Factors associated with incomplete adherence to integrase strand transfer inhibitor-containing single-tablet regimen among Japanese people living with HIV.

BACKGROUND: People living with human immunodeficiency virus (PLWH) require high rates of medication adherence to antiretroviral therapy (ART) for a successful treatment outcome. Understanding the factors associated with incomplete adherence among those receiving integrase strand transfer inhibitor-containing single-tablet regimens (INSTI-STRs) is crucial for improving treatment outcomes. This study aimed to identify the factors contributing to incomplete ART adherence among Japanese PLWH receiving INSTI-STRs. METHODS: This multicenter cross-sectional study was conducted at 11 Japanese institutions as an anonymous survey. ART adherence was assessed using a self-reported questionnaire. We defined incomplete ART adherence as missing ≥ 1 dose of antiretroviral drugs (ARVs) over the past month. The factors associated with incomplete ART adherence were assessed using logistic regression analysis. Additionally, we investigated the associations between patients' satisfaction score with and need for ARVs and their adherence to ART. RESULTS: The final analysis included data of 387 patients who were treated with INSTI-STRs. Multivariate logistic regression demonstrated significant association of younger age (adjusted odds ratio [aOR], 0.79; 95%confidence interval [CI]: 0.64-0.99 for each 10-year increment) with incomplete ART adherence. Additionally, female sex (aOR, 3.98; 95%CI: 1.36-11.60); depressive symptoms (mild depression: aOR, 1.68; 95%CI: 1.001-2.82, moderate depression: aOR, 2.98; 95%CI: 1.35-6.53, and severe depression: aOR, 8.73; 95%CI: 1.38-55.00 vs. minimal depression); were also significantly associated with incomplete ART adherence when compared with the reference categories. Concomitant medication usage was significantly associated with a lower rate of incomplete ART adherence (1-4 medications: aOR, 0.53; 95%CI: 0.31-0.89 and ≥ 5 medications: aOR, 0.30; 95%CI: 0.13-0.70 vs. no concomitant medication usage). In the incomplete ART adherence group, satisfaction scores for various aspects were significantly lower. Furthermore, a lower proportion of patients in the incomplete ART adherence group preferred the option of "taking tablets daily and visiting the hospital every 3 months," compared to those in the complete ART adherence group (p = 0.008). CONCLUSIONS: This study demonstrated that factors associated with incomplete ART adherence include younger age, female sex, no concomitant medication, and depressive symptoms. Despite ART simplification, incomplete adherence among PLWH receiving INSTI-STRs, remains a challenge, requiring additional actions.

Relationship between nephrotoxicity and area under the concentration-time curve of vancomycin in critically ill patients: a multicenter retrospective study.

We aimed to assess the frequency of acute kidney injury (AKI) in different areas under the concentration-time curve (AUC) values of vancomycin (VAN) using a two-point blood collection method, allowing for accurate AUC assessment in critically ill patients. This multicenter retrospective observational study was conducted in eight hospitals. We retrospectively analyzed the data of patients who had received VAN in an intensive care unit (ICU) between January 2020 and December 2022. The primary outcome was the incidence of AKI. Patients were classified into three groups according to the AUC24-48h at the initial therapeutic drug monitoring (TDM) as follows: <500, 500-600, and ≥600 µg·h/mL. The AUC24-48h values were calculated using the Bayesian estimation software Practical AUC-guided TDM. Among 146 patients [median age (interquartile range), 67 (56-78) years; 39% women], the AUC24-48h <500 µg·h/mL had an AKI rate of 6.5% (7/107), the AUC24-48h 500-600 µg·h/mL had an AKI rate of 28.0% (7/25), and the AUC24-48h ≥600 µg·h/mL had an AKI rate of 42.9% (6/14). In multivariate Cox proportional hazard analysis, the AUC24-48h 500-600 µg·h/mL [hazard ratio 5.4, 95% confidence interval (CI) 1.64-17.63] and the AUC24-48h ≥600 µg·h/mL (hazard ratio 7.0, 95% CI 2.31-21.18) significantly correlated with a higher incidence of AKI compared with the AUC24-48h <500 µg·h/mL. In conclusion, we identified an association between AUC on day 2 and the risk of AKI in ICU patients, suggesting that not only AUCs above 600 µg·h/mL but also those between 500 and 600 µg·h/mL pose a risk for AKI. IMPORTANCE: Vancomycin (VAN) is a glycopeptide antibiotic and one of the most commonly used antibiotics for severe infections caused by methicillin-resistant Staphylococcus aureus. However, higher VAN concentrations have been associated with an increased risk of acute kidney injury (AKI). Herein, we aimed to assess the frequency of AKI in different areas under the concentration-time curve (AUC) values of VAN using a two-point blood collection method, allowing for accurate AUC assessment in critically ill patients. We identified an association between AUC on day 2 and the risk of AKI in intensive care unit patients, suggesting that not only AUCs above 600 µg·h/mL but also those between 500 and 600 µg·h/mL pose a risk for AKI. Therefore, individualized dosing is feasible, with pharmacists being able to optimize VAN doses to attain appropriate targets.

