Successful Isavuconazole Treatment for Pulmonary Mucormycosis in a Patient Intolerant to Liposomal Amphotericin B with Pharmacokinetic Insights: A Case Report.

INTRODUCTION: Mucormycosis presents a diagnostic challenge characterized by high morbidity and mortality rates due to its swift and pervasive nature, which leads to extensive tissue destruction and dissemination. Immunocompromised individuals, notably those with hematological malignancies, are at a heightened risk. First-line antifungal agents include liposomal amphotericin B (L-AMB), posaconazole, and isavuconazole (IVZ), which offer advantages, such as minimal drug interactions and a favorable safety profile. However, the necessity and efficacy of therapeutic drug monitoring (TDM) of IVZ remain unclear. CASE PRESENTATION: We report a successful case of IVZ therapy in a patient who was intolerant of L-AMB, highlighting the efficacy and pharmacokinetics of IVZ in treating pulmonary mucormycosis. Pharmacokinetic analysis revealed steady plasma IVZ concentrations, emphasizing the importance of monitoring IVZ levels, particularly in patients undergoing renal replacement therapy. CONCLUSION: This case highlights the efficacy of IVZ therapy for mucormycosis and the potential utility of TDM in a specific patient population. Further research is needed to elucidate the optimal IVZ dosing and monitoring strategies to ensure safe and efficacious treatment.

Monitoring of blood levels in patients administered CYP3A4 inhibitor during the maintenance phase of venetoclax administration
.

OBJECTIVE: Venetoclax, an oral B-cell lymphoma-2 inhibitor, necessitates dose adjustment when combined with a CYP3A4 inhibitor; however, the dosing regimen remains unclear on adding a CYP3A4 inhibitor after venetoclax administration. CASE SUMMARY: We present a case report of a patient who was simultaneously treated with a CYP3A4 inhibitor and a steady daily dose of venetoclax. A 30-year-old male diagnosed with acute myeloid leukemia received a combination of venetoclax and azacitidine as remission induction therapy. He was prescribed 400 mg/day venetoclax at a steady daily dose, with fosfluconazole initiated on day 18. Given that fosfluconazole can induce moderate CYP3A4 inhibitory effects, the venetoclax dosage was reduced to 200 mg/day on the same day. Despite dose reduction, plasma trough levels of venetoclax continued rising gradually. Nearly 10 days were required to decrease blood levels to a steady state. CONCLUSION: The risk of elevated venetoclax blood levels needs to be considered when initiating CYP3A4 inhibitors and reducing venetoclax dosage on the same day.

Adverse Metabolic Effects on Glucose in Patients Receiving Anamorelin Using a Japanese Claims Database.

BACKGROUND: Anamorelin is the first drug approved for the treatment of cancer cachexia, a debilitating condition characterized by weight loss, anorexia, and muscle mass depletion. Cachexia negatively affects a patient's quality of life, survival, and response to chemotherapy. Studies describing anamorelin use are currently limited to a small number of pancreatic cancer cases. OBJECTIVES: We aimed to examine the incidence and risk factors of adverse metabolic effects on glucose levels in cachexia patients with various carcinomas treated with anamorelin. METHOD: We used real-world data of patients who received anamorelin between August 2021 and July 2022 and were registered in the JMDC claims database. We investigated the impact of metabolic adverse effects on glucose in patients receiving anamorelin with respect to the following factors: sex (male), age (>75 years), types of carcinoma, history of diabetes mellitus (DM), and concomitant use of steroids. RESULTS: The incidence of adverse metabolic effects on glucose was 12.3%, and pancreatic cancer and history of DM were associated with adverse metabolic effects on glucose. The median onset of adverse metabolic effects on glucose was 17 days after anamorelin treatment. CONCLUSIONS: This study highlights the need to monitor and manage hyperglycemia in cachexia patients receiving anamorelin, especially in those with pancreatic cancer and a history of DM.

Effect of infusion time of intravenous acetaminophen on blood pressure in the intensive care unit.

OBJECTIVE: To understand the effect of prolonged intravenous acetaminophen infusion on blood pressure. MATERIALS AND METHODS: We retrospectively studied a cohort of intensive care patients receiving initial intravenous acetaminophen. We used propensity score matching to adjust for differences between patients who were classified into two groups: control (acetaminophen infusion for 15 minutes) and prolonged administration (acetaminophen infusion for > 15 minutes). RESULTS: After acetaminophen administration, diastolic blood pressure was unchanged in the control group, and was significantly lower at 30 and 60 minutes in the prolonged administration group. CONCLUSION: Prolonged duration of acetaminophen infusion did not prevent acetaminophen-induced blood pressure reduction.

