Real-World Prevalence and Tolerability of Immune-Related Adverse Events in Older Adults with Non-Small Cell Lung Cancer: A Multi-Institutional Retrospective Study.

With cancer diagnosis occurring at older ages, the use of immune checkpoint inhibitors (ICIs) has extended to older adults. However, the safety of immune-related adverse events (irAEs) in this population remains unclear and relies on data extrapolated from younger adults. This multicenter retrospective study aimed to examine irAE prevalence and tolerability in older adults. We included 436 patients with non-small lung cancer undergoing ICI therapy and dichotomized them into two age groups (< or ≥75 years). Incidence of any irAE grade, grade ≥3 irAEs, and steroid usage after irAE occurrence was similar between younger (n = 332) and older groups (n = 104). While the younger patients with irAEs showed prolonged overall survival in the 12-month landmark Kaplan-Meier analysis (Hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.38-0.89, p = 0.013), the older cohort did not (HR 0.80, 95% CI 0.36-1.78, p = 0.588). Although no differences were observed with ICI continuation or re-challenge after irAE onset, the elderly cohort had double the irAE cases that required a transition to best supportive care (BSC) (11.3% vs. 22.4%, p = 0.026). In conclusion, although irAE prevalence remains consistent regardless of age, the increased conversion to BSC post-irAE onset in older adults suggests diminished tolerability and the potential absence of favorable prognosis associated with irAEs in this population.

Risk Factors of Cetuximab-Induced Hypomagnesemia and the Effect of Magnesium Prophylaxis in Patients with Head and Neck Cancer: A Retrospective Study.

Hypomagnesemia is a characteristic adverse event of cetuximab in patients with head and neck cancer (HNC). However, there is limited information about its prevalence, risk factors, and preventive strategies. This study aimed to investigate the risk factors of hypomagnesemia and examine the preventive effects of prophylactic magnesium (Mg) administration. We initially investigated HNC patients treated with cetuximab between 2013 and 2019. Our institute started prophylactic Mg treatment (20-mEq Mg sulfate administration before cetuximab) in practice during this period. We retrospectively assess the preventive efficacy by comparing patients before and after its implementation. In total, 109 patients were included. In 60 patients without prophylaxis, all-grade and grade ≥2 hypomagnesemia at 3 months occurred in 61.7 and 15.0% of patients. The incidence of hypomagnesemia was not affected by regimens and concomitant medications. In 49 patients treated with prophylactic Mg treatment, there was no significant decrease in the cumulative incidence of hypomagnesemia. However, the preventive Mg treatment eliminated the need for additional Mg repletion to maintain Mg levels in patients treated with paclitaxel + cetuximab. A risk factor in patients without prophylaxis was a low Mg level at pre-treatment (≤2.0 mg/dL) (odds ratio: 6.03, 95% confidence interval: 1.78-20.4, p = 0.004), whereas that in patients with prophylaxis was the number of cetuximab doses (≥10) (odds ratio: 5.50, 95% confidence interval: 1.52-19.87, p = 0.009). In conclusion, a low pre-treatment Mg level was the only risk factor that could be avoided by prophylactic Mg administration. This preventive intervention is recommended for managing cetuximab-induced hypomagnesemia.

Systematic surveillance of immune-related adverse events in clinical practice and impact of subsequent steroid medication on survival outcomes.