Flowchart for predicting achieving the target area under the concentration-time curve of vancomycin in critically ill Japanese patients: A multicenter retrospective study.

INTRODUCTION: In therapeutic drug monitoring (TDM) of vancomycin (VCM), the area under the concentration-time curve (AUC) is related to the clinical efficacy and toxicity. Therefore, herein, we examined the factors associated with achieving the target AUC at follow-up and developed a decision flowchart for achieving the target AUC in critically ill patients. METHODS: This multicenter retrospective observational study was conducted at eight hospitals. We retrospectively analyzed data from patients who had received VCM in the intensive care unit from January 2020 to December 2022. Decision-tree (DT) analysis was performed using factors with p < 0.1 in univariate analysis as the independent variables. Case data were split up to two times, and four subgroups were included. The primary endpoint was achieving the target AUC at the follow-up TDM (AUCfollow-up) and target AUCfollow-up achievement was defined as an AUC of 400-600 µg‧h/mL. The initial AUC values were calculated with the 2-point concentrations (peak and trough) using the Bayesian estimation software Practical AUC-guided TDM (PAT). RESULTS: Among 70 patients (median age [interquartile range], 66 [56, 79] years; 50 % women), the AUCfollow-up was achieved in 70 % (49/70). Three factors were selected for the decision flow chart: predicted AUCfollow-up of 400-600 µg‧h/mL, dosing at 12-h intervals, and CCr of 130 mL/min/1.73 m2 or higher; the accuracy was adequate (92 %, R2 0.52). CONCLUSION: We successfully identified the factors associated with achieving the target AUC of VCM at follow-up TDM and developed a simple-to-use DT model. However, the validity of the findings needs to be evaluated.

Case Report: Case series: association between blood concentration and side effects of sotorasib.

Introduction: Sotorasib is a crucial therapeutic agent for patients with non-small cell lung cancer (NSCLC) harboring the KRAS p.G12C mutation. Despite its efficacy, the relationship between blood sotorasib concentrations and side effects remains largely unexplored. Methods: This study enrolled five patients with KRAS p.G12C-positive NSCLC treated with sotorasib (LUMAKRAS® Tablets, Amgen, Japan) between July 2022 and February 2023 at Asahikawa Medical University Hospital. Blood sotorasib levels were monitored, and their association with adverse events was examined, with no adjustments made to drug dosages based on these levels. Results: Variable blood sotorasib levels were observed among the participants. Notably, one patient developed interstitial pneumonitis, although a definitive attribution to sotorasib was uncertain due to prior pembrolizumab treatment. The study revealed no consistent association between blood sotorasib levels and adverse events or therapeutic outcomes, with some patients experiencing severe side effects at higher concentrations, while others did not. Conclusion: Preliminary findings suggested that monitoring blood sotorasib levels may aid in anticipating adverse events in this small cohort. However, future studies with larger sample sizes and extended follow-up periods are required to validate these initial observations. Such studies could potentially offer insights into personalized dosing strategies, thereby mitigating adverse effects and enhance patient care for individuals with KRAS p.G12C-positive NSCLC.

Adherence of denosumab treatment for low bone mineral density in Japanese people living with HIV: a retrospective observational study.

