Safety and blood levels of daratumumab after switching from intravenous to subcutaneous administration in patients with multiple myeloma.

The intravenous administration (IV) of daratumumab sometimes causes an infusion reaction and needs a long infusion time. Recently, a subcutaneous formulation (SC) of daratumumab, which has fewer infusion reactions and shorter administration time, was approved. However, because SC has a fixed dose, overdosing is a concern for patients with low body weights. In this study, we investigated the safety and blood levels of daratumumab after switching from IV to SC in patients with multiple myeloma (MM). Patients who switched from IV to SC of daratumumab between June 2021 and May 2022 at Kobe City Medical Center General Hospital were included in the study. Blood daratumumab levels were measured using liquid chromatography-tandem mass spectrometry. Safety after switching from IV to SC was evaluated for six months and graded according to the Common Terminology Criteria for Adverse Events, version 5.0. The median body weight of ten patients included in the analysis was 57.4 kg (range: 45.0-74.4). Blood daratumumab levels were significantly increased after switching to SC (p = 0.002); median through concentration at the last IV dose was 403.6 µg/mL (range: 96.3-776.3) and that at the third SC dose was 557.1 µg/mL (range: 288.3-997.2). Grade 1-2 injection site reactions were observed in six patients (60.0%) after switching to SC. A new grade 3 adverse event was observed in only one patient (neutropenia). The blood levels of daratumumab were significantly increased after switching from IV to SC in patients with MM; however, the dosage was tolerable.

Pharmacist-Urologist Collaborative Management for Patients with Renal Cell Carcinoma Receiving Pazopanib Monotherapy.

Pazopanib is one of recommended treatment for metastatic renal cell carcinoma (RCC). Despite its effectiveness, patients often difficult to continue pazopanib treatment due to adverse events (AEs). We established an ambulatory care pharmacy practice that enables pharmacist-urologist collaboration to manage patients with RCC. This study evaluated the usefulness of this collaborative management. We retrospectively reviewed the medical records of 51 consecutive patients with metastatic RCC receiving pazopanib at the Kobe City Medical Center General Hospital between April 2014 and December 2020. Our collaborative management was implemented in October 2016. The time to pazopanib discontinuation was compared between patients who started pazopanib before (n = 30) and after (n = 21) the implementation of the collaborative management. A multivariate Cox regression analysis was performed to analyze the factors associated with pazopanib discontinuation. In the collaborative management, the oncology pharmacists had a total of 245 face-to-face patient consultations, and provided 286 suggestions [according to supportive care in pazopanib treatment (214 suggestions) were most frequent], and 236 (82.5%) were accepted by urologists. The median time to discontinuation (6.1 months vs. 2.4 months, p = 0.024) was significantly longer in the after group. Multivariate analysis showed that collaborative management (hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.26-0.88, p = 0.017), and Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 at pazopanib initiation (HR 3.87, 95% CI 1.47-9.13, p = 0.008) were significantly associated with pazopanib discontinuation. These results suggested that, compared to conventional management, collaborative management is effective at prolonging the time to pazopanib discontinuation.

Pharmacokinetics of Temozolomide in a Patient With Glioblastoma Undergoing Hemodialysis: A Short Communication.

BACKGROUND: Temozolomide (TMZ) is an alkylating agent used to treat glioblastoma. However, the pharmacokinetics of TMZ to establish a treatment strategy for patients undergoing hemodialysis (HD) remain unclear. In this case report, we evaluated the pharmacokinetics and HD removal rate of TMZ in a patient with glioblastoma undergoing HD to determine optimal dosing of TMZ. METHODS: A 78-year-old man with glioblastoma who underwent HD 3 times a week was treated with TMZ concomitant with radiotherapy. One dose of TMZ was prescribed at 75 mg/m 2 on the day before HD and another dose of 37.5 mg/m 2 on the day before non-HD. Peak and trough concentrations (1 hour and 12 hours after dosing, respectively) were evaluated before HD and on non-HD days. HD removal rate of TMZ was calculated based on the predialyzer and postdialyzer plasma concentrations. Furthermore, the TMZ plasma concentrations were measured using liquid chromatography-tandem mass spectrometry. RESULTS: The mean plasma peak and trough concentrations ± SD after 75 mg/m 2 TMZ were 2917 ± 914 and 108 ± 17.6 ng/mL, respectively. Those after 37.5 mg/m 2 TMZ dosage were 1305 ± 650 and 53.8 ± 11.8 ng/mL, respectively. The mean HD TMZ removal rate was 84.9 ± 1.9%. CONCLUSIONS: TMZ was tolerable in patients undergoing HD. Based on the data from a single individual pharmacokinetic perspective, the pharmacokinetics of TMZ in this patient undergoing HD were comparable with those observed in patients with normal renal function. In addition, it may be reasonable to administer TMZ after HD because of the high HD removal rate.

