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PurposeThis study aimed to evaluate the association between clinical characteristics and development of medication-related osteonecrosis of the jaw (MRONJ) in patients who underwent dental examinations before the initiation of treatment with denosumab or zoledronic acid, which are bone-modifying agents (BMAs), for bone metastases. Additionally, the clinical outcomes of patients who developed MRONJ were evaluated along with the time to resolution of MRONJ.MethodsThe medical charts of patients with cancer who received denosumab or zoledronic acid for bone metastases between January 2012 and September 2016 were retrospectively reviewed. Patients were excluded if they did not undergo a dental examination at baseline.ResultsAmong the 374 included patients, 34 (9.1%) developed MRONJ. The incidence of MRONJ was significantly higher in the denosumab group than in the zoledronic acid (27/215 [12.6%] vs 7/159 [4.4%], P = 0.006) group. Multivariate Cox proportional hazards regression analysis revealed that denosumab treatment, older age, and tooth extraction before and after starting BMA treatments were significantly associated with developing MRONJ. The time to resolution of MRONJ was significantly shorter for patients who received denosumab (median 26.8 months) than for those who received zoledronic acid (median not reached; P = 0.024).ConclusionThe results of this study suggest that treatment with denosumab, age > 65 years, and tooth extraction before and after starting BMA treatments are significantly associated with developing MRONJ in patients undergoing treatment for bone metastases. However, MRONJ caused by denosumab resolves faster than that caused by zoledronic acid.

Since December 2019, a novel coronavirus (severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2)) infection has been rapidly spreading worldwide and causing the respiratory illness, coronavirus disease 2019 (COVID‐19). The antiretroviral drug favipiravir (FPV) has been experimentally used for COVID‐19 treatment since March 2020 in Japan. However, the pharmacokinetics of FPV in critically ill patients is unknown. We measured the serum concentration of FPV using high‐performance liquid chromatography in patients with severe COVID‐19 who were admitted to the intensive care unit and placed on mechanical ventilation. The patients were administered 1,600 mg of FPV twice daily on day 1, followed by 600 mg twice daily from day 2 to day 5 (or more if needed). Suspensions of FPV tablets were administered through a nasogastric tube. Seven patients were enrolled in this study. Forty‐nine blood samples were obtained from the eligible patients to evaluate FPV concentration. The FPV trough (after 8–12 hours) concentrations of most samples were lower than the lower limit of quantification (1 µg/mL) and half‐maximal effective concentration (9.7 µg/mL) against SARS‐CoV‐2 previously tested in vitro. FPV trough concentration in critically ill patients was much lower than that of healthy subjects in a previous clinical trial, which is a cause for great concern. Further study is required to determine the optimal strategy for treatment of patients with severe COVID‐19.

Background: Everolimus is one of the key drugs for the treatment of advanced breast cancer. The optimal target concentration range for everolimus therapy in patients with breast cancer has not yet been established. This study aimed to characterize everolimus pharmacokinetics (PK) and determine the relationship between blood concentration and efficacy as well as adverse events in patients with breast cancer. Methods: This was a prospective, observational PK study. Patients receiving everolimus between November 2015 and November 2018 at our hospital were enrolled in this study. The whole blood samples for the everolimus assay were collected at least two weeks after initiation of treatment or the last everolimus dose change. PK parameters were estimated using Bayesian analysis. Statistical differences in everolimus trough concentrations between patient cohorts were assessed using the Mann–Whitney test. Progression-free survival was assessed using the Kaplan-Meier method and the log-rank test. Results: Eighteen patients were enrolled in the study. The median follow-up period was 35 months. The most frequently observed adverse event was stomatitis (all grade 94%). There was high inter-individual variation in PK parameters such as clearance [range: 5.1–21.3 L/h/70 kg and co-efficient of variation (CV): 38.5%] and volume of distribution of the central compartment (range: 9.9–103.6 L/70 kg and CV: 57.8%). The trough concentrations at dose-limiting toxicities were significantly higher than trough concentrations in the absence of these toxicities ( p = 0.0058). Progression-free survival was significantly longer in the 10–20 ng/ml group than in the other groups ( p = 0.0078). Conclusion: This study characterized the everolimus PK parameters in Japanese patients with breast cancer. High everolimus exposure was found to be associated with poor tolerability. Based on our data, trough concentrations in the range of 10–20 ng/ml may be associated with prolonged progression-free survival. Thus, determining the blood concentration of everolimus and subsequent dose adjustments will potentially reduce side effects and enhance the therapeutic effect in Japanese patients with advanced breast cancer.