BACKGROUND: Long-term care issues, specifically metabolic bone disorders, are a concern for people living with human immunodeficiency virus (PLWH) who undergo life-long antiretroviral therapy (ART). Previous clinical trials with denosumab, an anti-RANKL antibody inhibitor, have revealed its effectiveness in increasing bone mineral density (BMD) in patients with osteoporosis. However, there are limited data on adherence and effectiveness of denosumab treatment for osteoporosis in PLWH. Hence, this study aimed to investigate the adherence and effectiveness of denosumab treatment for osteoporosis in Japanese PLWH. METHODS: This study is a retrospective exploratory analysis of 29 Japanese PLWH who initiated denosumab treatment for osteoporosis, between 2013 and 2021. The study included patients who received at least one dose of denosumab every 6 months. Adherence and persistence were defined as receiving two consecutive injections of denosumab 6 months ± 4 weeks apart and 6 months + 8 weeks apart, respectively. The primary outcome measure of the study was the adherence of denosumab treatment for 24 months. The secondary outcome measures included treatment persistence and BMD. The period after January 2020 was defined as the coronavirus disease 2019 (COVID-19) pandemic period, and its impact on adherence was investigated. RESULTS: The treatment adherence rates at 12 and 24 months were 89.7% and 60.7%, respectively. By contrast, the treatment persistence at 12 and 24 months was 100% and 85.7%, respectively. More patients in the group who initiated denosumab treatment after the COVID-19 pandemic reached non-adherence than in the group who initiated denosumab treatment before the pandemic. BMD at the lumbar spine and femoral neck significantly increased compared to that at baseline, with median percentage changes of 8.7% (p < 0.001) and 3.5% (p = 0.001), respectively. CONCLUSIONS: The results showed that patients in the study had a high rate of non-adherence but a lower rate of non-persistence. Additionally, PLWH on ongoing ART experienced increased BMD with denosumab treatment. This study provides an opportunity to improve future strategies for denosumab treatment in the Japanese PLWH.

Tazobactam/ceftolozane and tobramycin combination therapy in extensively drug-resistant Pseudomonas aeruginosa infections in severe burn injury: a case report.

BACKGROUND: Combination therapy with tazobactam/ceftolozane (TAZ/CTLZ) and high-dose aminoglycosides has been reported to be efficacious in extensively drug-resistant (XDR)-Pseudomonas aeruginosa infection. However, there are no reports of efficacy in XDR-P. aeruginosa infection for combination therapy with low-dose aminoglycosides and TAZ/CTLZ. Herein, we describe a rare case of severe burn injury patients with persistent bacteremia due to XDR-P. aeruginosa, which was successfully treated with TAZ/CTLZ and low-dose tobramycin (TOB). CASE PRESENTATION: A 31-year-old man was admitted to the intensive care unit with severe burn injury involving 52% of the total body surface area and a prognostic burn index of 79.5. The patient had recurrent bacterial infections since admission, and blood cultures collected on the 37th day of admission revealed the presence of P. aeruginosa strains that were resistant to all ß-lactams and amikacin (AMK). The results of the antimicrobial synergistic study showed no synergistic effect of low-dose meropenem (MEPM) and AMK combination therapy. The patient had acute renal failure, and it was difficult to increase the dose of MEPM and AMK, respectively. Thus, we initiated TAZ/CTLZ 1.5 g/8 h instead of the AMK and MEPM combination therapy on the 43rd day of hospitalization. Low-dose TAZ/CTLZ was continued because of prolonged renal dysfunction and resulted in a transient clinical improvement. However, the dosage of TAZ/CTLZ could be increased as the renal function improved, but despite an increased TAZ/CTLZ dose, bacteremia persisted, and the blood cultures remained positive. Thus, TOB was added to TAZ/CTLZ at low doses for synergistic effect against Gram-negative bacteria. Blood cultures collected after initiation of combination therapy with TAZ/CTLZ and low-dose TOB were negative on two consecutive follow-up evaluations. Thereafter, although the patient had several episodes of fever and increased inflammatory response, blood cultures consistently tested negative, and all of the wounds healed. On the 93rd day, due to the good healing progress, the patient was transferred to another hospital. CONCLUSIONS: TAZ/CTLZ and low-dose TOB combination therapy showed the potential for synergistic effects. Our present report suggests a novel synergistic treatment strategy for rare cases that are refractory to the treatment of infections, such as XDR-P. aeruginosa infection.

Simulation of Vancomycin Exposure Using Trough and Peak Levels Achieves the Target Area under the Steady-State Concentration-Time Curve in ICU Patients.

