in lesions with maximum eruptive CN arc angles exceeding 180°.

Two Cases of Children With Black Hairy Tongue and Tooth Discoloration Caused by Antibacterial Agents.

Black hairy tongue (BHT) is a lesion in which the filiform papillae of the tongue are significantly extended by hyperkeratosis, thereby giving the tongue a hairy appearance. Here, we report two rare cases of children with BHT and tooth discoloration caused by antimicrobial agents. Case 1: A four-year-old female patient received intravenous linezolid after spinal surgery, and BHT developed on day eight of treatment. Subsequently, the patient developed teeth discoloration. Linezolid was continually administered for 50 days, and BHT and teeth discoloration improved 10 days after the end of linezolid treatment. Case 2: A two-year-old male patient with a brain abscess received intravenous meropenem and vancomycin. On the fourth day of treatment, BHT developed, and teeth discoloration was subsequently observed. Antibiotic therapy was continued for 82 days, and BHT and tooth discoloration improved 20 days after the treatment was discontinued.

Establishment of a measurement system to evaluate breast milk transfer of biological agents using dry filter paper: A multi-institutional study.

AIMS: Information on breastfeeding and safety of biologics in infants is lacking due to difficulties in case collection. We evaluated methods for determining the concentration of biologics in breast milk using a dry filter method that can simplify the collection, storage and transport of breast milk. METHODS: To generate dried filter paper (DFP) samples, approximately 30 µL of breast milk was placed onto a Whatman 903 card and punched out. After extraction, the supernatant was measured using an enzyme-linked immunosorbent assay. Three concentrations of each drug were prepared in liquid breast milk (LBM) and DFP samples to determine their stability up to 28 days after storage at 2-8°C or -20°C for LBM and 25 ± 5°C for DFP. LBM and DFP samples were also provided by nursing mothers using biologics during lactation, and drug concentrations in both samples were compared. The agreement between the two measurement methods was confirmed by Bland-Altman analysis. RESULTS: Breast milk was provided by 12 mothers who used biologics (tocilizumab, abatacept, etanercept, golimumab, sarilumab and belimumab). The coefficients of variation for within-run and between-run precision for the six drugs were within 15% for both LBM and DFP, and accuracy was within 90%-110% of the quality controls. After 28 days, concentrations remained at more than 90%. The difference between the values obtained by each method was within the acceptable range of error (-12.1 to +16.6 ng/mL). CONCLUSIONS: A method for determining the concentration of biologics using DFP is expected to help improve pharmacotherapy for lactating women.

Quantitative Investigation on Exposure to Potentially Harmful Excipients by Injection Drug Administration in Children Under 2 Years of Age and Analysis of Association with Adverse Events: A Single-Center, Retrospective Observational Study.

INTRODUCTION: Potentially harmful excipients (PHEs) for children have been reported and the need for information collection has been advocated. However, studies on the actual occurrence of adverse events are limited. This study investigated the quantitative exposure of PHEs via injection and their association with adverse events in children under 2 years of age. MATERIALS AND METHODS: As a single-center observational study, children aged 0-23 months received injectable drugs from April 1, 2018, to March 31, 2023 were included. Information on PHE exposure and adverse events after administration were extracted from medical records. Sodium benzoate, benzyl alcohol, ethanol, glycerol, lactose, polyethylene glycol paraben, polysorbate, propylene glycol, sorbitol, sucrose, sulfite, and thimerosal were selected as PHEs. RESULTS AND DISCUSSION: 6265 cases, 333,694 prescriptions, and 368 drugs (264 ingredients) were analyzed. The median age was 0.63 years (interquartile range [IQR] 0.1-1.1). 72,133 prescriptions, 132 drugs and 99 ingredients contained PHE; 2,961 cases exposed to PHE and 1825 cases exceeding permitted daily exposure. The drug with the highest number of exposure cases was hydroxyzine, and the highest number of prescriptions was heparin (both drugs contain benzyl alcohol). In association between adverse events and PHE exposure, higher doses in cases of adverse event occurrence were found in benzyl alcohol, glycerol, polyethylene glycol, and polysorbate exposed cases. Among thimerosal-exposed cases, "developmental delay" was more frequent in exposed cases, but the causal relationship was unknown. Further investigation is needed to clarify the relationship between adverse events and PHE exposure. Additionally, more precise information on PDE for pediatrics including neonates is necessary.