SEM Observation of the Filter after Administration of Blinatumomab: A Possibility of Leakage during Home Administration Using a Portable Infusion Pump.

Blinatumomab (Blincyto® injection solution) is classified as a bispecific T-cell engaging (BiTE) antibody and is intended for the treatment of relapsed/refractory acute lymphoblastic leukemia. It requires continuous infusion to maintain therapeutic levels. Therefore, it is often administered at home. Monoclonal antibodies, which are administered intravenously, have the potential to leak depending on the nature of the administration devices. Therefore, we investigated device-associated causes of blinatumomab leakage. We observed no apparent changes to the filter and its materials after exposure to the injection solution and surfactant. From scanning electron microscopic images, precipitate on the surface of the filters was observed after physical stimulation of the injection solution. Therefore, physical stimulations should be avoided during the prolonged administration of blinatumomab. In conclusion, the findings of this study assist in the safe administration of antibodies using portable infusion pumps, taking into consideration the composition of drug excipients and the choice of filter type and structure.

Pharmacokinetics of ibrutinib in a patient with chronic lymphocytic leukemia on hemodialysis.

Ibrutinib, an oral Bruton's tyrosine kinase inhibitor, is a key drug for the treatment of chronic lymphocytic leukemia (CLL). It is primarily metabolized by cytochrome P450 3A. However, there are no data on the pharmacokinetics of ibrutinib in patients with severe renal impairment or on hemodialysis (HD). We evaluated the pharmacokinetics of ibrutinib in a patient with CLL undergoing HD. An 84-year-old man on HD was diagnosed with CLL and was started on ibrutinib 140 mg daily. The second day of ibrutinib administration was an HD day, and its plasma concentrations before and 1, 2, 4, and 24 hours after administration were measured and found to be 0, 6.9, 28.4, 57.1, and 0 ng/mL, respectively. The maximum plasma concentration (Cmax) and time taken to reach Cmax (tmax) on days 14 and 15 of ibrutinib treatment were 64.8 ng/mL (4 hours) and 48.1 ng/mL (2 hours), respectively. Thus, we concluded that HD did not have a significant effect on the pharmacokinetics of ibrutinib in this patient. Therefore, dose adjustment of ibrutinib between HD and non-HD days is not recommended. Interestingly, we found that tmax of the drug was prolonged, and Cmax was higher on HD days compared to those on non-HD days.

A Survey of Near-Miss Dispensing Errors in Hospital Pharmacies in Japan: DEPP-J Study-Multi-Center Prospective Observational Study-

The aim of this study was to determine the proportion of near-miss dispensing errors in hospital pharmacies in Japan. A prospective multi-center observational study was conducted between December 2018 and March 2019. The primary objective was to determine the proportion of near-miss dispensing errors in hospital pharmacy departments. The secondary objective was to determine the predictive factors for near-miss dispensing errors using multiple logistic regression analysis. The study was approved by the ethical committee at The Institute of Medical Sciences, University of Tokyo, Japan. A multi-center prospective observational study was conducted in 20 hospitals comprising 8862 beds. Across the 20 hospitals, we assessed data from 553 pharmacists and 53039 prescriptions. A near-miss dispensing error proportion of 0.87% (n = 461) was observed in the study. We found predictive factors for dispensing errors in day-time shifts: a higher number of drugs in a prescription, higher number of quantified drugs, such as liquid or powder formula, in a prescription, and higher number of topical agents in a prescription; but we did not observe for career experience level for clinical pharmacists. For night-time and weekend shifts, we observed a negative correlation of near-miss dispensing errors with clinical pharmacist experience level. We found an overall incidence of near-miss dispensing errors of 0.87%. Predictive factors for errors in night-time and weekend shifts was inexperienced pharmacists. We recommended that pharmacy managers should consider education or improved work flow to avoid near-miss dispensing errors by younger pharmacists, especially those working night or weekend shifts.

Preceding bortezomib administration for a certain period reduces the risk of lenalidomide-induced skin rash.