The therapeutic drug monitoring (TDM) of vancomycin (VCM) in critically ill patients often results in the estimated area being under the concentration-time curve (AUC) values that deviate from individual observations. In this study, we investigated the factors influencing the achievement of the target AUC of VCM at steady-state in critically ill patients. We retrospectively collected data from patients treated with VCM in an intensive care unit (ICU). Multivariate analysis was used to adjust for significant factors with p < 0.05 and identify new factors affecting the achievement of the target AUC at steady-state for VCM. Among the 113 patients included in this study, 72 (64%) were in the 1-point group (trough only), whereas 41 (36%) were in the 2-point group (trough/peak). The percentage of patients achieving the target AUC at the follow-up TDM evaluation was significantly higher in the two-point group. Multivariate analysis showed that being in the 2-point group and those with a 20% or more increase (or decrease) in creatinine clearance (CCr) were both significantly associated with the success rate of achieving the target AUC at the follow-up TDM. Novel findings revealed that in patients admitted to the ICU, changes in renal function were a predictor of AUC deviation, with a 20% or more increase (or decrease) in CCr being an indicator. We believe the indicators obtained in this study are simple and can be applied clinically in many facilities. If changes in renal function are anticipated, we recommend an AUC evaluation of VCM with a two-point blood collection, close monitoring of renal function, and dose adjustment based on reanalyzing the serum concentrations of VCM.

Effect of renal clearance on vancomycin area under the concentration-time curve deviations in critically ill patients.

INTRODUCTION: Augmented renal clearance (ARC) increases vancomycin (VCM) clearance. Therefore, higher VCM doses are recommended in patients with ARC; however, impacts of ARC on the area under the concentration-time curve (AUC) discrepancies between initial dosing design and therapeutic drug monitoring (TDM) period remains unclear. METHODS: We retrospectively collected data from critically ill patients treated with VCM. The primary endpoint was the association between ARC and AUC24-48h deviations. ARC and AUC deviation were defined as a serum creatinine clearance (CCr) ≥130 mL/min/1.73 m2 and an AUC at TDM 30% or more higher than the AUC at the initial dosing design, respectively. The pharmacokinetic profiles of VCM were analyzed with the trough levels or peak/trough levels using the Bayesian estimation software Practical AUC-guided TDM (PAT). RESULTS: Among 141 patients (median [IQR]; 66 [58-74] years old; 30% women), 35 (25%) had ARC. AUC deviations were significantly more frequent in the ARC group than in the non-ARC group (20/35 [57.1%] and 17/106 [16.0%] patients, respectively, p < 0.001). Age- and sex-adjusted multivariate analyses revealed that the number of VCM doses before TDM ≥5 (odds ratio, 2.56; 95% confidence interval [CI]: 1.01-6.44, p = 0.047) and CCr ≥130 mL/min/1.73 m2 were significantly associated with AUC deviations (odds ratio, 7.86; 95%CI: 2.91-21.19, p < 0.001). CONCLUSION: Our study clarifies that the AUC of VCM in patients with ARC is higher at the time of TDM than at the time of dosage design.

Drug interactions between ALK inhibitors and warfarin with concurrent use of bucolome: a case report.

BACKGROUND: Alectinib, crizotinib, and ceritinib, are anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) that exhibit high protein binding, and their metabolism is associated with the cytochrome P450 (CYP) isoenzymes 2C9 or 3A4. The plasma protein binding rate of warfarin, which is used to prevent and treat venous thromboembolism, is also high. Warfarin is a racemate of S-warfarin and R-warfarin, which are metabolized by CYP2C9 and CYP3A4, respectively. Reports on the drug interactions between each of the above-mentioned ALK-TKIs and warfarin with concurrent use of bucolome are currently lacking. CASE PRESENTATION: We report a case of a patient receiving warfarin and bucolome, whose international normalized ratio (INR) increased after sequential treatment with alectinib, crizotinib, and ceritinib. The patient was a 61-year-old man with a history of aortic valve regurgitation, who was receiving warfarin treatment following aortic valve replacement. Bucolome, which can enhance the effect of warfarin, was also used simultaneously. The patient was diagnosed with primary lung adenocarcinoma, and ALK rearrangement was detected during second-line chemotherapy. After progression of the disease with chemotherapy, sequential treatment with alectinib, crizotinib, and ceritinib was initiated. Pretreatment INR values were in the therapeutic range (target INR of 2-3) but increased to supratherapeutic levels each time after initiation of alectinib, crizotinib, or ceritinib treatment. Adjustment of warfarin dose or discontinuation of bucolome were necessary to maintain the therapeutic INR range. There were no serious bleeding events or substantial changes in dietary intake. Displacement of plasma protein binding or competitive inhibition of metabolism by alectinib, crizotinib, and ceritinib could increase the plasma concentration of the unbound form of warfarin, resulting in high INR values. In addition, alectinib, crizotinib, and ceritinib might cause displacement of bucolome from plasma proteins, followed by displacement of warfarin or inhibition of warfarin metabolism caused by the unbound form of bucolome. CONCLUSIONS: Close monitoring of INR and adjustment of warfarin dosage are needed during treatment with alectinib, crizotinib, or ceritinib in patients who receive warfarin with concurrent use of bucolome.