Impact of prior bevacizumab therapy on the incidence of ramucirumab-induced proteinuria in colorectal cancer: a multi-institutional cohort study.

BACKGROUND: The association between prior bevacizumab (BEV) therapy and ramucirumab (RAM)-induced proteinuria is not known. We aimed to investigate this association in patients with metastatic colorectal cancer (mCRC). METHODS: mCRC patients who received folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus RAM were divided into with and without prior BEV treatment groups. The cumulative incidence of grade 2-3 proteinuria and rate of RAM discontinuation within 6 months (6M) after RAM initiation were compared between the two groups. RESULTS: We evaluated 245 patients. In the Fine-Gray subdistribution hazard model including prior BEV, age, sex, comorbidities, eGFR, proteinuria ≥ 2 + at baseline, and later line of RAM, prior BEV treatment contributed to proteinuria onset (P < 0.01). A shorter interval between final BEV and initial RAM increased the proteinuria risk; the adjusted odds ratios (95% confidence intervals) for the intervals of < 28 days, 28-55 days, and > 55 days (referring to prior BEV absence) were 2.60 (1.23-5.51), 1.51 (1.01-2.27), and 1.04 (0.76-1.44), respectively. The rate of RAM discontinuation for ≤ 6M due to anti-VEGF toxicities was significantly higher in the prior BEV treatment group compared with that in the no prior BEV treatment group (18% vs. 6%, P = 0.02). Second-line RAM discontinuation for ≤ 6M without progression resulted in shorter overall survival of 132 patients with prior BEV treatment (P < 0.01). CONCLUSION: Sequential FOLFIRI plus RAM after BEV failure, especially within 55 days, may exacerbate proteinuria. Its escalated anti-VEGF toxicity may negatively impact the overall survival.

Population Pharmacokinetics of Nivolumab in Japanese Patients with Nonsmall Cell Lung Cancer.

BACKGROUND: Nivolumab is an antiprogrammed death-1 (PD-1) antibody used for immuno-oncological therapy of various cancers, including nonsmall cell lung cancer (NSCLC). This study aimed to characterize the real-world population pharmacokinetics (PK) of nivolumab in patients with NSCLC. METHODS: PK samples were collected by opportunistic sampling of Japanese patients with NSCLC treated with nivolumab monotherapy. Population PK analysis was performed using a two-compartment model in Nonlinear Mixed Effect Model. Patient-specific factors such as body weight, age, sex, serum albumin, estimated glomerular filtration rate, performance status, programmed cell death receptor ligand 1 expression in tumors, and treatment periods were evaluated as potential covariates for clearance. RESULTS: A total of 223 serum samples collected from 34 patients were available for analysis. The median (min-max) age and weight were 69 years (38-83 years) and 62.7 kg (36.8-80.5 kg), respectively. The mean (95% confidence interval) clearance estimate was 0.0064 L/h (0.0058-0.0070 L/h). The inclusion of the ALB level, estimated glomerular filtration rate, and treatment period significantly improved the model fit. CONCLUSIONS: A real-world nivolumab population PK model was developed using an opportunistic sampling strategy in Japanese patients with NSCLC. Further studies are warranted to characterize the exposure-response relationship and determine the optimal dosing regimens for these patients.

Everolimus pharmacokinetics and exposure-response relationship in Japanese patients with advanced breast cancer.

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.