Study on the Preparation Method of Quality-Assured In-Hospital Drug Formulation for Children-A Multi-Institutional Collaborative Study.

The quality-assured preparation of crushed and diluted preparations for children is a challenge. In this study, a multicenter study was conducted to validate the preparation method for the quality assurance of baclofen powder, clonidine powder, and hydrocortisone powder prepared from tablets according to a previously established method. In-hospital preparations were prepared at five medical facilities under different crushing and mixing conditions. After storage in closed bottles, in-use bottles, and laminated paper for 120 days, ingredients stability, drug elution, and content uniformity after packaging were evaluated. All three ingredients were maintained at between 90% and 110% of their initial content for 120 days under packaging conditions of 25 ± 2 °C and 60 ± 5% relative humidity, with no change in dissolution in all formulations made at all five facilities. The content uniformity was also acceptable. The established method may contribute to quality-assured pediatric dosage form modification.

Drug Formulation for Pediatric Oral Antimicrobial Agents in Japan: Current Status, Prospects, and Challenges.

The development of antibiotics that are acceptable and easy for children to take and use is highly desirable. As advocated by the World Health Organization, solid oral formulations with excellent shelf-life, taste masking and dose adjustment are attracting attention as appropriate pediatric oral antimicrobial formulations, but liquid formulations remain the most common worldwide. Apparently unique to Japan, the most common formulations of oral antimicrobials for pediatric use are dispensed as a powder with most being flavored powders. Powdered formulations are packaged in single doses, which eliminates the need for parents to weigh them before administration and may reduce the possibility of dosage errors. On the other hand, there are some formulations that require large doses of powder due to inappropriate concentrations, granular formulations that have a rough texture that affects palatability, and some formulations that require flavoring agents to mask the bitter taste of the main drug. Such inappropriate formulations have a significant impact on adherence to antimicrobial therapy. It remains unclear whether solid oral dosage forms might be as acceptable worldwide as in Japan. To ensure that appropriate antimicrobials are delivered to children worldwide, a direction for the development of appropriate dosage forms in children needs to be established.

Use of Machine Learning for Dosage Individualization of Vancomycin in Neonates.

BACKGROUND AND OBJECTIVE: High variability in vancomycin exposure in neonates requires advanced individualized dosing regimens. Achieving steady-state trough concentration (C0) and steady-state area-under-curve (AUC0-24) targets is important to optimize treatment. The objective was to evaluate whether machine learning (ML) can be used to predict these treatment targets to calculate optimal individual dosing regimens under intermittent administration conditions. METHODS: C0 were retrieved from a large neonatal vancomycin dataset. Individual estimates of AUC0-24 were obtained from Bayesian post hoc estimation. Various ML algorithms were used for model building to C0 and AUC0-24. An external dataset was used for predictive performance evaluation. RESULTS: Before starting treatment, C0 can be predicted a priori using the Catboost-based C0-ML model combined with dosing regimen and nine covariates. External validation results showed a 42.5% improvement in prediction accuracy by using the ML model compared with the population pharmacokinetic model. The virtual trial showed that using the ML optimized dose; 80.3% of the virtual neonates achieved the pharmacodynamic target (C0 in the range of 10-20 mg/L), much higher than the international standard dose (37.7-61.5%). Once therapeutic drug monitoring (TDM) measurements (C0) in patients have been obtained, AUC0-24 can be further predicted using the Catboost-based AUC-ML model combined with C0 and nine covariates. External validation results showed that the AUC-ML model can achieve an prediction accuracy of 80.3%. CONCLUSION: C0-based and AUC0-24-based ML models were developed accurately and precisely. These can be used for individual dose recommendations of vancomycin in neonates before treatment and dose revision after the first TDM result is obtained, respectively.

