BACKGROUND:Several studies have suggested that naldemedine may reduce opioid-induced constipation (OIC) as well as opioid-induced nausea and vomiting (OINV). This study aimed to investigate prophylactic effects of naldemedine on OINV in patients initiating regular, oral, strong opioids for cancer pain. METHODS:In this preplanned secondary analysis of a multicenter, double-blind, randomized, placebo-controlled trial investigating the preventive effects of naldemedine on OIC, eligible patients were randomized in a 1:1 ratio to receive either naldemedine 0.2 mg or placebo once daily for 14 days. The primary endpoint was the complete response (CR) rate, defined as the proportion of patients with no vomiting episodes and no use of rescue antiemetics within the first three days of opioid initiation. The secondary endpoint was the nausea and vomiting score of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 Palliative Care (EORTC QLQ-C15-PAL). RESULTS:Of the 103 patients, 48 and 47 patients in each group started protocol treatment, respectively. The CR rate was significantly higher in the naldemedine group than in the placebo group (81.3% vs 38.3%, P < .001). Nausea and vomiting scores on the QLQ-C15-PAL at weeks 1 and 2 were significantly better in the naldemedine group (means 7.1 and 6.4) versus placebo (means 44.6 and 35.3; both P < .001). Within the total effect of naldemedine on the QLQ-C15-PAL nausea and vomiting scores at week 2, the proportion mediated through OIC reduction was 21.9%. CONCLUSIONS:Naldemedine may have intrinsic antiemetic potency to prevent both OIC and OINV. TRIAL REGISTRATION:https://jrct.niph.go.jp/ (Japan Registry of Clinical Trials) Identifier: jRCTs031200397.

Although venlafaxine has shown efficacy for hot flashes in hormone receptor–positive breast cancer, evidence in Asian women (especially premenopausal) remains limited. Hot flashes reduce endocrine therapy adherence and severity may increase with ovarian suppression. We conducted a prospective, single-arm, open-label study to evaluate the efficacy and safety of venlafaxine in tamoxifen-treated patients with moderate-to-severe hot flashes. Twenty patients received venlafaxine at 37.5 mg/day for 4 weeks, with optional escalation to 75 mg/day. Weekly hot flash scores, adverse events, and serum concentrations of tamoxifen, its metabolites, and venlafaxine (as well as CYP2D6 genotype associations) were assessed. Of the 20 patients, 17 were included in the primary efficacy analysis, 20 in the safety population for adverse events, and 18 in the pharmacokinetic analysis. At Week 4, hot flash scores declined by 49.8

AIM:Eltrombopag, a thrombopoietin receptor agonist for aplastic anaemia, can cause hepatotoxicity. It is metabolized by uridine diphosphate-glucuronosyltransferase (UGT) 1A1 to form an acyl glucuronide metabolite; however, the relationships among serum concentrations of the acyl glucuronide metabolite, UGT1A1 genotypes and hepatotoxicity remain unclear. METHOD:We examined the serum concentrations of eltrombopag and its acyl glucuronide metabolite, UGT1A1 genotypes and occurrence of hepatotoxicity (abnormal liver function tests or drug-induced liver injury [DILI]) in 104 samples from 42 patients with aplastic anaemia receiving eltrombopag. RESULTS:The concentrations of eltrombopag and its acyl glucuronide metabolite were significantly higher in samples with abnormal liver function than in those with normal liver function (23.0 ± 18.5 vs. 10.6 ± 9.3 μg/mL and 6.9 ± 4.5 vs. 2.1 ± 1.2 μg/mL, respectively). Receiver operating characteristic (ROC) analysis demonstrated that the concentration of the acyl glucuronide metabolite provided superior predictive accuracy for hepatotoxicity, with a threshold of 4.0 μg/mL, compared with eltrombopag (area under the ROC curve, 0.83 vs. 0.68). All patients with DILI had higher concentrations of the acyl glucuronide metabolite than the cutoff value. The incidence of hepatotoxicity differed across UGT1A1 genotype: 43% in extensive metabolizers (EMs), 11% in intermediate metabolizers (IMs) and none in poor metabolizers (PMs). The formation of the acyl glucuronide metabolite was 1.5-fold greater in EMs than in IMs/PMs. CONCLUSION:These findings suggest that eltrombopag-induced hepatotoxicity is dependent on the concentration of eltrombopag acyl glucuronide and influenced by UGT1A1 genotype, highlighting the potential utility of serum acyl glucuronide monitoring and UGT1A1 genotyping for preventing and managing the hepatotoxicity.