Purpose This study evaluated the risk of medication-related osteonecrosis of the jaw (MRONJ) in patients with cancer who received denosumab or zoledronic acid (ZA) for treating bone metastasis. Methods The medical records of patients were retrospectively reviewed. Patients who did not undergo a dental examination at baseline were excluded. The primary endpoint was a comparison of the risk of developing MRONJ between the denosumab and ZA groups. Propensity score matching was used to control for baseline differences between patient characteristics and compare outcomes for both groups. Results Among the 799 patients enrolled, 58 (7.3%) developed MRONJ. The incidence of MRONJ was significantly higher in the denosumab group than in the ZA group (9.6% [39/406] vs. 4.8% [19/393], p  = 0.009). Multivariate Cox proportional hazards regression analysis revealed that denosumab treatment (hazard ratio [HR], 2.89; 95% confidence interval [CI], 1.65–5.25; p  < 0.001) and tooth extraction after starting ZA or denosumab (HR, 4.26; 95% CI, 2.38–7.44; p  < 0.001) were significant risk factors for MRONJ. Propensity score–matched analysis confirmed that the risk of developing MRONJ was significantly higher in the denosumab group than in the ZA group (HR, 2.34; 95% CI, 1.17–5.01; p  = 0.016). Conclusion The results of this study suggest that denosumab poses a significant risk for developing MRONJ in patients treated for bone metastasis, and thus these patients require close monitoring.

PurposeSwitch from zoledronic acid (ZA) to denosumab may increase the risk of medication-related osteonecrosis of the jaw (MRONJ) owing to the additive effect of denosumab on the jawbone and residual ZA activities. We evaluated the risk of developing MRONJ in patients who received ZA, denosumab, or ZA-to-denosumab for the treatment of bone metastases.MethodsThe medical charts of patients with cancer who received denosumab or ZA for bone metastases were retrospectively reviewed. Patients who did not undergo a dental examination at baseline were excluded. Primary endpoint was the evaluation of the risk of developing MRONJ in the ZA-to-denosumab group. Secondary endpoints were probability of MRONJ and the relationship between risk factors and the time to the development of MRONJ.ResultsAmong the 795 patients included in this study, 65 (8.2%) developed MRONJ. The incidence of MRONJ was significantly higher in the ZA-to-denosumab group than in the ZA group [7/43 (16.3%) vs. 19/350 (5.4%), p = 0.007]. Multivariate Cox proportional hazards regression analysis revealed that denosumab treatment [hazard ratio (HR), 2.41; 95% confidence interval (CI), 1.37–4.39; p = 0.002], ZA-to-denosumab treatment (HR, 4.36; 95% CI, 1.63–10.54, p = 0.005), tooth extraction after starting ZA or denosumab (HR, 4.86; 95% CI, 2.75–8.36; p < 0.001), and concomitant use of antiangiogenic agents (HR, 1.78; 95% CI, 1.06–2.96; p = 0.030) were significant risk factors for MRONJ.ConclusionOur results suggest that switching from ZA to denosumab significantly increases the risk for developing MRONJ in patients with bone metastases.