Massive pulmonary thrombosis caused by a popliteal venous aneurysm: A case report.

A venous aneurysm is characterized by a localized dilated lesion in most major veins. Popliteal venous aneurysms (PVAs) are rare; however, they are one of the causes of deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE), which can be critical due to the high mortality risk. We present a 21-year-old woman without prior medical history, who arrived by ambulance after having a transient cardio-pulmonary arrest. Contrast computed tomography revealed a massive PTE and a right PVA with a thrombus. Laboratory data suggested that she had no thrombotic predisposition. Therefore, we diagnosed her condition as a massive PTE that derived from a thrombus, which arose from the right PVA. After successful intravenous thrombolysis of the PTE and DVT, surgical plication of the right PVA was performed to prevent the recurrence of PTE. She has had no recurrence of PTE or DVT two years after surgical treatment. This case suggests that surgical plication might be an effective way of preventing recurrence in patients with PVA. Learning objective: Popliteal venous aneurysm (PVA) occurrence is rare, but it can result in deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE). To treat our patient who suffered transient cardiac-pulmonary arrest caused by a massive PTE, we first used a recombinant tissue plasminogen activator and anticoagulant therapy. After the condition was stabilized, surgical plication of the right PVA was performed to prevent DVT recurrence. The present case suggests that surgical plication might be beneficial.

Zinc supplementation in patients with acute myocardial infarction.

This single-centre prospective feasibility study (UMIN000030232) evaluated whether zinc supplementation was safe and effective for improving outcomes among patients with acute myocardial infarction (AMI). Within 24 h after successful primary percutaneous coronary intervention, consenting patients with AMI were randomly assigned 1:1 to receive conventional treatment (conventional treatment group) or conventional treatment plus zinc acetate supplementation (zinc supplementation group). The two groups were compared in terms of major adverse cardiovascular events (MACE), and scar size, which was evaluated using cardiac magnetic resonance imaging (CMR) at 4 weeks after discharge. A total of 56 patients underwent randomization (with 26 assigned to the zinc supplementation group and 27 to the conventional treatment group). The two groups had generally similar laboratory findings and clinical characteristics. The two groups also had similar lengths of hospital stay and rates of MACE. Forty of the 53 patients underwent CMR and it revealed that % core zone was numerically lower in the zinc supplementation group than in the conventional treatment group (9.3 ± 6.9% vs. 14.2 ± 9.1%, P = 0.07). This small single-centre study failed to detect a significant reduction in mid-term MACE after AMI among patients who received zinc supplementation.

Relationship between early drop in systolic blood pressure, worsening renal function, and in-hospital mortality in patients with heart failure: a retrospective, observational study.

This study aimed to determine the optimal cut-off value of the early drop in systolic blood pressure (SBP) for worsening renal function (WRF) in hospitalized patients with heart failure (HF) and analyze predictors of WRF and the early drop in SBP at that threshold. We retrospectively enrolled 396 patients with acute decompensated HF. The early drop in SBP was defined as the difference between baseline and SBP measured 24 h after hospitalization. We performed receiver operating characteristic (ROC) analysis to determine the optimal cut-off value of the early drop in SBP for WRF and evaluated the effect of the early drop in SBP on in-hospital mortality by multivariate logistic regression analyses. The mean age of the patients was 73.4 ± 14.7 years, and 61.2% were men. A 14.0% drop in SBP was identified as the optimal cut-off value for WRF from the ROC curve analysis. An early drop in SBP ≥ 14.0% was associated with WRF in multivariate logistic regression analysis (odds ratio 7.84; 95% confidence interval 4.06-15.14; P < 0.0001). The dose of intravenous furosemide within 24 h of admission was one of the predictors of the early drop in SBP ≥ 14.0%, while no early drop in SBP was a predictor of in-hospital mortality in multivariate logistic regression models. In conclusion, the optimal cut-off value for WRF in patients with HF was a 14.0% drop in SBP within 24 h of admission. The early drop in SBP ≥ 14.0% was one of the predictors of WRF in patients with HF. However, no early drop in SBP was associated with in-hospital mortality. This study was registered with the University Hospital Medical Information Network in Japan (UMIN000035989).