Glycyrrhetinic acid (GA) and glycyrrhizin (GL), active ingredients derived from Glycyrrhiza, Glycyrrhizae Radix (The Japanese Pharmacopia), exhibit various pharmacological effects, such as anti-inflammatory and anti-allergic activities, and a side effect of licorice-induced pseudoaldosteronism. GA is also produced as a metabolite of GL in gastrointestinal bacterial flora when Glycyrrhiza-containing Kampo medicines are orally administered. The present study aimed to confirm that a galacturonic-glycyrrhizin (gala-GL), an analog of GL contained in Glycyrrhiza, contributes to gastrointestinal GA production as well as GL. Gala-GL was hydrolyzed to GA by the intestinal flora, although the hydrolysis rate was slower than that of GL. This is the first report to reveal hydrolyzation of gala-GL into GA in the intestinal flora. The gala-GL content in the 16 Kampo extracts containing 1.0-4.0 g/daily dose of Glycyrrhiza and 8 commercially available Shakuyakukanzoto (SKT) products containing 2.0-4.8 g/daily dose of Glycyrrhiza were 2.2-9.5 and 2.9-7.2 mg/daily dose, respectively. The gala-GL contents corresponded to 7.3-10.9% and 8.0-9.4% of the total GL contents (sum of GL and gala-GL) for the Kampo extracts and SKT products, respectively. These results suggest that gala-GL also can be as sources of gastrointestinal GA, although the contents in Glycyrrhiza-containing Kampo medicines and the hydrolytic rate of conversion to GA in intestinal bacterial flora were much smaller than those of GL.

This case demonstrates an inverse relationship between serum carbamazepine concentration and the prothrombin time-international normalized ratio (PT-INR) adjusted for the warfarin dose. The concomitant use of sodium valproate further contributes to an unstable PT-INR, emphasizing the importance of careful and continuous monitoring of anticoagulant effects.

Venetoclax (VEN) combined with azacitidine (AZA) or low-dose cytarabine (LDAC) has significantly improved outcomes for older patients with acute myeloid leukemia (AML). However, severe cytopenia often leads to treatment interruptions. Previous literature has reported that Asian patients tend to have higher plasma VEN concentrations and are more prone to severe neutropenia. We hypothesized that VEN pharmacokinetics (PK) influence these adverse events in the Japanese population. In a prospective observational study (UMIN000047371) involving 76 patients, we monitored VEN PK (trough, maximum plasma concentration, and area under the plasma concentration-time curve from 0 to 12 hours [AUC0-12]). Our analysis of an 81-sample PK data set revealed that samples taken 6 hours after VEN dose offered the best correlation to AUC0-12 (r = 0.945). Importantly, in patients who achieved composite complete remission, a positive correlation was found between the duration of grade 3 neutropenia and VEN AUC0-12 (r = 0.338; P = .028). We further investigated potential factors influencing VEN PK and neutropenia, specifically considering tumor burden and renal function. Samples from patients with pretreatment white blood cell (WBC) counts of <3000/μL and an estimated glomerular filtration rate (eGFR) of <60 mL/min exhibited significantly higher VEN AUC0-12 levels (P = .037) than other groups. These patients also demonstrated a significantly more extended period of grade 3 neutropenia (P = .037). These results suggest that VEN PK could be crucial for predicting neutrophil recovery after VEN-containing regimens in AML. Specifically, patients with low pretreatment WBC counts and low eGFR may represent a risk factor for higher VEN concentrations and, consequently, prolonged neutropenia.