WHAT IS KNOWN AND OBJECTIVE: It was previously reported that the incidence of lenalidomide (LEN)-induced skin rash is reduced by administration of bortezomib (BOR) prior to LEN administration in patients with multiple myeloma (MM). Therefore, we investigated whether LEN-induced skin rash is affected by the duration of BOR administration and the dosing interval between BOR and LEN administration. METHOD: A retrospective investigation was conducted among MM patients who received BOR treatment prior to LEN treatment in Eiju General Hospital from May 2010 to December 2020. We investigated whether the BOR administration duration and interval duration from the completion of BOR administration to the initial LEN administration affect the development of LEN-induced skin rash. RESULT AND DISCUSSION: Twenty-eight of the 81 patients exhibited LEN-induced skin rash (34.6%). The administered duration, but not the interval, was significantly longer in the group without skin rash. Cut-off values were set for the duration of administration and interval, which were 35 days and 30 days, respectively. Multivariate analysis was performed on patients which are administered duration of more than 35 days and intervals of less than 30 days, and those who are not applicable. A significant difference was observed in the incidence of skin rash for each factor. WHAT IS NEW AND CONCLUSION: The risk of reduced LEN-induced skin rash is affected not only by the presence of prior BOR administration, but also by the duration of BOR and the interval from the completion of BOR to the initial LEN administration.

[Evaluation of Usefulness of the Tools for Collaboration between Hospital and Community Pharmacists in the Provision of Outpatient Cancer Chemotherapy].

Outpatient cancer chemotherapy is becoming increasingly widely adopted. It is, therefore, essential to strengthen the collaboration between hospital and community pharmacists. Although there have been several reports on the collaboration between these two health care providers in the provision of outpatient cancer chemotherapy, there have been no reports on the usefulness of the tools provided by hospital pharmacists to their community counterparts. Hence, this study examined the usefulness of the Adverse Drug Reaction Information Form, which was provided to insurance pharmacies. The response rate of community pharmacists to the information provided was 80%. The most common content of the information provided was related to supportive care(55.9%). Telephone consultations between community pharmacists and patients were conducted in 20 cases(34.8%)to confirm the symptoms of adverse drug reactions. The telephone follow-up rate for each grade of adverse drug reaction was 34.8% for grade 1 and 45.5% for Grade 2, with the number of Grade 2 adverse drug reaction cases being the highest. These findings demonstrate that collaboration between hospital and community pharmacists using the Adverse Drug Reaction Information Form can help provide high-quality outpatient cancer care.

Efficacy and safety of tedizolid in a patient with linezolid-induced neutropenia: A case report.

Linezolid is used to treat prosthetic joint infection after total hip arthroplasty. Here, we present a case of linezolid-induced severe neutropenia, which improved after switching to tedizolid. Grade 3 neutropenia developed 5 days after linezolid injection (1,200 mg/day) and 33 days after oral administration of the same dose. However, during the 70 days of treatment with tedizolid, grade 3 neutropenia did not occur, and C-reactive protein levels remained in the normal range. No grade ≥ 1 thrombocytopenia or bleeding event occurred during the course of tedizolid treatment. Tedizolid may be an alternative drug for patients who develop linezolid-induced neutropenia.

Simple desensitization protocol for multiple myeloma patients with lenalidomide-induced skin rash: Case series.

WHAT IS KNOWN AND OBJECTIVE: Skin rash is one of the typical side effects of lenalidomide (LEN) treatment. Desensitization therapies have been reported to be effective in patients with severe skin rash caused by LEN. However, they have proved impractical due to the complexity of the protocols. CASE SUMMARIES: We present 5 patients who developed severe LEN-induced skin rash. The five patients received our simple, slow desensitization protocol, and all were re-administered LEN with no adverse reaction. WHAT IS NEW AND CONCLUSION: Our simpler and slow desensitization protocol, which desensitizes the patients without reducing the effect of LEN, includes drug holidays, similar to the usual LEN dosing schedule, and moreover is recommended as a treatment option especially for elderly patients with no housemate to help with medical management.

Determination of the concentration of gilteritinib in human plasma using HPLC.

Gilteritinib, an oral inhibitor of FMS-like tyrosine kinase 3 (FLT3), is a standard treatment for FLT3-mutated acute myeloid leukemia. We developed a simple HPLC-UV-based method for determining the concentration of gilteritinib in human plasma. The analysis requires the extraction of a 200-µL plasma sample and the precipitation of proteins by solid-phase extraction. Gilteritinib was isocratically separated within 10 min using a mobile phase of acetonitrile:0.5% monopotassium phosphate (KH2 PO4 , pH 3.5, 28:72, v/v) on a Capcell Pack C18 MG II (250 × 4.6 mm) column at a flow rate of 1.0 mL/min and monitored at 250 nm. The calibration curve was found to be linear within a plasma concentration range of 25-2500 ng/mL, with the coefficient of determination (r2 ) being 0.9997. The coefficients of intra-day and inter-day validation were 2.3-3.7 and 1.3-5.2%, respectively. The accuracy and recovery of the assay were -9.6 to 0.1 and >81.8%, respectively. This HPLC-UV method for determining the plasma concentration of gilteritinib is simple and can be effectively applied to routine drug monitoring.