BACKGROUND: Recent advances in immune-checkpoint inhibitors (ICIs) have highlighted the need for effective management of immune-related adverse events (irAEs). This study aimed to conduct a systematic surveillance of real-world development of irAEs for understanding their characteristics and examine the prognostic impact of steroid use for these events. METHODS: We retrospectively investigated cancer patients treated with ICIs between 2014 and 2021 and collected information about irAEs throughout their development, management, and clinical outcomes. RESULTS: Overall, 458 patients (45.4%) developed 670 irAEs. The prevalence of irAEs varied by cancer type, but it was increased in regimens with longer treatment durations. Severe irAEs were more common in the nivolumab + ipilimumab and pembrolizumab + axitinib regimens. Patients who received steroids for irAEs at a dosage of < 2 mg/kg had comparable prognosis to those who did not receive steroids; however, patients who received methylprednisolone pulse therapy, primarily for severe pneumonitis and hepatitis, had shorter overall survival than those who did not receive steroids (7.8 versus 23.4 months, p = 0.016). Furthermore, methylprednisolone pulse therapy for irAEs was a poor prognostic factor in multivariate analysis (hazard ratio: 2.19, 95% confidence interval: 1.34-2.86, p < 0.001). CONCLUSION: Steroid treatment for irAE does not affect prognosis and should thus be used promptly to control inflammation. However, pulse therapy for severe cases is a poor prognostic factor, and early detection remains the key to managing such irAEs. The irAE characteristics in each regimen should be clarified to establish and provide more sophisticated irAE management, and the current findings will be beneficial to this goal.

Analysis of the thinking process of pharmacists in response to changes in the dispensing environment using the eye-tracking method.

BACKGROUND: Pharmacists must understand the mechanisms by which dispensing errors occur and take appropriate preventive measures. In this study, the gaze movements of pharmacists were analyzed using an eye-tracking method, to elucidate the thinking process of pharmacists when identifying target drugs and avoiding dispensing errors. METHODS: We prepared verification slides and projected them on a large screen. Each slide comprised a drug rack area and a prescription area; the former consisted of a grid-like layout with 55 drugs and the latter displayed dispensing information (drug name, drug usage, location number, and total amount). Twelve pharmacists participated in the study, and three single-type drugs and six double-type drugs were used as target drugs. We analyzed the pharmacists' method of identifying the target drugs, the mechanisms by which errors occurred, and the usefulness of drug photographs using the error-induction (-) /photo (+), error-induction (+) / (+), and error-induction (+) /photo (-) models. RESULTS: Visual invasion by non-target drugs was found to have an effect on the subsequent occurrence of dispensing errors. In addition, when using error-induction models, the rate of dispensing error was 2.8 and 11.1% for the photo (+) and photo (-) models, respectively. Furthermore, based on the analysis of eight pharmacists who dispensed drugs without errors, it was clear that additional confirmation of "drug name" was required to accurately identify the target drug in the photo (+) model; additionally, that of "location number" was required to pinpoint directly the position of target drug in the photo (-) model. CONCLUSIONS: By analyzing the gaze movements of pharmacists using the eye-tracking method, we clarified pharmacists' thinking process which was required to avoid dispensing errors in a complicated environment and proved the usefulness of drug photographs in terms of both reducing the complexity of the dispensing process and the risk of dispensing errors. Effective measures to prevent dispensing errors include ensuring non-adjacent placement of double-type drugs and utilization of their image information.

Clinical Pharmacokinetics and Pharmacodynamics of Fostamatinib and Its Active Moiety R406.

Fostamatinib is the first approved spleen tyrosine kinase inhibitor for chronic immune thrombocytopenia. This review summarizes the clinical development, pharmacokinetics, pharmacodynamics, drug-drug interactions, adverse events, and comprehensive analyses of fostamatinib. While integrating these findings, we discuss the fostering and improvement of fostamatinib for further clinical applications. Fostamatinib is designed as a prodrug and cleavage of its active moiety R406 in the intestine. As R406 is the major product in the blood, this review mainly discusses the pharmacokinetics and pharmacodynamics of R406. It is metabolized by cytochrome 3A4 and UGT1A9 in the liver and is dominantly excreted in feces after anaerobic modification by the gut microbiota. As fostamatinib and R406 strongly inhibit the breast cancer resistance protein, the interaction with those substrates, particularly statins, should be carefully monitored. In patients with immune thrombocytopenia, fostamatinib administration started at 100 mg twice daily, and most patients increased to 150 mg twice daily in the clinical trial. Although responders showed a higher R406 concentration than non-responders, the correlation between R406 exposure and achievement of the platelet count as a pharmacodynamic marker was uncertain in the pharmacokinetic/pharmacodynamic analysis. Additionally, R406 concentration was almost halved in patients with a heavy body weight; hence, the exposure-efficacy study for suitable dosing should be continued with post-marketing data. In contrast, the pharmacokinetic/pharmacodynamic analysis for exposure safety revealed that R406 exposure significantly correlated with the incidence of hypertension. Even though the influence of elevated exposure on other toxicities, including diarrhea and neutropenia, is still unclear, careful management is required with dose escalation to avoid toxicity-related discontinuation.