BACKGROUND:Hand-foot syndrome (HFS) is a common adverse event associated with lenvatinib treatment. Lenvatinib dose adjustment using therapeutic drug monitoring may be beneficial in the management of HFS, as symptoms improve with dose reduction or treatment interruption. The serum lenvatinib levels were monitored in a patient with lenvatinib-induced HFS. CASE PRESENTATION:A 74-year-old woman was administered lenvatinib (24 mg/d) for papillary thyroid cancer. Although lenvatinib was withheld several times owing to the occurrence of HFS, the severity of the HFS was controlled to within grade 1 by reducing the dose to 4 mg/d. The lenvatinib dose was subsequently increased to 8 mg/d owing to the progression of lung metastases, resulting in increased HFS severity. The association between serum lenvatinib levels and the severity of HFS was examined in this case: serum lenvatinib levels were higher in grade 2 HFS than in grade 1 HFS (median 42.1 vs. 22.5 ng/mL; P < 0.05). CONCLUSIONS:This case's findings suggest that serum lenvatinib concentrations are associated with the severity of lenvatinib-induced HFS and that there may be an overlap between drug concentrations, metastatic suppression, and the grade of HFS.

The bleeding risk associated with dabigatran etexilate (DABE) dosing remains unclear in patients undergoing catheter ablation for atrial fibrillation (AF) because these patients were excluded from the pivotal clinical trial of DABE. This study aimed to evaluate the bleeding risk factors in patients undergoing catheter ablation for AF with anticoagulant therapy using DABE. A retrospective cohort study included 343 patients who underwent catheter ablation with minimally interrupted DABE dosing (n = 167), where only the morning dose was withheld, or with uninterrupted dosing (n = 176), in adherence to the recommended dose reduction criteria. Bleeding events were assessed for 2 d following catheter ablation. Multivariable logistic regression analysis was performed to identify the bleeding risk factors. Bleeding events were observed in 45 (13.1%) patients. Multivariable analysis revealed that concomitant P-glycoprotein inhibitor use was significantly associated with bleeding events (odds ratio, 2.77; 95% confidence interval, 1.40-5.51; p = 0.004), after adjusting for moderate renal impairment. Among patients with uninterrupted DABE dosing, bleeding events occurred more frequently in concomitant users of P-glycoprotein inhibitors than in non-users (32.4 vs. 9.8%, p = 0.002). However, no significant difference was found among those with minimally interrupted dosing (18.2 vs. 10.4%, p = 0.24). Concomitant P-glycoprotein inhibitor use is a significant bleeding risk factor in patients undergoing catheter ablation with DABE. The increased bleeding risk associated with concomitant P-glycoprotein inhibitor use is more pronounced in patients with uninterrupted DABE dosing. Uninterrupted DABE dosing should be employed cautiously in patients using P-glycoprotein inhibitors.

AIM:Neonatal withdrawal syndrome is characterized by withdrawal symptoms in neonates because of the discontinuation of transplacental drug transfer after delivery. This study aimed to examine the risk factors for withdrawal symptoms to clarify the impact of the number of neuropsychiatric drugs administered during pregnancy. METHODS:This was a retrospective observational study including 344 neonates born to 341 mothers receiving neuropsychiatric drugs, including antipsychotics, antidepressants, antiepileptics, and anxiolytics/sedatives during pregnancy. The presence of withdrawal symptoms was assessed using the Isobe score, comprising 15 symptoms. Multivariable logistic regression analysis was performed to identify significant risk factors for the presence of withdrawal symptoms. RESULTS:Withdrawal symptoms developed in 178 (51.7 %) neonates. The frequency of neonates with withdrawal symptoms was higher in neonates born to mothers receiving ≥3 neuropsychiatric drugs compared to those born to mothers receiving 1-2 neuropsychiatric drugs (73.2 % vs. 45.0 %; P < 0.001). By multivariable logistic regression analysis, the presence of withdrawal symptoms was associated with the concurrent use of ≥3 neuropsychiatric drugs during pregnancy (adjusted odds ratio, 2.24; 95 % confidence interval, 1.09-4.62; P = 0.029) and the maternal use of antipsychotics (adjusted odds ratio, 1.77; 95 % confidence interval, 1.06-2.94; P = 0.028). CONCLUSIONS:The concurrent use of ≥3 neuropsychiatric drugs during pregnancy and the maternal use of antipsychotics were significant risk factors for the presence of withdrawal symptoms.