Evaluating the safety and efficiency of robotic dispensing systems.

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.

Pharmacist-Urologist Collaborative Management Improves Clinical Outcomes in Patients With Castration-Resistant Prostate Cancer Receiving Enzalutamide.

Background: Enzalutamide is useful for the treatment of castration-resistant prostate cancer (CRPC). Despite its usefulness, adverse events (AEs) sometimes force patients to discontinue treatment. To maximize patient care, we developed an ambulatory care pharmacy practice that allows collaboration between a pharmacist and urologist to manage patients with CRPC receiving enzalutamide. In this study, we investigated the efficacy of this collaborative management. Methods: A retrospective chart review of 103 patients with CRPC receiving enzalutamide in our hospital between May 2014 and December 2020 was performed. Our collaborative management was implemented in October 2016. Before being examined by urologists, patients visited the oncology pharmacy consultation room for a face-to-face consultation, wherein the oncology pharmacists assessed factors such as adherence to enzalutamide, any AEs and their grades, and provided their suggestions to the urologists. The time to enzalutamide discontinuation and prostate-specific antigen progression were compared between patients who started enzalutamide before (n = 41) and after (n = 62) the implementation of the collaborative management. A multivariate Cox regression analysis was performed to analyze the factors associated with enzalutamide discontinuation. Results: After implementing collaborative management, the pharmacists had 881 patient consultations. Among the 476 suggestions from pharmacists, 345 were accepted by urologists. The most frequent suggestion was supportive care in enzalutamide treatment (224 suggestions). Multivariate analysis showed that collaborative management [hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.31-0.89, p = 0.017] and higher prostate-specific antigen (PSA; HR 2.41, 95% CI 1.36-4.28, p = 0.003) were significantly associated with enzalutamide discontinuation. The median time to discontinuation (18.9 vs. 7.6 months, p = 0.012), time to discontinuation due to AEs (not reached in both groups, p = 0.001), and time to PSA progression (13.3 vs. 5.8 months, p = 0.002) were all significantly longer in the after group. Conclusions: We implemented a pharmacist-urologist collaborative management program for outpatients with CRPC receiving enzalutamide. The results revealed that collaborative management was useful for prolonging the time to enzalutamide discontinuation.

Risk Factors of Proteinuria in Patients with Hepatocellular Carcinoma Receiving Lenvatinib.

Proteinuria is one of the most frequently reported adverse events leading to the discontinuation of lenvatinib treatment in patients with advanced hepatocellular carcinoma (HCC). However, there are no reports regarding the risk factors of proteinuria in patients with HCC or patients receiving lenvatinib. We retrospectively reviewed the medical records of patients with HCC receiving lenvatinib at the Kobe City Medical Center General Hospital between April 2018 and December 2020. The severity of proteinuria was graded based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. A multivariate Cox proportional hazards model was employed to identify the risk factors of developing grade ≥2 proteinuria. Among the 37 patients included, 3 patients had grade-1 proteinuria at baseline and 10 patients had estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at baseline. Grades 1, 2, and 3 proteinuria were observed in 15 (40.5%), 10 (27.0%), and 2 (5.4%) patients, respectively, during lenvatinib treatment. The median value of eGFR was significantly lower in patients who developed grade ≥2 proteinuria than those with grade ≤1 proteinuria (59.6 vs. 78.1 mL/min/1.73 m2, p = 0.045). Multivariate analysis revealed that pre-existing proteinuria at baseline (hazard ratio (HR), 9.72; 95% confidence interval (CI), 1.29-52.21; p = 0.030), and eGFR <60 mL/min/1.73 m2 at baseline (HR, 4.49; 95% CI, 1.32-16.07; p = 0.017) were significantly associated with developing grade ≥2 proteinuria. These patients should be monitored carefully, and our preliminary data should be confirmed by further studies.

Risk factors of proteinuria and potentially protective effect of renin-angiotensin system inhibitors in patients with renal cell carcinoma receiving axitinib.