Comparison of the Treatment Persistence Among 4 Direct Oral Anticoagulants in Patients With Nonvalvular Atrial Fibrillation: A 5-Year Retrospective Cohort Study.

Four direct oral anticoagulants (DOACs) are used in Japan (edoxaban, rivaroxaban, apixaban, and dabigatran); however, few studies have examined the long-term treatment persistence of these DOACs. Furthermore, the factors associated with persistence remain unclear. This single-center, retrospective cohort study enrolled participants who were newly prescribed the 4 DOACs between January 1, 2012, and April 30, 2020. We assessed the treatment persistence rate by calculating the cumulative incidence rate of prescription switch or discontinuation for 5 years from the initial prescription. The factors associated with persistence were examined using multivariate analysis. The edoxaban was used as a reference for comparison with the other DOACs. The persistence rate at 5 years was 52.9% for all DOACs, including 67.0%, 51.6%, 50.2%, and 37.0% for edoxaban, rivaroxaban, apixaban, and dabigatran, respectively. Multivariate analysis revealed that age >65 years (hazard ratio [HR], 0.62 [95%CI, 0.41-0.93]), chronic kidney disease (HR, 1.63 [95%CI, 1.11-2.39]), baseline hemoglobin (HR, 0.85 [95%CI, 0.78-0.93]), diabetes mellitus (HR, 0.51 [95%CI, 0.29-0.93]), and type of DOACs (rivaroxaban: HR, 1.81 [95%CI, 1.03-3.18]; apixaban: HR, 2.00 [95%CI, 1.15-3.48]; and dabigatran: HR, 2.84 [95%CI, 1.66-4.86]) were significantly associated with nonpersistence at 1 year. At 5 years, diabetes mellitus (HR, 0.60 [95%CI, 0.37-0.97]) and type of DOAC were significantly associated with nonpersistence (rivaroxaban: HR, 1.79 [95%CI, 1.09-2.94]; apixaban: HR, 2.04 [95%CI, 1.26-3.31]; and dabigatran: HR, 2.76 [1.73-4.42]). Long-term treatment persistence differed according to the type of DOAC, with edoxaban exhibiting the highest level of persistence. The factors associated with persistence may change over the treatment course, but larger studies are required to generalize our findings.

Delayed dexamethasone treatment at initiation of oxygen supplementation for coronavirus disease 2019 is associated with the exacerbation of clinical condition.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) frequently causes inflammatory lung injury as its symptoms progress. While dexamethasone reportedly reduces inflammation and prevents progression to respiratory failure, the appropriate time to administer dexamethasone in patients with COVID-19 remains unclear. METHODS: This was a single-center, retrospective cohort study, where we consecutively enrolled patients hospitalized with COVID-19 who received oxygen and oral dexamethasone (n = 85). We assessed the association between the number of days to the initiation of dexamethasone and the cumulative rate of exacerbation defined as death or initiation of mechanical ventilation within 28 days of symptom onset. RESULTS: The optimal cut-off value from the initiation of oxygen supplementation to that of dexamethasone administration was two days (sensitivity, 85%; specificity, 59%), whereas that from oxygen saturation (SpO2) < 95% to the initiation of dexamethasone administration was five days (sensitivity, 78%; specificity, 59%). adjusting for age, sex, body mass index, Charlson comorbidity index score, time of oxygen supplementation (two or more days), and SpO2 < 95% (five or more days), Cox regression analysis results showed that delayed dexamethasone administration since the initiation of oxygen supplementation was significantly associated with a higher risk of death or greater need for mechanical ventilation (hazard ratio: 5.51, 95% confidence interval, 1.79-16.91). CONCLUSIONS: In patients with COVID-19 and hypoxemia, early administration of dexamethasone, preferably less than two days from initiation of oxygen supplementation, may be required to improve clinical outcomes.

Utility of a Score for Predicting Glomerular Filtration Rate Overestimation in Patients with Cardiovascular and Renal Diseases and Their Risk Factors.