BACKGROUND:The administration of eltrombopag, used to restore low blood count, demonstrates a positive interference of blood bilirubin levels when analyzed through the diazo assay. However, research on bilirubin measurements using other methods is limited. Therefore, using an enzymatic assay, this study aimed to investigate the effect of serum eltrombopag on bilirubin measurements in patients with aplastic anemia. It further assessed the concentration-dependent effect of eltrombopag on bilirubin measurements using enzymatic and vanadate oxidation assays. METHODS:Total and conjugated bilirubin concentrations measured using an enzymatic assay and serum eltrombopag concentrations were examined in 227 serum samples collected from 30 patients with aplastic anemia receiving eltrombopag. Eltrombopag-spiked samples were analyzed using the enzymatic and vanadate oxidation assays for total and conjugated bilirubin to determine its concentration-dependent effects. RESULTS:A strong positive correlation was observed between total bilirubin and serum eltrombopag concentrations in patients receiving eltrombopag ( r = 0.820). However, the correlation between conjugated bilirubin and serum eltrombopag concentrations was weaker ( r = 0.413). In eltrombopag-spiked serum samples, the enzymatic assay showed significant false elevation of total bilirubin concentrations at ≥6.0 mcg/mL; no interference with conjugated bilirubin measurements was observed. The vanadate oxidation assay showed mild positive biases of 0.2 and 0.1 mg/dL for total and conjugated bilirubin concentrations, respectively, at a high eltrombopag concentration (50 mcg/mL). CONCLUSIONS:Eltrombopag causes clinically significant concentration-dependent interference in total blood bilirubin, but not in conjugated bilirubin measurements through the enzymatic assay in patients with aplastic anemia. The vanadate oxidation assay may be used as an alternative to measure total blood bilirubin when the eltrombopag concentration is below 50 mcg/mL.

AIMS:Vascular endothelial growth factor (VEGF)-A binding to VEGF receptor (VEGFR)2 promotes tumour angiogenesis and progression. Proton pump inhibitors (PPIs) upregulate VEGF-A expression in various cancers. This study examined the association between concomitant PPI use and survival outcomes in patients with advanced gastric cancer (AGC) receiving ramucirumab, a VEGFR2-targeting monoclonal antibody, plus paclitaxel (PTX) or nab-paclitaxel (nab-PTX). The impact of PPI use on serum VEGF-A concentrations was also evaluated. METHODS:This retrospective study included 152 patients with AGC receiving ramucirumab plus PTX/nab-PTX as a second-line therapy. Progression-free survival (PFS) was compared between PPI and non-PPI users. Multivariate Cox proportional hazards analysis was used to assess the prognostic factors for PFS. Serum VEGF-A concentrations were measured in blood samples from 25 patients at baseline and on Day 14 following the first ramucirumab infusion. RESULTS:Median PFS was 3.7 months (95% confidence interval [CI]: 2.8-4.7) for PPI users and 4.7 months (95% CI: 4.0-5.3) for non-PPI users (hazard ratio [HR]: 1.44; 95% CI: 1.01-2.06; P = 0.040). Multivariate analysis, adjusted for age, the Glasgow prognostic score, total gastrectomy and massive ascites, identified PPI use as a prognostic factor for PFS (HR: 1.48; 95% CI: 1.02-2.14; P = 0.038). Serum VEGF-A concentrations were higher in PPI users than in non-PPI users at baseline and during ramucirumab therapy. CONCLUSIONS:Concomitant PPI use was associated with shorter PFS in patients with AGC receiving ramucirumab plus PTX/nab-PTX, likely due to elevated serum VEGF-A concentrations during treatment.