Investigation on the Usefulness of Sulfamethoxazole Trimethoprim Combination Small Tablets in Pediatric Pharmacotherapy: A Single Center Observational Study Using a Questionnaire.

Sulfamethoxazole trimethoprim (ST) combinations are used to prevent infection in immunocompromised patients. In pediatric patients, conventional ST combination tablets (cTab) are large and granules are not preferred due to their rough and bitter taste in the mouth. Since a new formulation of smaller tablets (sTab, 1 cTab = 1-gram granules = 4 sTab) was approved, a study regarding the usability of sTab in pediatric patients was conducted. Children who started taking sTab of the ST combination at our hospital between August 2021 and August 2022 were included. Using an anonymous questionnaire, the dosage of ST combinations, the child's response (3-point visual scale: positive, neutral, or negative), preparation and administration time, and method of taking the drug were asked. Twenty-two patients (median age: 11.0 years) receiving cTab. Median (range) number of tablets per dose was 1 (0.5-1.5) tablet, and was 4 tablets (1.0-4.0) after switching to sTab. Twenty patients (median age: 5.0 years) receiving granules. Median (range) single dose was 0.75 (0.2-2.0) gram, and was 2.0 (1.0-4.0) tablets after switching to sTab. Post-dose reactions were positive in 5, neutral in 7, and negative in 10 cases for cTab, and positive in 1, neutral in 7, and negative in 12 cases for granules. After switching to sTab, 9, 13 and 0 cases, and 10, 9 and 1 cases were positive, neutral, and negative, respectively. Median preparation and administration times were decreased after switching to sTab in both cTab and granules groups. The frequency of dosage manipulations was also decreased. The switch to sTab improved acceptability, and decreased burden of administration, suggesting that sTab is a user-friendly formulation in pediatric medications.

Transfer of Zolpidem to Cord Blood and Breast Milk: A Case Series Evaluating Zolpidem Serum Levels and Outcomes in Birth and Suckling Infants.

Background: Zolpidem is used for insomnia in pregnant and lactating women. Although zolpidem has been shown to cross the placenta and to be secreted into breast milk, it would not be expected to cause any adverse effects in newborn and breastfed infants. However, there is no relevant information on serum zolpidem levels in the newborn and breastfed infant from zolpidem-treated mother. This study aimed to present the outcomes of zolpidem exposure into infant who was delivered or breastfed by a zolpidem-treated mother. Methods: In this case series, zolpidem-treated pregnant women were recruited between September 2019 and April 2022, and maternal serum, cord blood, breast milk, and infants' serum were collected, and the zolpidem concentration in each sample was evaluated. Childbirth outcomes, including 1-month health care checkup, were also evaluated. Results: Three cases were recruited during investigation period. No spontaneous abortion or preterm live deliveries occurred. Oxygen intervention was required in one term infant, but the findings resolved on postpartum day 1. No medical intervention was required in other three infants. Zolpidem was not detected in infants' serum even after breastfeeding. There are no abnormal developmental findings in any of the infants in their 1-month health checkups. Conclusions: Zolpidem transferred into fetal circulation in utero and breast milk, however no harmful findings existed in infants during pregnancy and lactation. Exposure doses through breastfeeding is small, which may be a cause of rare detection from the infants' serum. Due to the limited number of cases, larger studies and integrated review are needed.