Objective We recently reported a novel score for the detection of glomerular filtration rate (GFR) overestimation using a creatinine-based equation. We examined the utility of this score in patients with cardiovascular/renal diseases and diabetes mellitus. Methods We enrolled 1,425 patients (65±15 years old; 37% women) who were admitted to our hospital for the management of cardiovascular and renal diseases and their risk factors. Overestimation of the GFR (OE) was defined as a creatinine-based GFR (eGFRcre) ≥120% of the cystatin C-based estimated GFR. The OE score was calculated as the sum of the scores for the body weight, hemoglobin concentration, and blood urea nitrogen (BUN)/serum creatinine (Scr), totaling 1 point if the body weight was <63.0 kg in men or <42.0 kg in women, 1 point if the hemoglobin concentration was <12.4 g/dL in men or <11.0 g/dL in women, and 1 point if the BUN/Scr was >26.5. Results The proportion of patients with OE was 14.2%. The score predicted OE with a sensitivity of 70.8% and a specificity of 99.6%, and the sensitivity was increased in patients ≥75 years old (88.3%) and decreased in diabetics (58.6%). When patients were divided into subgroups by the total score, the frequencies of OE were 8% (59/754), 14% (72/502), 38% (58/151), and 72% (13/18) in patients with scores of 0, 1, 2, and 3, respectively. Conclusion The OE score is useful for detecting elderly cases of cardiovascular and renal diseases in which eGFRcre overestimates the GFR, although its utility is limited in diabetics.

Potential drug-drug interactions in the era of integrase strand transfer inhibitors: a cross-sectional single-center study in Japan.

BACKGROUND: Potential drug-drug interactions (PDDIs) commonly occur because of aging and comorbidities in people living with human immunodeficiency virus (HIV; PLWH). Protease inhibitors and non-nucleoside reverse transcriptase inhibitors have been reported to cause PDDIs in these patients. However, there are few reports of PDDIs in the era of treatment using integrase strand transfer inhibitors. Therefore, we investigated PDDIs in Japanese PLWH receiving antiretroviral drugs (ARVs). METHODS: This was a cross-sectional observational study conducted in Japanese outpatients. All eligible patients who had received ARV therapy for at least 48 weeks were enrolled. The primary endpoint was the incidence of PDDIs detected using the Lexicomp® interface. RESULTS: Of the 71 eligible patients, 51 (71.8%) were prescribed concomitant non-ARV medications. In 21 patients (29.6%), PDDIs with the potential to reduce the effects of ARVs occurred, although the HIV load was suppressed in all cases. Polypharmacy (the use of ≥5 non-ARVs) was observed in 25 patients (35.2%). There was a significantly higher median number of non-ARV medications in the PDDI group than in the non-PDDI group (6 vs. 3, P <  0.001). Furthermore, the proportion of patients on polypharmacy was significantly higher in those with PDDIs than in those without PDDIs (81.0% vs. 26.7%, P <  0.001). CONCLUSIONS: The incidence of PDDIs is relatively high in Japanese PLWH, even in the era of treatment using integrase strand transfer inhibitors. Therefore, it is important for patients and health care providers to be constantly aware of PDDIs associated with ARV treatment.

Real-world pharmacokinetics and pharmacodynamics of everolimus in metastatic breast cancer.

Purpose This study investigated the relationship between the pharmacokinetics and pharmacodynamics of everolimus in patients with metastatic breast cancer (mBC) in real-world practice.Methods Twenty-two patients with mBC treated with everolimus plus exemestane were enrolled. Blood everolimus concentrations were measured at outpatient visits. The inhibition of the mammalian target of rapamycin (mTOR) activity in peripheral blood mononuclear cells (PBMCs) was examined. The efficacy and safety endpoints were progression-free survival (PFS) and the cumulative incidence of dose-limiting toxicities (DLTs), respectively. Results Blood samples were obtained from 19 consenting patients. Everolimus did not completely inhibit mTOR activity in PBMCs at therapeutic concentrations (~ 56 % maximal inhibition). The most common adverse event was stomatitis (any grade 77 %). The trough concentration (Ctrough) was significantly higher in patients experiencing DLTs than in those without any DLTs (P = 0.030). The optimal Ctrough cutoff predicting DLT development was 17.3 ng/mL. The cumulative incidence of DLTs was significantly higher in patients with Ctrough ≥17.3 ng/mL than in other patients (sub-hazard ratio 4.87, 95 % confidence interval [CI] 1.53-15.5; P = 0.007). Furthermore, the median PFS was numerically longer in patients who maintained a steady-state Ctrough below the threshold than in those who did not (327 days [95 % CI 103-355 days] vs. 194 days [95 % CI 45 days-not estimable]; P = 0.35). Conclusions The suggested upper threshold for the therapeutic window of everolimus Ctrough was 17.3 ng/mL. Pharmacokinetically guided dosing may improve the efficacy and safety of everolimus for mBC, warranting further investigation in a larger study.Clinical trial registry: Not applicable.