Abstract Background Neonatal abstinence syndrome (NAS) is characterized by withdrawal symptoms in neonates because of the discontinuation of transplacental drug transfer after delivery. Although the use of neuropsychiatric drugs in pregnant women is associated with the onset of NAS (Kanemura, 2020), it remains unclear which types of and how many neuropsychiatric drugs are the risk for NAS. Aims & Objectives The aim of this study is to investigate the type and number of neuropsychiatric drugs in pregnant women in association with onset of NAS. Method Three hundred sixteen mothers who were receiving neuropsychiatric drugs (antipsychotics, antidepressants, antiepileptics, anxiolytics/sedatives) during the pregnancy and their 320 neonates were investigated in University of Tsukuba Hospital during January 2016 to December 2022. NAS was assessed by Isobe score using the checklist for 15 withdrawal symptoms (Kanemura, 2020). Multivariate logistic regression analysis was used to evaluate the relationship between maternal and neonatal background factors, and withdrawal symptoms. This study was approved by the Ethics Committee of the University of Tsukuba Hospital. Results The mothers were receiving one (n=169, 53%), two (n=86, 27%), and three or more neuropsychiatric drugs (n=65, 20%) (a maximum, seven drugs). One hundred sixty-three neonates developed withdrawal symptoms 1-10 days after delivery. The incidence of withdrawal symptoms depended on the number of neuropsychiatric drugs during the pregnancy. Significant difference was observed in the incidence of withdrawal symptoms between one or two drugs (45%) and three or more drugs (74%) (P<0.001). The mean Isobe scores also increased with the number of neuropsychiatric drugs: 1.0 in one drug, 1.4 in two drugs, 2.5 in three drugs, and 2.6 in four or more drugs. Multivariate logistic regression analysis revealed that the onset of withdrawal symptoms was associated with the use of three or more neuropsychiatric drugs during the pregnancy (adjusted odds ratio [95% confidence interval]: 2.40 [1.08-5.32], P=0.03) and primiparity (1.74 [1.08-2.80], P=0.02). In contrast, the type of neuropsychiatric drugs was not a significant risk factor for the onset of withdrawal symptoms: 1.64 [0.96-2.80] for antipsychotics, 1.59 [0.95-2.67] for antidepressants, and 0.93 [0.53-1.65] for anxiolytics/sedatives. Discussion & Conclusion The onset of neonatal withdrawal symptoms was associated with the use of three or more neuropsychiatric drugs, regardless the type of pharmacological effects, during the pregnancy. It is considered that concurrent use of multiple neuropsychiatric medications in pregnant women is a risk factor for NAS. References [1]Kanemura, A et al. (2020). Evaluation of neonatal withdrawal syndrome in neonates delivered by women taking psychotropic or anticonvulsant drugs: A retrospective chart review of the effects of multiple medications and breastfeeding. European Journal of obstetrics, gynecology, and reproductive biology, 254, 226–230.

Objective To assess the role of prostaglandin E2 (PGE2) by measuring blood prostaglandin E2 metabolite (PGEM) concentrations in preterm infants with patent ductus arteriosus (PDA). Study design A prospective observational study of preterm infants born before 32 weeks of gestational age (GA) was performed in a single tertiary hospital in Japan. Blood samples were collected to measure serum concentrations of PGEM, ibuprofen (IBU), and cytokines. Multiple regression analyses assessed associations between blood PGEM levels and perinatal factors, development of hemodynamically significant PDA (hsPDA), and IBU treatment response of hsPDA. Results Seventy-nine infants (median GA 28 weeks) were enrolled in this study. Forty-seven received IBU for hsPDA treatment 1 d after birth in median. PDA closure occurred in 25 infants after a single IBU treatment. Serum PGEM concentrations were associated with histological chorioamnionitis (p <0.01), but not with GA, respiratory distress syndrome, or serum IL-6 concentrations. Serum PGEM concentrations decreased after initial IBU treatment; however, they were not associated with hsPDA development (p = 0.39). IBU concentrations correlated with IBU treatment response (aOR 1.29, p <0.01). However, pre-IBU serum PGEM levels and PGEM reduction ratio did not (p = 0.13, 0.15, respectively). Conclusions Serum PGEM concentrations in preterm infants were associated with maternal histological chorioamnionitis, but not hsPDA development. IBU treatment response was associated with higher blood IBU concentrations, but not PGEM concentrations.