A TRPC3/6 Channel Inhibitor Promotes Arteriogenesis after Hind-Limb Ischemia.

Retarded revascularization after progressive occlusion of large conductance arteries is a major cause of bad prognosis for peripheral artery disease (PAD). However, pharmacological treatment for PAD is still limited. We previously reported that suppression of transient receptor potential canonical (TRPC) 6 channel activity in vascular smooth muscle cells (VSMCs) facilitates VSMC differentiation without affecting proliferation and migration. In this study, we found that 1-benzilpiperadine derivative (1-BP), a selective inhibitor for TRPC3 and TRPC6 channel activities, induced VSMC differentiation. 1-BP-treated mice showed increased capillary arterialization and improvement of peripheral circulation and skeletal muscle mass after hind-limb ischemia (HLI) in mice. 1-BP had no additive effect on the facilitation of blood flow recovery after HLI in TRPC6-deficient mice, suggesting that suppression of TRPC6 underlies facilitation of the blood flow recovery by 1-BP. 1-BP also improved vascular nitric oxide bioavailability and blood flow recovery after HLI in hypercholesterolemic mice with endothelial dysfunction, suggesting the retrograde interaction from VSMCs to endothelium. These results suggest that 1-BP becomes a potential seed for PAD treatments that target vascular TRPC6 channels.

Neuroprotective effects of ibudilast against tacrolimus induced neurotoxicity.

Neurotoxicity is one of the major side effects caused by calcineurin inhibitors such as tacrolimus in clinical practice. The underlying mechanisms remain unclear, and no potential protective agents have been identified yet. Here, we aimed to investigate tacrolimus-induced neurotoxicity and assess the protective effects of ibudilast, a nonselective phosphodiesterase inhibitor with neuroprotective effects, against tacrolimus-induced neurotoxicity. An in vitro assay of human neuroblastoma SH-SY5Y cells showed that ibudilast reduced tacrolimus-induced cell death. Subsequently, using in vivo studies, we assessed the pathological mechanism of neurotoxicity and evaluated the protective effect of ibudilast. Wistar rats were subcutaneously administered tacrolimus (2.5 or 5.0 mg/kg/day) for 14 d, and ibudilast (7.5 mg/kg/day) was intraperitoneally administered once a day beginning 2 d prior to tacrolimus (5 mg/kg/day) administration. We observed that ibudilast significantly reduced the tacrolimus-induced neurotoxic events. From the assessment of excised brains, we found that tacrolimus was penetrated to brain and the brain concentration was correlated with the neurotoxicity-score, although ibudilast had no effect on this pharmacokinetics. Tacrolimus-induced neuronal damage was histopathologically evaluated using Nissl and TUNEL staining, where only the cerebral cortex and CA1 region in hippocampus exhibited neuronal death, but not the CA3 region, dendrite gyrus, and cerebellum. Co-administration of ibudilast significantly attenuated these histopathological changes. In conclusion, these results suggest that tacrolimus translocation into the brain and neuronal damage in the cerebral cortex and CA1 are the underlying mechanisms of tacrolimus-induced neurotoxicity and that ibudilast could be a protective agent against this adverse event.

Effects of Letermovir and/or Methylprednisolone Coadministration on Voriconazole Pharmacokinetics in Hematopoietic Stem Cell Transplantation: A Population Pharmacokinetic Study.