Stability Study of Baclofen in an Oral Powder Form Compounded for Pediatric Patients in Japan.

Baclofen is used as a skeletal muscle relaxant for multiple sclerosis patients and pediatric patients with cerebral palsy and is prescribed to pediatric patients at 0.3 to 1.0 mg/kg/dose. Baclofen tablets, an oral drug, are usually administered as a powder in pediatric wards after a formulation change by the pharmacist. However, there is no information about stability and assurance of quality for compounded products. The purpose of this study was to design a 10 mg/g oral powder of baclofen and to investigate the stability and changes in the physical properties of this compounded product. A 10 mg/g baclofen powder was prepared by adding extra-fine crystal lactose hydrate to crushed and filtrated baclofen tablets and was stored in a polycarbonate amber bottle with desiccant or in a coated paper laminated with cellophane and polyethylene. The stability of baclofen at 25 ± 2 °C/60 ± 5%RH was tested for 120 days in 'bottle (closed)', 'bottle (in use)', and 'laminated' storage conditions. Baclofen concentrations ranged from 90.0% to 110.0% of the initial concentration under all storage conditions. No crystallographic or dissolution changes were observed after storage. This information can help with the management of baclofen compounded powder in pharmacies.

Ustekinumab during pregnancy and lactation: drug levels in maternal serum, cord blood, breast milk, and infant serum.

BACKGROUND: Patients with ulcerative colitis (UC) may be concerned about medication safety during preconception, pregnancy, and lactation, and they should be closely followed up to ensure that UC activity is controlled during the perinatal period. Reported information on the safety of ustekinumab during pregnancy and lactation is limited. In this case report, we examined the safety of ustekinumab in a fetus and breastfed infant with reference to drug concentrations in maternal serum, cord blood, breast milk, and infant serum. CASE PRESENTATION: A 36-year-old female who developed hematochezia and was diagnosed with ulcerative colitis at age 24 was pregnant with her first child. During pregnancy she was treated with subcutaneous bimonthly ustekinumab, at a dose of 90 mg, until 29 weeks of gestation. Her ulcerative colitis symptoms remained in remission. At 38 weeks of gestation she underwent cesarean section and delivered a healthy female infant weighing 3043 g and with no congenital malformations. The infant received routine vaccinations with no adverse events. Ustekinumab treatment was resumed at 7 weeks postpartum. The ustekinumab concentration in maternal serum at 12 days after injection (30.7 weeks of gestation) was 7968.5 ng/mL, and it decreased to 106.1 ng/mL at 114 days after the last dose. In cord blood, the ustekinumab concentration was 1131.2 ng/mL at 65 days after the last dose; this was 2.5 times higher than that in the maternal serum, which was consistent with a previous report. Ustekinumab was detected in infant serum collected at 71 days after the last maternal dose (299.0 ng/mL), with rapid elimination from the infant's body. In breast milk, the maximum ustekinumab concentrations were 13.6 ng/mL at 9 days after the last maternal dose, respectively. The ratio of the calculated areas under the time-concentration curves of ustekinumab in breast milk and maternal serum was 0.0008 (257.1/327632.7), which was comparable with a previous human study. CONCLUSION: The placental transfer and breast milk secretion of ustekinumab in our case were comparable with previous reports. Use of ustekinumab during pregnancy and lactation was feasible in this case. Further research is needed to clarify the safety of ustekinumab during pregnancy and lactation.

Current Aspects of Pediatric Pharmacokinetics and Pharmacodynamics of Antimicrobials in Japan: Importance of the Promotion of Population PK/PD Analysis.