To the Editor: We read with great interest the recent article by Saito et al., who developed a method to quantify six biologic agents in dried milk spots.1 The study provides new insights into the pharmacokinetic properties of these biologics. It also provides clinically important information for their safe use. Our comments on the paper include the following four points. First, we believe that additional data on analyte stability in the filter paper are required to interpret the results. As the authors stated that the dried milk spot samples were transported by regular mail, an additional stability test under extreme conditions2 should have been performed to improve the reliability of the quantification results. We found that dried filter paper samples are exposed to temperatures >30°C during postal transport in Japan3; however, the authors did not perform stability tests under this condition. The resulting data from such tests would be critical for interpreting the drug concentrations in dried milk spots obtained in the study because high-temperature and high-humidity conditions can cause degradation of the analytes in the filter paper.4 In this context, the selectivity of the analytical method should be further evaluated. Enzyme-linked immunosorbent assay (ELISA) is a standard method for quantifying the concentrations of biologics in human serum and plasma. As the application of ELISA for monitoring the concentrations of compounds in breast milk is still limited, a careful validation process is required. We believe that testing the integrity of the analytes (i.e., whether they are intact or fragmented) extracted from breast milk would provide new insights into predicting the effects of biologics on breastfed infants. Our second comment is related to the conclusions drawn from the study. The authors concluded that “this might help collect information on the concentrations of drugs in breastfed infants”1; however, they did not measure the drug concentrations in the infants' blood. As discussed in the article, biologic agents are generally extensively digested in the gastrointestinal tract after oral administration. One study in which 152–1120 mg/day of immunoglobulin G (IgG) solution was administered orally to low-birth-weight infants reported that the serum IgG levels on day five after therapy initiation were 67% to 106% of the pretreatment levels,5 suggesting that a negligible amount of IgG from breast milk can be absorbed by the gastrointestinal tract of infants. The highest concentration of biologics in breast milk observed in Saito et al.’s study was approximately 200 ng/mL (in Case 3).1 Assuming that the infants' feed volume and body weight were 150 mL/kg/day6 and 5 kg, respectively, the amount of these agents ingested through breast milk was calculated to be 150 μg/day, which is at least less than 1/1000 of that reported in the other study.5 The authors cited a study by Goonatilleke et al.7 to discuss the absorption of monoclonal antibodies through the gastrointestinal tract of infants. However, Goonatilleke et al.7 reported that the IgG concentrations in breast milk remained constant throughout lactation (from colostrum to 24 weeks) and discussed the physiological role of immunoglobulins in infants. It should be noted that these findings do not support the intestinal absorption of IgG antibodies or biologics. In contrast, another study reported that tocilizumab was undetectable in the serum of a breastfed infant immediately after maternal administration of tocilizumab and at 22.9 and 28 days after the last administration.8 These results suggest that the absorption of biologics from breast milk in infants is likely negligible. However, we believe that the strength of Saito et al.'s study1 is that it provides valuable data for the rational use of biologics during lactation, along with previous reports, which have revealed that the milk-to-serum concentration ratio of tocilizumab ranges from 0.00045 to 0.0015.8-10 Third, as shown in fig. 3 of Saito et al.'s article, relatively large fluctuations were observed at some time points in Cases 1, 4–7, and 9 compared to the within-run variability reported in their tab. 1. The authors stated that the homogeneity of the dried spots was not sufficiently evaluated. In addition, the components of breast milk showed inter- and intra-variability.7 We suggest that the effects of these factors be evaluated before future clinical applications. Finally, the authors compared the drug concentrations between dried and liquid breast milk specimens by using a single Bland–Altman plot based on pooled data from patients treated with different drugs. The assay performance of the measurement method would vary among the drugs studied. Therefore, this analysis should be performed separately for each drug. In conclusion, further analytical validation and careful evaluation of the clinical relevance of monitoring concentrations of biologics in breast milk are required to apply the method established by Saito et al.1 in future clinical trials or clinical practice. All authors declare that they have no conflict of interest regarding this manuscript.