OBJECTIVE: The aim of this study was to identify factors affecting blood concentrations of voriconazole following letermovir coadministration using population pharmacokinetic (PPK) analysis in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. METHODS: The following data were retrospectively collected: voriconazole trough levels, patient characteristics, concomitant drugs, and laboratory information. PPK analysis was performed with NONMEM® version 7.4.3, using the first-order conditional estimation method with interaction. We collected data on plasma voriconazole steady-state trough concentrations at 216 timepoints for 47 patients. A nonlinear pharmacokinetic model with the Michaelis-Menten equation was applied to describe the relationship between steady-state trough concentration and daily maintenance dose of voriconazole. After stepwise covariate modeling, the final model was evaluated using a goodness-of-fit plot, case deletion diagnostics, and bootstrap methods. RESULTS: The maximum elimination rate (Vmax) of voriconazole in patients coadministered letermovir and methylprednisolone was 1.72 and 1.30 times larger than that in patients not coadministered these drugs, respectively, resulting in decreased voriconazole trough concentrations. The developed PPK model adequately described the voriconazole trough concentration profiles in allo-HSCT recipients. Simulations clearly showed that increased daily doses of voriconazole were required to achieve an optimal trough voriconazole concentration (1-5 mg/L) when patients received voriconazole with letermovir and/or methylprednisolone. CONCLUSIONS: The development of individualized dose adjustment is critical to achieve optimal voriconazole concentration, especially among allo-HSCT recipients receiving concomitant letermovir and/or methylprednisolone.

Prognostic significance of pre-treatment ALBI grade in advanced non-small cell lung cancer receiving immune checkpoint therapy.

The liver is an essential organ for regulating innate and acquired immunity. We hypothesized that the pre-treatment hepatic function affects the clinical outcome of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). We analyzed 140 patients with NSCLC who received ICIs. We investigated the association between pre-treatment liver function, assessed using the albumin-bilirubin (ALBI) grade, and clinical outcomes in univariate, multivariate, and propensity score matching analyses. Patients were divided into four grades according to pre-treatment liver function. Eighty-eight patients had good hepatic reserve (ALBI grade 1 or 2a), whereas 52 patients had poor hepatic reserve (ALBI grade 2b or 3). In the univariate Kaplan-Meier analysis, the ALBI grade 1, 2a group had a significantly prolonged progression-free survival (PFS, 5.3 versus 2.5 months, p = 0.0019) and overall survival (OS, 19.6 vs. 6.2 months, p = 0.0002). These results were consistent, regardless of whether the analysis was performed in patients with a performance status of 0 or 1 at pre-treatment (N = 124) or in those selected using propensity score matching (N = 76). In the multivariate analysis, pre-treatment ALBI grade was an independent prognostic factor for both PFS (hazard ratio [HR] 0.57, 95% confidence interval [95% CI] 0.38-0.86, p = 0.007) and OS (HR 0.45, 95% CI 0.29-0.72, p = 0.001). Our results suggest that pre-treatment hepatic function assessed by ALBI grade could be an essential biomarker for predicting the efficacy of treatment with ICIs in NSCLC.

Continuous monitoring of neutrophils to lymphocytes ratio for estimating the onset, severity, and subsequent prognosis of immune related adverse events.

Immune checkpoint inhibitors (ICIs) play a central role in various cancers. ICIs can cause immune-related adverse events (irAEs). As severe irAEs can be life-threatening, biomarkers for estimating irAE onset are crucial. The neutrophils-to-lymphocytes ratio (NLR) reflects the systemic immune condition and known as a prognostic marker in ICI treatment. Our study evaluated if the NLR corresponded with irAEs, and its feasibility as a biomarker for irAE onset. We retrospectively analyzed 275 cancer patients treated with anti-PD-1 monotherapy. We observed 166 irAEs in 121 patients. The NLR was significantly elevated during irAEs. Patients experiencing interstitial pneumonitis showed NLR elevation 4 weeks before initial symptoms and diagnosis. Analyzing receiver operating characteristics curves revealed that elevated NLR distinguished subsequent pneumonitis severity with high accuracy (AUC 0.93, sensitivity 88.9%, specificity 88.2%, cut-off 2.37, p = 0.0004). After a severe irAE occurred, two NLR trends were observed. Patients who showed a prompt reduction in elevated NLRs had favorable progression-free survival (hazard ratio 0.32, 95% CI 0.10-1.01, p = 0.0140) and overall survival (hazard ratio 0.23, 95% CI 0.06-0.86, p = 0.0057) compared to the patients who maintained elevated NLRs. These findings suggest that continuous monitoring of NLR trends may predict irAE onset and severity and subsequent prognosis.