PURPOSE: Patients receiving vascular endothelial growth factor-tyrosine kinase inhibitors are at a risk of developing proteinuria. Renin-angiotensin system (RAS) inhibitors exert renoprotective effects and might reduce proteinuria risk in these patients. We investigated the risk factors for and protective effect of RAS inhibitors against proteinuria in patients with renal cell carcinoma (RCC) receiving axitinib. METHODS: We retrospectively reviewed the medical records of patients with RCC receiving axitinib at Kobe City Medical Center General Hospital between September 2012 and October 2020. Patients with proteinuria ≥ 2+ at baseline were excluded. The patients were categorized into RAS inhibitor user, non-RAS inhibitor user, and non-user groups. The severity of proteinuria was graded based on the Common Terminology Criteria for Adverse Events, version 5.0. A multivariate Cox proportional hazards model was employed to identify the risk factors for developing grade ≥ 2 proteinuria. RESULTS: Among 42 patients, 28 received antihypertensive drugs at baseline. Among these, 17 and 11 patients were in the RAS inhibitor and non-RAS inhibitor user groups, respectively. Twenty-three patients (54.8%) developed grade ≥ 2 proteinuria. The multivariate analysis revealed that the non-RAS inhibitor user group (P = 0.001) and patients with pre-existing grade 1 proteinuria (P = 0.022) were significantly associated with the development of grade ≥ 2 proteinuria, whereas the RAS inhibitor user group was not significantly associated with it. CONCLUSION: In patients with RCC receiving axitinib, pre-existing proteinuria and non-RAS inhibitor use were significantly associated with grade ≥ 2 proteinuria development. Our preliminary data should be confirmed by further studies.

Risk evaluation of denosumab and zoledronic acid for medication-related osteonecrosis of the jaw in patients with bone metastases: a propensity score-matched analysis.

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.

[Consideration on Expiration Days Setting for the Introduction of Drug Vial Optimization].

When drug vial optimization(DVO)is implemented, the medical facilities will be forced to bear the cost of the divided- use drugs not used up within the expiration date. We determined the expiration days to use up the residual drugs in the vial within the expiration period. The cost of discarded drugs was calculated from the prescription data of anticancer drugs. We estimated the discarded drug volumes when the expiration period was 0, 1, 2, 7, 8, 14, or 28 days for each liquid anticancer drug. When the expiration period was 7 days, the discarded amount was equivalent to 5.5% of the amount on 0-day expiration period. Only one drug with a 28 day expiration period had to be discarded. When the expiration period is 1 to 2 days, drugs are always discarded and the medical facilities must bear the cost of the wasted drugs. If the expiration period is 7 days or more, most of the medicine will not be discarded. To introduce DVO to medical facilities without economic loss, extending the expiration period of DVO must be considered.

Direct Oral Anticoagulants for the Treatment of Venous Thromboembolism in Patients With Active Cancer.

BACKGROUND/AIM: Although direct oral anti - coagulants (DOACs) are as safe and effective as conventional anticoagulants for treating venous thromboembolism (VTE), we have insufficient evidence justifying their use in patients with active cancer. We investigated the safety and effectiveness of DOACs in patients with active cancer. PATIENTS AND METHODS: To investigate the safety and efficacy of DOACs, we retrospectively extracted 312 consecutive patients with active cancer who were prescribed edoxaban, rivaroxaban or apixaban for VTE. RESULTS: The most common primary cancer sites were the lung, stomach, colon/rectum, hematology, ovary, and pancreas. Fifty patients (16%) discontinued DOACs due to clinically relevant bleeding; major bleeding events occurred in 18 patients (5.4%). Thrombosis reduced or resolved in 144 of 167 evaluable patients (86%). In particular, pulmonary embolism was reduced or resolved in 46 of 50 patients (92%). CONCLUSION: Our findings revealed that DOACs for cancer-associated VTE are as safe and effective as conventional anticoagulation therapy.

Switching from zoledronic acid to denosumab increases the risk for developing medication-related osteonecrosis of the jaw in patients with bone metastases.

PURPOSE: Switch 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. METHODS: The 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. RESULTS: Among 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. CONCLUSION: Our results suggest that switching from ZA to denosumab significantly increases the risk for developing MRONJ in patients with bone metastases.