Potential thiamine deficiency in elderly patients with gastrointestinal cancer undergoing chemotherapy
.

Gastrointestinal cancer and its treatment using fluorouracil-based anticancer agents are risk factors for thiamine deficiency (TD). Therefore, we aimed to determine the prevalence of TD among elderly patients with gastrointestinal cancer undergoing chemotherapy. We retrospectively reviewed the medical records of 12 elderly patients with gastrointestinal cancers who underwent chemotherapy. Median serum thiamine level was 22.5 ng/mL (range, 17 - 42 ng/mL). Four patients (33.3%) exhibited TD (< 20 ng/mL). We found that the prevalence of TD among elderly patients with gastrointestinal cancer undergoing chemotherapy was high. For these patients, careful monitoring of thiamine levels is warranted because TD may not produce overt clinical symptoms.

[Survey of Methotrexate Prescription and Blood Concentration in Patients Treated with High-Dose Methotrexate].

High-dose methotrexate therapy(HDMTX)is effective against lymphoid malignancies. However, delayed elimination of methotrexate(MTX)after HDMTX administration may lead to severe adverse drug reactions. We surveyed the drugs coadministered with MTX and the incidence of delayed MTX elimination in patients treated with HDMTX in a clinical setting. We analyzed the plasma MTX concentration in 110 samples after 55 cycles of HDMTX in 33 patients. Delayed MTX elimination was defined as a plasma MTX concentration ≥1.0 mmol/L at 48 h after the start of HDMTX administration or ≥0.1 mmol/L at 72 h after the start of HDMTX administration. The incidence of the combined use of drugs affecting MTX excretion and drugs that exhibited typical renal excretion was 84.8%(n=28). The incidence of delayed MTX elimination was 39.4%(n=13). MTX-induced acute kidney injury occurred in 9 patients, all of whom also exhibited delayed MTX elimination. Therefore, when prescribing HDMTX, it is important to monitor adverse events, including acute kidney injury, which may be induced by prolonged MTX blood concentrations.

[Optimization of Preparation, and Stability of Indomethacin Mouth Wash for Oral Mucositis Caused by Cancer Therapy].

OBJECTIVE: Severe oral mucositis caused by chemo- and radio-therapy is a common adverse event in patients with cancer. In this study, we investigated the development of an indomethacin mouth wash(IM-MW)as a novel approach to treat pain due to oral mucositis. METHODS: We examined the appropriate preparation methods for IM-MW with suitable stability. IM- MW was made from bulk IM, controlled release IM capsules, and IM capsules. Dissolution in water was tested at water temperatures of 70℃, 90℃, and 98℃(n=3), and with a shaking time of 30 or 60s(n=3). We determined the IM concentration in IM-MW by HPLC-UV analysis(n=5)at time points between just after preparation and day 7, to estimate the shelf- life at 4℃ and 25℃. RESULTS: At 70℃, bulk IM did not dissolve, but at 90℃ and 98℃, bulk IM, controlled release IM capsules, and IM capsules all dissolved effectively. Shaking times of 30 and 60s were sufficient to dissolve bulk IM, controlled release IM capsules, and IM capsules. The stability of IM in IM-MW was 98.6±2.8%(bulk), 99.2±6.0%(controlled release capsule), and 98.5±6.0%(capsule)over 7 days at 4℃. However, at 25℃, IM stability in IM-MW decreased to 95.3±1.8% (bulk), 86.1±4.8%(controlled release capsule), and 83.6±1.6%(capsule). CONCLUSION: In this study, we identified the most suitable method for the preparation of IM-MW(90℃, shaking time of over 30s). IM-MW was stable when stored at 4℃ for at least 7 days after preparation.

Efficacy and safety of micafungin in unrelated cord blood transplant recipients.

Micafungin (MCFG) is an echinocandin antifungal drug used for prophylaxis and treatment of fungal infections after allogeneic hematopoietic cell transplantation (HCT). However, its efficacy and safety in patients undergoing cord blood transplantation (CBT) has not been clarified. We retrospectively analyzed the efficacy and safety of MCFG in 92 adult patients undergoing CBT in our institute. Of the entire cohort, 83 patients (90%) received MCFG for empirical or preemptive therapy. Documented breakthrough fungal infection occurred in 2 patients during MCFG treatment. Among the 49 patients who received MCFG as empirical therapy for febrile neutropenia, 41 (84%) patients had resolution of fever during neutropenia. Elevation of serum levels of hepatobiliary parameters during MCFG treatment was commonly observed, but grade 3 or higher elevation was rare. We also compared the efficacy and safety of 2 different initial daily doses of MCFG (150 mg vs. 300 mg). There were no significant differences of efficacy and safety between the two groups. These data suggest that MCFG was effective and safe for adult patients undergoing CBT. The optimal daily dose of MCFG treatment is a matter of future investigation for adult patients undergoing CBT.