Netupitant (NTP), the active form of fosnetupitant (FosNTP), a novel NK1 receptor antagonist, has been reported to possess a longer half-life than conventional drugs and demonstrates favorable antiemetic effects in the delayed phase. However, NTP has been reported to exert an inhibitory effect on CYP3A4, similar to conventional NK1 receptor antagonists. Paclitaxel (PTX), which is utilized in the treatment of non-small cell lung cancer, undergoes metabolism via CYP3A4. The enhancement of myelosuppression resulting from this interaction may necessitate dose reduction or withdrawal of anticancer drugs, which may compromise treatment continuation. While it has been reported that aprepitant (APR) does not influence the incidence of adverse events associated with anticancer drugs metabolized via CYP3A4, reports on FosNTP remain limited. Therefore, this study retrospectively examined the differences in the incidence of myelosuppression as an adverse event in patients with non-small cell lung cancer treated with FosNTP and APR. Patients treated with PTX or nanoparticle albumin-bound paclitaxel (nab-PTX) combined with platinum-based anticancer regimens for non-small cell lung cancer between January 2019 and September 2024 were included in this study. Patients receiving FosNTP and APR as antiemetic agents were stratified into groups, and the incidence of grade ≥3 myelosuppression served as the primary endpoint. Statistical analysis was performed using the chi-square test, with statistical significance established at P < 0.05. The incidence of grade ≥3 neutropenia was 15/31 in the FosNTP group and 18/68 in the APR group among PTX-treated patients, demonstrating a significantly higher incidence in the FosNTP group (48.4% vs. 26.5%; p = 0.019). The extended half-life of NTP compared to that of APR may have contributed to prolonged CYP3A4 inhibition and subsequent inhibition of PTX metabolism. Conversely, among nab-PTX users, 10/49 patients in the FosNTP group and 8/53 patients in the APR group developed grade ≥3 neutropenia, with no significant difference observed (20.4% vs. 17.0%; p = 0.182). This study suggests that the use of FosNTP in PTX-containing regimens may lead to a higher incidence of grade ≥3 neutropenia compared to APR, emphasizing the importance of vigilant monitoring throughout the treatment period.

Background Although automated dispensing robots have been implemented for medication dispensing in Japan, their effect is yet to be fully investigated. In this study, we evaluated the effect of automated dispensing robots and collaborative work with pharmacy support staff on medication dispensing. Methods A robotic dispensing system integrating the following three components was established: (1) automated dispensing robot (Drug Station®), which is operated by pharmacy support staff, (2) automated dispensing robot for powdered medicine (Mini DimeRo®), and (3) bar-coded medication dispensing support system with personal digital assistance (Hp-PORIMS®). Subsequently, we evaluated the incidences of dispensing errors and dispensing times before and after introducing the robotic dispensing system. Dispensing errors were classified into two categories, namely prevented dispensing errors and unprevented dispensing errors. The incidence of dispensing errors was calculated as follows: incidence of dispensing errors = total number of dispensing errors/total number of medication orders in each prescription. Results After introducing the robotic dispensing system, the total incidence of prevented dispensing errors was significantly reduced (0.204% [324/158,548] to 0.044% [50/114,111], p  < 0.001). The total incidence of unprevented dispensing errors was significantly reduced (0.015% [24/158,548] to 0.002% [2/114,111], p  < 0.001). The number of cases of wrong strength and wrong drug, which can seriously impact a patient’s health, reduced to almost zero. The median dispensing time of pharmacists per prescription was significantly reduced (from 60 to 23 s, p  < 0.001). Conclusions The robotic dispensing system enabled the process of medication dispensing by pharmacist to be partially and safely shared with automated dispensing robots and pharmacy support staff. Therefore, clinical care for patients by pharmacists could be enhanced by ensuring quality and safety of medication.