Early favipiravir treatment was associated with early defervescence in non-severe COVID-19 patients.

INTRODUCTION: The antiviral drug favipiravir has been shown to have in vitro antiviral activity against severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2). In this study, we investigated the clinical benefits and initiation of favipiravir treatment in patients with non-severe coronavirus-disease-2019 (COVID-19). METHODS: This study was a single-center retrospective cohort study. Receiver operating characteristic curves were drawn to calculate the area under the curve, and the optimal cut-off values for the time to initiate favipiravir treatment were calculated to predict defervescence within seven days. Univariate and multivariate Cox regression analyses were performed to identify potential influencing factors of defervescence. This was defined as a body temperature of less than 37 °C for at least 2 days. RESULTS: Data from 41 patients were used for the efficacy assessment. The days from the onset of fever to defervescence showed a positive correlation with the duration from the onset of fever to initiation of favipiravir treatment (r = 0.548, P < 0.001). The optimal cut-off value was the administration of favipiravir on day 4. Patients were assigned to two groups based on the optimal cut-off value from onset to initiation of favipiravir treatment: early treatment group (within 4-days) and late treatment group (more than 4-days). In the multivariate analysis, when adjusted for age, sex, and days from onset to initiation of favipiravir treatment, the significant factors were male sex and days of initiation of the favipiravir treatment. CONCLUSIONS: We recommend that if favipiravir is to be used for treatment, it should be initiated as early as possible.

Pharmacokinetics of the oral multikinase inhibitor regorafenib and its association with real-world treatment outcomes.

Purpose Despite the established activity of regorafenib in metastatic colorectal cancer (CRC), gastrointestinal stromal tumor (GIST), and hepatocellular carcinoma (HCC), its toxicity profile has limited clinical use. We aimed to evaluate the pharmacokinetics of regorafenib and its active metabolites M-2/M-5, and to clarify the relationships between total drug-related exposure and clinical outcomes in real-world practice. Methods Blood samples at steady state were obtained during Cycle 1 from patients treated with regorafenib. Plasma concentrations of regorafenib and its metabolites were measured by liquid chromatography-tandem mass spectrometry. The efficacy and safety endpoints were progression-free survival (PFS) and dose-limiting toxicities (DLTs), respectively. The exposure-response relationships were assessed. Results Thirty-four Japanese patients with advanced cancers were enrolled (CRC, n = 26; GIST and HCC, each n = 4). Nine patients started regorafenib treatment at the recommended dose of 160 mg once daily (3 weeks on / 1 week off), while the other patients received a reduced starting dose to minimize toxicities. The median PFS was significantly longer in patients achieving total trough concentrations (Ctrough) of regorafenib and M-2/M-5 ≥2.9 µg/mL than those who did not (112 vs. 57 days; p = 0.044). Furthermore, the cumulative incidence of DLTs during the first 2 cycles was significantly higher in patients with summed Ctrough levels ≥4.3 µg/mL than in others (p = 0.0003). Conclusions Dose titration of regorafenib to achieve drug-related Ctrough levels between 2.9 and 4.3 µg/mL in Cycle 1 may improve efficacy and safety, warranting further investigation in a larger patient population.Clinical trial registry: Not applicable.

[Efficacy and Safety of Linaclotide in Elderly Patients].

The efficacy and safety of linaclotide in elderly patients are poorly understood. Herein, we aimed to assess the efficacy and safety of linaclotide in elderly patients in real-world setting. We retrospectively enrolled consecutive patients who started linaclotide therapy at Sapporo Medical University Hospital from October 1, 2017 to December 31, 2019. The efficacy and safety of linaclotide were examined in relation to various factors, including age (<65 or ≥65 years) and dose (0.25 or 0.5 mg/d). Fifty-two patients were enrolled, 60% of whom were over 65 years old and 40% were female. Thirty-six patients received a linaclotide dose of 0.25 mg/d. The most common side effect was diarrhea, but there was no difference in the incidence of diarrhea between the elderly (64.5%) and non-elderly patients (42.9%, p=0.130). No significant difference was observed with respect to improvement in constipation in the elderly (83.9%) and non-elderly patients (71.4%, p=0.318). Additionally, the difference in efficacy of linaclotide in patients who received a reduced dose (80.6%) vs. those who received the recommended dose (75.0%) was not statistically significant (p=0.719). Multivariate analysis revealed that age, gender, and dose were not associated with diarrhea induced by linaclotide treatment. However, concurrent treatment with constipation-inducing medications [odds ratio (OR) 5.79, p=0.047] and linaclotide monotherapy (OR 11.1, p=0.040) were both risk factors contributing to diarrhea. Linaclotide is effective and safe for use in elderly patients. The incidence of diarrhea may increase when linaclotide is administered alone or concurrently used with medications that cause constipation.