Influence of POR*28 Polymorphisms on CYP3A5*3-Associated Variations in Tacrolimus Blood Levels at an Early Stage after Liver Transplantation.

It is well known that the CYP3A5*3 polymorphism is an important marker that correlates with the tacrolimus dose requirement after organ transplantation. Recently, it has been revealed that the POR*28 polymorphism affects the pharmacokinetics of tacrolimus in renal transplant patients. In this study, we examined whether POR*28 as well as CYP3A5*3 polymorphism in Japanese recipients and donors would be another biomarker for the variation of tacrolimus blood levels in the recipients during the first month after living-donor liver transplantation. We enrolled 65 patients treated with tacrolimus, who underwent liver transplantation between July 2016 and January 2019. Genomic DNA was extracted from whole-blood samples, and genotyping was performed to examine the presence of CYP3A5*3 and POR*28 polymorphisms in the recipients and donors. The CYP3A5*3/*3 genotype (defective CYP3A5) of the recipient (standard partial regression coefficient [median C/D ratio of CYP3A5 expressor vs. CYP3A5 non-expressor, p value]: Pod 1-7, ß= -0.389 [1.76 vs. 2.73, p < 0.001]; Pod 8-14, ß = -0.345 [2.03 vs. 2.83, p < 0.001]; Pod 15-21, ß= -0.417 [1.75 vs. 2.94, p < 0.001]; Pod 22-28, ß = -0.627 [1.55 vs. 2.90, p < 0.001]) rather than donor (Pod 1-7, ß = n/a [1.88 vs. 2.76]; Pod 8-14, ß = n/a [1.99 vs. 2.93]; Pod 15-21, ß = -0.175 [1.91 vs. 2.94, p = 0.004]; Pod 22-28, ß = n/a [1.61 vs. 2.67]) significantly contributed to the increase in the concentration/dose (C/D) ratio of tacrolimus for at least one month after surgery. We found that the tacrolimus C/D ratio significantly decreased from the third week after transplantation when the recipient carried both CYP3A5*1 (functional CYP3A5) and POR*28 (n = 19 [29.2%], median C/D ratio [inter quartile range] = 1.58 [1.39-2.17]), compared with that in the recipients carrying CYP3A5*1 and POR*1/*1 (n = 8 [12.3%], median C/D ratio [inter quartile range] = 2.23 [2.05-3.06]) (p < 0.001). In conclusion, to our knowledge, this is the first report suggesting that the POR*28 polymorphism is another biomarker for the tacrolimus oral dosage after liver transplantation in patients carrying CYP3A5*1 rather than CYP3A5*3/*3.

TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy.

Myocardial atrophy is a wasting of cardiac muscle due to hemodynamic unloading. Doxorubicin is a highly effective anticancer agent but also induces myocardial atrophy through a largely unknown mechanism. Here, we demonstrate that inhibiting transient receptor potential canonical 3 (TRPC3) channels abolishes doxorubicin-induced myocardial atrophy in mice. Doxorubicin increased production of ROS in rodent cardiomyocytes through hypoxic stress-mediated upregulation of NADPH oxidase 2 (Nox2), which formed a stable complex with TRPC3. Cardiomyocyte-specific expression of TRPC3 C-terminal minipeptide inhibited TRPC3-Nox2 coupling and suppressed doxorubicin-induced reduction of myocardial cell size and left ventricular (LV) dysfunction, along with its upregulation of Nox2 and oxidative stress, without reducing hypoxic stress. Voluntary exercise, an effective treatment to prevent doxorubicin-induced cardiotoxicity, also downregulated the TRPC3-Nox2 complex and promoted volume load-induced LV compliance, as demonstrated in TRPC3-deficient hearts. These results illustrate the impact of TRPC3 on LV compliance and flexibility and, focusing on the TRPC3-Nox2 complex, provide a strategy for prevention of doxorubicin-induced cardiomyopathy.