Associated characteristics and treatment outcomes of medication-related osteonecrosis of the jaw in patients receiving denosumab or zoledronic acid for bone metastases.

PURPOSE: This 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. METHODS: The 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. RESULTS: Among 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). CONCLUSION: The 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.

Safety evaluation of enzalutamide dose-escalation strategy in patients with castration-resistant prostate cancer.

PURPOSE: Enzalutamide (ENZ) is an androgen receptor inhibitor used for the treatment of castration-resistant prostate cancer (CRPC). The aim of this study was to evaluate the safety of the ENZ by dose-escalation strategy in patients with CRPC. METHODS: We retrospectively reviewed patients with CRPC who received standard ENZ (started at 160 mg) or dose-escalation ENZ (started at 80 mg followed by dose escalation) from May 2014 to June 2019 in our hospital. Safety and time to treatment failure (TTF) were evaluated. Multivariate logistic regression analysis was used to evaluate adverse events and drug discontinuation. Multivariate Cox regression analysis was used to evaluate TTF. RESULTS: Among 107 patients, 17 patients received standard ENZ and 90 patients received dose-escalation ENZ therapy. Adverse events (any grade) were observed in 88.2% of patients in the standard group and 63.3% in the dose-escalation group (P = 0.020). Grade ≥3 adverse events were observed in 23.5% and 6.7% of the patients in the standard and dose-escalation groups, respectively, (P = 0.021). Discontinuation due to adverse events was 35.3% and 12.2% in the standard and dose-escalation groups, respectively (P = 0.070). Median TTF was 10.4 months (95% confidential interval [CI]: 2.6-31.3 months) and 18.0 months (95% CI: 11.5-22.8 months) in the standard and dose-escalation groups, respectively (Hazard ratio: 0.60, 95% CI: 0.29-1.30, P = 0.194). CONCLUSIONS: With the ENZ dose-escalation strategy, adverse events related to ENZ of any grade and grade ≥3 were significantly decreased, and discontinuation due to adverse events also decreased. Therefore, the dose-escalation strategy could be useful in optimizing the dose of ENZ.

Evaluation of the usefulness of protocol-based pharmacist-facilitated laboratory monitoring to ensure the safety of immune checkpoint inhibitors in patients with lung cancer.

WHAT IS KNOWN AND OBJECTIVE: Immune checkpoint inhibitors can cause immune-related adverse events (irAEs). Improved monitoring systems for irAEs, which include laboratory tests by a qualified multidisciplinary team, might prevent patients from irAE-associated events. Kobe City Medical Center General Hospital developed protocol-based pharmacist-facilitated laboratory tests named protocol-based pharmacotherapy management (PBPM) to aid the administration of immunotherapy to patients with lung cancer. The protocol defines the laboratory test items and times at which they should be performed. It requires pharmacists to check laboratory orders initiated by physicians and enter additional test items if the orders are incomplete. We evaluated the efficacy of PBPM in irAE monitoring and compared it with those of conventional care systems. METHODS: From January 2016 to March 2018, 114 patients with lung cancer received immunotherapy, which was managed by conventional care (conventional group). From April to September 2018, 62 patients were managed by PBPM (PBPM group), among those 28 patients were transited from conventional group to PBPM group. Data on whether the laboratory tests were conducted or omitted were collected retrospectively for the conventional group and prospectively for the PBPM group. RESULTS: Within the conventional group, 4604 (87.6%) out of the 5253 laboratory test items were ordered by physicians. Of the remaining 649 test items, 224 (4.3%) items were added by physicians based on recommendations by pharmacists. However, of the 1581 (86.6%, from among 1826) test items that were previously ordered by physicians, only 231 (12.7%) test items were added by pharmacists. The execution rate was found to be significantly higher in the PBPM group (99.2% vs 91.9%, P < .001). WHAT IS NEW AND CONCLUSION: PBPM-based pharmacist-facilitated laboratory monitoring systems provided higher executing rate of laboratory order to monitor irAEs during immunotherapy.

A simplified method for therapeutic drug monitoring of mitotane by gas chromatography-electron ionization-mass spectrometry.