Pharmacokinetically guided dosing has the potential to improve real-world outcomes of pazopanib.

It remains unclear whether therapeutic drug monitoring (TDM) of pazopanib improves treatment outcomes in routine clinical practice. We did a prospective cohort study to evaluate the benefits of TDM for pazopanib therapy in real-world practice. Among 25 patients with pharmacokinetically guided dosing, only 5 (20%, 95% confidence interval 6.8-40.7%) discontinued treatment because of adverse events. However, 5 (41.7%, 95% confidence interval 15.2-72.3%) of historical controls including 12 patients not receiving such a strategy experienced adverse events leading to early termination. PK-guided dosing significantly increased median time-to-treatment discontinuation (252 vs 74 days, P = .012) with reduced toxicity and improved overall survival (not reached vs 313 days, P = .002) relative to conventional dosing in the control group. In conclusion, PK-guided dose adaptation through the use of TDM has the potential to improve treatment outcomes of pazopanib in routine clinical practice, warranting larger, randomized studies.

Absorption of the orally active multikinase inhibitor axitinib as a therapeutic index to guide dose titration in metastatic renal cell carcinoma.

Purpose Axitinib is an orally active multikinase inhibitor currently used to treat patients with metastatic renal cell carcinoma (RCC). This study examined the pharmacokinetics of axitinib and the relationship between peak drug concentration (Cmax) and clinical outcomes in real-world practice. Methods Twenty patients with metastatic RCC treated with axitinib monotherapy were enrolled. Post-dose (1-4 h) blood samples were obtained, and axitinib Cmax in plasma was measured by liquid chromatography-tandem mass spectrometry. Efficacy endpoints were best overall response (per RECIST 1.1) and progression-free survival (PFS). The safety endpoint was the cumulative incidence of dose-limiting toxicities (DLTs). Results Large inter- and intra-individual variability in dose-adjusted Cmax was observed (0.02-11.2 ng/mL/mg). Axitinib absorption was significantly influenced by glucuronidation activity (P = 0.040). Cmax at steady state was significantly higher in responders than in non-responders (P = 0.013). The optimal Cmax cutoff to predict a clinical response was 12.4 ng/mL. The median PFS was significantly longer in patients who achieved an average steady state Cmax above the threshold than in those who did not (799 vs. 336 days; P = 0.047). The cumulative incidence of DLTs was significantly higher in patients with Cmax ≥ 40.2 ng/mL than in other patients (sub-hazard ratio, 4.13; 95% confidence interval, 1.27-13.5; P = 0.019). Conclusions The potential therapeutic window of axitinib Cmax in metastatic RCC was estimated at 12.4-40.2 ng/mL. Pharmacokinetically guided dose titration using therapeutic drug monitoring may improve the efficacy and safety of axitinib, warranting further investigation in a larger patient population.

Real-World Nivolumab Wastage and Leftover Drug Stability Assessment to Facilitate Drug Vial Optimization for Cost Savings.

PURPOSE: Nivolumab dosage was initially selected on the basis of body weight, often resulting in leftover drug after sterile compounding. This study sought to investigate the real-world wastage of nivolumab and assess the long-term stability of leftover nivolumab within vials to facilitate drug vial optimization (DVO). METHODS: We collected all discarded vials after preparation from 17 regional hospitals in Japan over a 6-month period preceding the adoption of a fixed dose of 240 mg per administration. The actual amount of waste was measured for each preparation. Stability assessment was performed under different storage conditions. RESULTS: A total of 2,789 100-mg vials and 4,069 20-mg vials were collected. Overall, the drug cost associated with the expenditure of nivolumab alone was $12.1 million, whereas the total cost due to drug wastage was $0.735 million (rate of wastage, 6.1%). Furthermore, the immunoglobulin G concentrations of nivolumab remaining within vials, as well as binding activity to programmed death-1 protein, did not change significantly over 4 weeks of storage at either 4°C or room temperature. CONCLUSION: Significant drug wastage occurs during sterile preparation of nivolumab according to body weight-based dosing. Although nivolumab dosing has been changed to a fixed dose in Japan, body weight-based dosing is still applied in some other countries, as well as in combination therapy with ipilimumab. Our findings regarding the long-term stability of leftover nivolumab within the vials should motivate hospitals to implement DVO for cost savings.