Pharmacologic knowledge is important for pediatricians conducting feasible pharmacokinetic or pharmacodynamic (PK/PD) studies or applying effective antimicrobial therapies in children. Because of the difficulties in conducting PK/PD studies in children, antimicrobial PK/PD data in children are still limited. To fill in the lack of knowledge, promotion of population PK/PD analysis, which allows us to handle sparse sampling data from individual patients, is important because it is considered a suitable methodology to conduct PK/PD studies in children with limited blood drug concentration data for PK/PD analysis. Population PK/PD analysis is also useful in the clinical setting to provide individualized optimal dosage for each patient with various conditions. Here we summarized the current aspects of pediatric PK/PD studies of antimicrobials in Japan from clinical and research perspectives, specifically focusing on the importance of population PK/PD analysis.

Grid-mapping catheters versus PentaRay catheters for left atrial mapping on ensite precision mapping system.

INTRODUCTION: Areas displaying reduced bipolar voltage are defined as low-voltage areas (LVAs). Moreover, left atrial (LA) LVAs after pulmonary vein isolation (PVI) have been reported as a predictor of recurrent atrial fibrillation (AF). In this study, we compared grid mapping catheter (GMC) with PentaRay catheter (PC) for LA voltage mapping on Ensite Precision mapping system. METHODS: Twenty-six consecutive patients with LVAs and border zone within the LA were enrolled. After achieving PVI, voltage mapping under high right atrial pacing for 600 ms was performed twice using each catheter type (GMC first, PC next). Furthermore, LVA was defined as a region with a bipolar voltage of <0.50, and border zone was defined as a region with a bipolar voltage of <1.0, or <1.5 mV. RESULTS: Compared with PC, using GMC, voltage mapping contained more mapping points (20 242 [15 859, 26 013] vs. 5589 [4088, 7649]; p < .0001), and more mapping points per minute(1428 [1275, 1803] vs. 558 [372, 783]; p < .0001). In addition, LVA and border zone size using GMC was significantly less than that reported using PC: <1.0 mV (5.9 cm2 [2.9, 20.2] vs. 13.9 cm2 [6.3, 24.1], p = .018) and <1.5 mV voltage cutoff (10.6 cm2 [6.6, 27.2] vs. 21.6 cm2 [12.6, 35.0], p = .005). CONCLUSION: Bipolar voltage amplitude estimated by GMC was significantly larger than that estimated by PC on Ensite Precision mapping system. GMC may be able to find highly selective identification of LVAs with lower prevalence and smaller LVA and border zone size.

The Current States, Challenges, Ongoing Efforts, and Future Perspectives of Pharmaceutical Excipients in Pediatric Patients in Each Country and Region.

A major hurdle in pediatric formulation development is the lack of safety and toxicity data on some of the commonly used excipients. While the maximum oral safe dose for several kinds of excipients is known in the adult population, the doses in pediatric patients, including preterm neonates, are not established yet due to the lack of evidence-based data. This paper consists of four parts: (1) country-specific perspectives in different parts of the world (current state, challenges in excipients, and ongoing efforts) for ensuring the use of safe excipients, (2) comparing and contrasting the country-specific perspectives, (3) past and ongoing collaborative efforts, and (4) future perspectives on excipients for pediatric formulation. The regulatory process for pharmaceutical excipients has been developed. However, there are gaps between each region where a lack of information and an insufficient regulation process was found. Ongoing efforts include raising issues on excipient exposure, building a region-specific database, and improving excipient regulation; however, there is a lack of evidence-based information on safety for the pediatric population. More progress on clear safety limits, quantitative information on excipients of concern in the pediatric population, and international harmonization of excipients' regulatory processes for the pediatric population are required.

Serum and cerebrospinal fluid acyclovir pharmacokinetics in a neonate with HSV-2 meningoencephalitis.

A neonatal patient with Herpes simplex virus type-2 meningoencephalitis was treated by high-dose intravenous acyclovir therapy. Serum and cerebrospinal fluid (CSF) concentrations were measured retrospectively, showing that the CSF-to-serum concentration ratio was 0.67-0.71, which was higher than the previously reported values in other age groups.