Mitotane is a key drug for the treatment of adrenal cortical carcinoma. Due to its narrow therapeutic window, 14-20 µg/mL, monitoring its concentration is crucially important. In this study, a simplified method for measuring mitotane in plasma using gas chromatography-electron ionization-mass spectrometry (GC-EI-MS) was developed. Through deproteination and liquid-liquid extraction, mitotane and an internal standard (IS) were extracted from plasma samples. GC-EI-MS yielded retention times of 8.2 and 8.7 min, for mitotane and the IS, respectively, with a total run time of 12 min. Selectivity and intra-/inter-batch accuracy and precision analyses provided a lower limit of quantification of 0.25 µg/mL, and a calibration curve between 0.25 and 40 µg/mL had good linearity (coefficient of determination = 0.992). The matrix effect factor and percent recovery of the method had good precision. Additionally, long-term sample stability was observed below 4°C. In a clinical setting, mitotane levels in plasma from an adrenal cortical carcinoma patient were within calibration range. Therefore, this simplified method can be applied to routine therapeutic drug monitoring of mitotane, which may contribute to improved treatment of adrenal cortical carcinoma.

Successful oral desensitization with osimertinib following osimertinib-induced fever and hepatotoxicity: a case report.

Osimertinib is a standard second-line therapy for patients who develop EGFR Thr790Met resistance mutation after treatment with first-line epidermal growth factor receptor tyrosine kinase inhibitors. Although no other effective targeted treatment option exists for these patients, osimertinib might be permanently discontinued owing to the onset of severe drug-induced toxicities like hepatotoxicity. Herein, we report a case of successful oral desensitization with osimertinib after the patient developed osimertinib-induced fever and hepatotoxicity. In the present case report, a 62-year-old Japanese woman received osimertinib as the sixth-line therapy for non-small cell lung carcinoma harboring EGFR Thr790Met-mutation. After 15 days of treatment, she developed general malaise. Although we reduced the drug at a lower dose, she again presented with high fever and elevated serum AST/ALT levels three days after re-initiating treatment. We then attempted oral desensitization with osimertinib over a two-week period. Thereafter, the patient continued osimertinib treatment for 6 months without the recurrence of side effects. In conclusion, oral desensitization may be a useful method in treating hepatotoxicity and drug fever caused by osimertinib.

Predictive factors for ocular complications caused by anticancer drug S-1.

PURPOSE: To identify predictive factors for ocular complications caused by the anticancer drug S-1. METHODS: A questionnaire was administered to 39 patients who underwent S-1 chemotherapy at Kobe City Medical Center General Hospital, with the aim to determine whether these patients were aware of the ocular complications caused by S-1. Cognition rate was determined. The 26 patients who requested opthalmological examination for further evaluation studied further and classified into two groups-those who had developed corneal epithelial complications, conjunctival injection or chemosis, or lacrimal duct blockages (referred to as the positive group) and those without these findings (referred to as the negative group). Predictive factors, such as age, sex, total administration days, total dose, presence or absence of anticancer drug pretreatment, and single-drug or combination-drug therapy, were investigated and compared between groups. RESULTS: Of the 39 patients who completed the questionnaire, ten were aware of the potential for ocular complications due to S-1 chemotherapy (cognition rate 25.6 %). Of the 26 patients who had requested opthalmological examination and entered into the study, 13 (26 eyes) were classified into the positive group, with corneal complications observed in 15 eyes (57.7 %), conjunctivitis in 26 eyes (100 %), and lacrimal duct blockage in 14 eyes (53.8 %). Cognition rate in the 13 patients in the positive group and the 13 patients in the negative group was 38.5 % (5 patients) and 7.7 % (1 patient), respectively. Patient age was significantly different between the two groups, with the patients in the positive group being significantly older than those in the negative group (mean age ± standard deviation: 71.6 ± 6.8 vs. 63.5 ± 7.3 years, respectively; P = 0.0077, Student's t test). No other significant predictive factors were detected. CONCLUSION: Older patients were at greater risk of S-1-related ocular complications, but these complications were not associated with total administration days or total dose.