Hepatitis B virus reactivation (HBV-R) is a serious concern during cancer chemotherapy in patients with resolved HBV infection. We examined the levels of HBV surface (HBsAb) and core antibodies (HBcAb) to assess the incidence of HBV-R in patients with solid and hematopoietic cancers. Retrospective cohort study was conducted in 590 patients with resolved HBV infection. The patients consisted of solid (n = 466) and hematopoietic cancers (n = 124), including lymphoma receiving rituximab-containing chemotherapy. The incidenceof HBV-R was evaluated 761.5 (range, 4–3,898) days after the start of chemotherapy. Of 590 patients, 13 (2.2%) developed HBV-R after the start of chemotherapy. All HBV-R patients exhibited a lower HBsAb (<100 mIU/mL) at baseline. A higher HBcAb (≥100 C.O.I.) was identified as a risk factor for HBV-R,with an incidence of 9.6%. The simultaneous presence of HBsAb <100 mIU/mL and HBcAb ≥100 C.O.I. increased the risk of HBV-R by 18.5%. Patients treated with rituximab-containing chemotherapy had a higher risk of HBV-R (18.4%) despite having HBcAb <100 C.O.I. Our results indicate that baseline levels of HBsAb <100 mIU/mL and HBcAb ≥100 C.O.I are risk factors for HBV-R, except for the patients receiving chemotherapy containing rituximab.

Ceftriaxone (CTRX) is a commonly used cephalosporin antibiotic. It is suggested that monitoring plasma/serum concentrations is helpful for its safe use. This study aimed to develop and validate an analytical method for measuring CTRX concentrations in human serum according to International Conference on Harmonization guideline M10. Ten microliters of serum sample was purified using a salting-out assisted liquid-liquid extraction procedure with magnesium sulfate. The upper layer was then diluted threefold and analyzed using a liquid chromatography-tandem mass spectrometry-based method with a total run time of 12 min. The linear calibration curve was obtained over the concentration range 5-500 μg/ml. The within-run accuracy varied from 0.2 to 6.5%, and the precision was ≤8.0%. The between-run accuracy and precision ranged from 0.7% to 5.6% and ≤6.4%, respectively. Significant carryover was resolved by injecting four blanks after high-concentration CTRX samples. The recovery rates from spiked serum at low and high concentrations were 44.4 and 43.4%, respectively. Other factors, including selectivity, matrix effects, stability, dilution integrity and reinjection reproducibility also met the acceptance criteria. Serum concentrations in 14 samples obtained from two participants receiving 2 g/day of CTRX were successfully determined using this method.