Background Pneumocystis pneumonia (PCP) is a potentially life-threatening infection. Trimethoprim-sulfamethoxazole (TMP-SMX) is considered as the first regimen for PCP prophylaxis according to several guidelines. The recommended prophylactic dose of TMP-SMX has been determined based on patients with normal renal function, but the appropriate dosage for patients undergoing hemodialysis is unknown. The aim of this study was to investigate the efficacy and safety of low-dose TMP-SMX in patients undergoing hemodialysis. Methods HIV-uninfected adult patients who were undergoing hemodialysis and administered TMP-SMX for PCP prophylaxis, were included, and divided into standard-dose (≥6 single strength (SS, TMP-SMX 80 mg/400 mg tablets/week) and low-dose groups (< 6 SS tablets/week). The endpoints were cumulative incidence of PCP and cumulative discontinuation rate of TMP-SMX due to adverse events. For comparison of the groups, we employed the chi-squared test for categorical variables and the Mann-Whitney U test for continuous variables. Risk factors for the endpoints were evaluated using the Cox Fine and Gray method. Results The median age of the 81 patients included in the study was 67 years (IQR: 60–76 years), and 52 patients (64.2%) were men. No patients in either group developed PCP during the observation period. The yearly cumulative incidence of discontinuation was 12.1% (95% confidence interval [CI]: 0.027–0.29) in the low-dose group and 35.6% (95% CI: 0.20–0.52) in the standard-dose group ( P  = 0.019). The adjusted hazard ratio of the low-dose group compared to standard-dose group was 0.18 (95% CI: 0.04–0.86, P  = 0.032). Conclusions None of the study patients developed PCP, and the cumulative discontinuation rate of TMP-SMX due to adverse events was significantly lower in the low-dose group compared to that in the standard-dose group ( P  = 0.032). These results indicate that low-dose TMP-SMX is an appropriate regimen to maintain a balance between PCP prophylaxis and prevention of adverse events due to TMP-SMX administration. These findings can guide health care professionals to determine TMP-SMX dosage when considering PCP prophylaxis for patients undergoing hemodialysis.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event associated with several antineoplastic drugs; however, the precise risks and time course of reactions of particular drugs are not clearly understood. The aim of this study was to evaluate the relationship between anticancer agents and CIPN development using data from the Japanese Adverse Drug Event Report (JADER) database and to characterize the time-to-onset and outcomes of CIPN. Chemotherapy-induced peripheral neuropathy was defined using the Medical Dictionary for Regulatory Activities preferred terms. Disproportionality analysis was performed by calculating the reporting odds ratio (ROR) with 95% confidence interval for signal detection. Data of nine Anatomical Therapeutic Chemical (ATC) drug categories correlated with CIPN development, in addition to the data of the time-to-onset and outcomes. Among 622,289 reports in the JADER database from April 2004 to March 2020, there were 1883 reports of adverse events corresponding to peripheral neuropathy. The ROR (95% confidence interval) for vinblastine, sorbent-based paclitaxel (sb-PTX), oxaliplatin, and bortezomib was 20.4 (12.5–33.4), 13.6 (11.9–15.7), 26.2 (23.6–29.1), and 30.8 (26.6–35.8), respectively. The median duration (interquartile range) to CIPN development after the administration of vinca alkaloids and analogues, taxanes, platinum compounds, and monoclonal antibodies was 11.0 (5.0–46.5), 22.5 (6.0–82.5), 22.0 (6.0–68.5), and 32.5 (11.3–73.8) days, respectively. The median duration (interquartile range) of sb-PTX and nanoparticle albumin-bound (nab)-PTX was 35.0 (7.0–94.0) and 5.5 (3.0–29.3) days, respectively. Our analysis of records in the JADER database revealed several drugs associated with a high risk for CIPN development. In particular, the development of CIPN after vinca alkaloid administration should be closely monitored for 2 weeks after administration. CIPN caused by nab-PTX showed significantly faster onset than that by sb-PTX. Patients who receive taxanes or monoclonal antibodies often do not show an improvement; accordingly, early treatment is required.

The antiretroviral drug favipiravir (FPV) inhibits RNA‐dependent RNA polymerase. It has been developed for the treatment of the novel coronavirus (severe acute respiratory syndrome coronavirus 2) infection disease, coronavirus disease 2019 (COVID‐19). However, its pharmacokinetics in patients with COVID‐19 is poorly understood. In this study, we measured FPV serum concentration by liquid chromatography–tandem mass spectrometry and conducted population pharmacokinetic analysis. A total of 39 patients were enrolled in the study: 33 were administered FPV 1600 mg twice daily (b.i.d.) on the first day followed by 600 mg b.i.d., and 6 were administered FPV 1800 mg b.i.d. on the first day followed by 800 mg or 600 mg b.i.d. The median age was 68 years (range, 27–89 years), 31 (79.5%) patients were men, median body surface area (BSA) was 1.72 m2 (range, 1.11–2.2 m2), and 10 (25.6%) patients required invasive mechanical ventilation (IMV) at the start of FPV. A total of 204 serum concentrations were available for pharmacokinetic analysis. A one‐compartment model with first‐order elimination was used to describe the pharmacokinetics. The estimated mean clearance/bioavailability (CL/F) and distribution volume/bioavailability (V/F) were 5.11 L/h and 41.6 L, respectively. Covariate analysis revealed that CL/F was significantly related to dosage, IMV use, and BSA. A simulation study showed that the 1600 mg/600 mg b.i.d. regimen was insufficient for the treatment of COVID‐19 targeting the 50% effective concentration (9.7 µg/mL), especially in patients with larger BSA and/or IMV. A higher FPV dosage is required for COVID‐19, but dose‐dependent nonlinear pharmacokinetics may cause an unexpected significant pharmacokinetic change and drug toxicity. Further studies are warranted to explore the optimal FPV regimen.