Thiamine deficiency as a possible cofactor causing cognitive dysfunction in a patient with end-stage gastric cancer
.

We describe a case of a patient treated for cognitive dysfunction (CD) with suspected thiamine deficiency (TD). A 74-year-old man with gastric cancer presented with grade 3 diarrhea and grade 1 anorexia. He had been receiving trastuzumab plus tegafur (a chemotherapeutic fluorouracil prodrug), gimeracil, and oteracil (S-1) and oxaliplatin. On admission, cognitive function was assessed with the Hasegawa's Dementia Scale (HDS-R) because he had impaired short-term memory. His thiamine levels increased from 22 to 109 ng/mL after administration of 75 mg of thiamine. Furthermore, the patient's HDS-R score improved from 9 to 22, and cognitive and memory functions improved. TD should be considered in older CD patients receiving oral chemotherapy agents including fluorouracil.

Risk factors affecting the failed low-density lipoprotein level achievement rate in working-age male population at high cardiovascular risk.

WHAT IS KNOWN AND OBJECTIVE: The aim of this study was to clarify the low-density lipoprotein (LDL)-C level achievement rate and detect factors affecting the failed LDL-C achievement rate in patients treated with statins and anti-platelet agents using a large insurance claim database and health check-up data. METHODS: Access to a large health insurance claims database, and health check-up data were obtained from Japan Medical Data Center (JMDC) Co. Ltd., Tokyo. The database was searched to identify employed working-age male patients who had started treatment with statin and anti-platelet drugs for the secondary prevention of cardiovascular events. These patients were enrolled in the retrospective cohort study, which included screening at 3 months and observation for 3 years. LDL-C levels were obtained from the annual health check-up data. The achievement rate for LDL-C < 100 was assessed for three consecutive years. Adherence was assessed using the proportion of days covered (PDC) for the statin, which was calculated from prescription data over a 3-year period. RESULTS AND DISCUSSION: Overall, 294 patients (male/female, 294/0; age, 47.8 ± 6.0 years; body mass index, 24.8 ± 4.2 kg/m2 ; hypertension, 76.2%; and diabetes mellitus, 20.4%) were included. The LDL-C achievement rate for three consecutive years after starting treatment with statin and aspirin was 49.7%, 51.4% and 45.9%, respectively. Factors affecting failed LDL-C on adjusted odds were lower adherence to PDC [0.96 (0.94-0.99), P < 0.001, 1% increase] and higher baseline LDL-C [1.01 (1.00-1.02), P = 0.037, 1 mg/dL increase]. WHAT IS NEW AND CONCLUSION: Our results suggest that in the working-age male population need to improve statin adherence, especially those with higher baseline LDL-C levels.

Simple determination of plasma ibrutinib concentration using high-performance liquid chromatography.

Ibrutinib is an oral inhibitor of Bruton tyrosine kinase, which is one of the key drugs used for the treatment of chronic lymphocytic leukemia and mantle cell lymphoma. In this study, we aimed to develop a simple method for determining plasma ibrutinib concentration. The analysis required extraction of a 200 µL plasma sample and precipitation of proteins using solid-phase extraction. Ibrutinib and nilotinib, which was used as an internal standard, were separated using high-performance liquid chromatography (HPLC) using a mobile phase of acetonitrile-0.5% monopotassium phosphate (KH2 PO4 , pH 3.0; 52:48, v/v) on a Capcell Pack C18 MG II (250 × 4.6 mm) monitored at 260 nm, at a flow rate of 1.0 mL/min. The calibration curve was linear at the plasma concentration range of 10-500 ng/mL with a coefficient of determination (r2 ) of 0.9999. The coefficients of intra-day and inter-day validation were 4.0-6.6 and 2.6-7.7%, respectively. The assay accuracy was -4.4-8.6%, and the recovery was >84%. This HPLC method coupled with ultraviolet (UV) detection for determining ibrutinib plasma concentration has several advantages such as simplicity and applicability to routine therapeutic drug monitoring at hospital laboratories.