INTRODUCTION:A limited sampling strategy (LSS) for estimating the area under the plasma concentration-time curve (AUC0-12) of the immunosuppressant mycophenolic acid (MPA) is used for therapeutic drug monitoring (TDM) in clinical practice. Our study delves into the applicability of the MPA AUC0-12 LSS, originally developed using particle-enhanced turbidimetric inhibition immunoassay (PETINIA) measurements, to those obtained via high-performance liquid chromatography with ultraviolet detection (HPLC-UV). METHODS:We developed an LSS for estimating MPA AUC0-12 based on PETINIA measurements in 32 adult kidney transplant patients who were receiving mycophenolate mofetil. Validation of this strategy was conducted in an additional 14 adult kidney transplant patients (validation sets) through measurements obtained by both PETINIA and HPLC-UV. Predictive performance was assessed using mean absolute error (MAE), root mean squared error (RMSE), and "good guess" defined as predicted AUC within observed AUC ± 15%. RESULTS:The three time point equation (0, 2, and 6 h) emerged as optimal for estimating MPA AUC0-12, balancing predictive performance and usefulness in clinical settings. In validation sets, the coefficient of determination for observed versus predicted AUC0-12 was consistent between PETINIA (0.978) and HPLC-UV (0.958) measurements. Comparable MAE, RMSE, and "good guess" outcomes were observed for PETINIA (6.4%, 8.1%, and 85.7%, respectively) and HPLC-UV (7.6%, 9.4%, and 85.7%, respectively) measurements. CONCLUSION:Our findings support the application of the MPA AUC0-12 LSS, originally developed using PETINIA measurements, to those obtained via HPLC-UV.

PURPOSE Opioid-induced constipation is the most frequent and non-self-limiting adverse effect of opioid analgesia, reducing adherence and interfering with pain relief. This clinical trial aimed to clarify the preventive effect of naldemedine versus placebo for constipation in patients with cancer starting regularly dosed strong opioids therapy. METHODS This multicenter, double-blinded, randomized, placebo-controlled, confirmatory trial was conducted between July 2021 and May 2023 at four academic hospitals in Japan (Japan Registry of Clinical Trials identifier: jRCTs031200397). Patients with cancer starting a first-time regularly dosed strong opioid for cancer pain and age 20+ years were included. Eligible patients were randomly assigned to the naldemedine (Symproic 0.2 mg) or placebo group in a 1:1 ratio for 14 days with protocol treatment. The primary end point was the proportion of patients with a Bowel Function Index (BFI) of <28.8 on day 14. The secondary end points included frequency of spontaneous bowel movements (SBM), quality of life (QOL), and frequency of opioid-induced nausea and vomiting (OINV). RESULTS Of the 103 patients assessed for eligibility, 99 received either naldemedine (n = 49) or placebo (n = 50). A BFI of <28.8 on day 14 was significantly more likely to occur in the naldemedine group (64.6%; 95% CI, 51.1 to 78.1) versus placebo (17.0%; 95% CI, 6.3 to 27.8), and the difference between groups was 47.6% (95% CI, 30.3 to 64.8; P < .0001). The frequency of SBM, QOL, and the severity of OINV were nominally significant in the naldemedine group than in the control group. CONCLUSION Naldemedine prevented constipation and improved constipation-related QOL, with possible preventive effect on OINV in patients with cancer starting regularly dosed opioids therapy.

Considerable amounts of injected immunoglobulin G-based therapeutic monoclonal antibodies, such as ramucirumab, are distributed into ascites. This study aimed to examine the effect of massive ascites on ramucirumab pharmacokinetics in patients with gastrointestinal cancers. Population pharmacokinetic analysis of ramucirumab was performed using data on serum ramucirumab concentrations of 52 patients with gastrointestinal cancers, including 8 patients with massive ascites. The Bayesian method using the final population pharmacokinetic model was utilized to estimate trough ramucirumab concentrations after the first dose and at steady state. Population pharmacokinetic analysis revealed that massive ascites as well as body weight were influencing factors for ramucirumab clearance. The estimated ramucirumab clearance was significantly higher in patients with massive ascites than in those with no/mild ascites (0.020 ± 0.004 versus 0.013 ± 0.004 L/h, P < 0.001). The estimated trough ramucirumab concentrations were significantly lower in patients with massive ascites than in those with no/mild ascites after the first dose (26.4 ± 6.8 versus 36.1 ± 7.1 μg/mL, P < 0.001) and at steady state (41.4 ± 16.3 versus 65.9 ± 18.0 μg/mL, P < 0.001). In the present study, the presence of massive ascites affected the pharmacokinetics of ramucirumab in patients with gastrointestinal cancers. Our results suggest that dose optimization of ramucirumab may be necessary in patients with massive ascites due to higher ramucirumab clearance.