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.

Development of a simple high-performance liquid chromatography-ultraviolet detection method for olaparib in patients with ovarian cancer.

Olaparib is a small-molecule inhibitor of poly(ADP)-ribose polymerase (PARP) used as maintenance therapy for recurrent ovarian cancer and newly diagnosed advanced ovarian cancer after initial chemotherapy. An exposure-toxicity correlation has been reported between the probability of anemia, a common adverse event associated with olaparib, and the steady-state minimum plasma concentration (Cmin) as well as the predicted maximum plasma concentration (Cmax). On the other hand, olaparib exhibits high interpatient variability with regard to the area under the concentration-time curve, Cmax, and Cmin. Therefore, we developed a simple and sensitive assay based on high-performance liquid chromatography with ultraviolet light (HPLC-UV) for the therapeutic drug monitoring of olaparib. The analysis was performed on an octadecylsilyl column with a mobile phase consisting of 0.5% KH2PO4 (pH 4.5) and acetonitrile (71:29, v/v), at a flow rate of 0.8 mL/min. Olaparib and an internal standard (imatinib) were well separated from the co-extracted material, with retention times of 13.6 and 11.5 min, respectively. The calibration curve for olaparib showed linearity over the concentration range of 0.10-10.0 µg/mL (r2 = 0.9998). The intra- and inter- day validation coefficients ranged from 1.79 to 4.13% and 1.37 to 3.55%, respectively. Measurement accuracy ranged from - 6.07 to 3.26%, with a recovery rate of more than 91.06%. The developed method was then applied to evaluate the plasma olaparib concentrations in patients with ovarian cancer. Our findings demonstrate that HPLC-UV is an economical, simple, and sensitive method for clinical application and holds promise for the effective drug monitoring of olaparib during ovarian cancer treatment.

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

A Simple HPLC-UV Method for Ivosidenib Determination in Human Plasma.

Ivosidenib is used for the treatment of acute myeloid leukemia (AML) with isocitrate dehydrogenase 1 (IDH1) mutations. However, increased blood concentrations of ivosidenib are associated with a risk of a prolonged QT interval in patients with AML. Therapeutic drug monitoring in patients with AML with IDH1 mutation offers the potential to improve treatment efficacy while minimizing toxicity. In this study, we developed an efficient high-performance liquid chromatography-ultraviolet (HPLC-UV) method for the quantification of ivosidenib in plasma. Human plasma samples (50 µL) were processed by protein precipitation using acetonitrile, followed by chromatographic separation on a reversed-phase column with an isocratic mobile phase of 0.5% KH2PO4 (pH 4.5) and acetonitrile (45:55, v/v) at a flow rate of 1.0 mL/min, with ultraviolet detection at 245 nm. Calibration curves were linear over the range of 0.25-20 µg/mL with a coefficient of determination (r2) of 0.99999. Intra-day and inter-day precision were 1.20-8.04% and 0.69-4.20%, respectively. The assay accuracy was -2.00% to 1.93% and recovery was >91.2%. These findings support the effectiveness of the newly developed HPLC-UV method for the quantification of ivosidenib in human plasma. This simple and cost-effective method is expected to expand ivosidenib monitoring in laboratories lacking LC-MS/MS instruments.

Development of a simple high-performance liquid chromatography-ultraviolet method for sotorasib quantification in human plasma: Implications for therapeutic drug monitoring.

Sotorasib, an oral small-molecule inhibitor, reportedly exerts promising activity against Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant tumors. However, the currently administered dose may fail to represent the optimal dose based on the therapeutic efficacy. Herein, we developed a simple and sensitive method using high-performance liquid chromatography with ultraviolet (HPLC-UV) to measure the sotorasib concentration in human plasma. The sotorasib calibration curve exhibited linearity across the concentration range of 0.10-20.0 µg/mL (r2 = 0.9999). The coefficients of intra- and inter-day validation ranged between 0.79-9.75% and 3.01-6.13%, respectively. The assay accuracy ranged between -3.14 and 5.18%, with > 98.5% recovery. Subsequently, we applied the developed method to estimate sotorasib concentrations in a patient with KRAS G12C-mutated non-small cell lung cancer. We anticipate that our HPLC-UV method will be valuable for assessing the safety and efficacy of sotorasib in larger patient cohorts.

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.

Plasma Cabozantinib Level Measurement in Patients with Renal Cell and Hepatocellular Carcinomas Using a Simple HPLC-UV Method Suitable for Clinical Application.

Cabozantinib, which is used to treat renal cell and hepatocellular carcinomas, is often associated with dose-dependent adverse events. Monitoring the levels of cabozantinib in the blood may maximize the therapeutic effect and prevent serious adverse events. In this study, we developed a high-performance liquid chromatography-ultraviolet (HPLC-UV) method of measuring plasma cabozantinib concentration. Human plasma samples (50 µL) were processed by simple deproteinization with acetonitrile, followed by chromatographic separation on a reversed-phase column with an isocratic mobile phase of 0.5% KH2PO4 (pH 4.5) and acetonitrile (43:57, v/v) at a flow rate of 1.0 mL/min, with a 250 nm ultraviolet detector. The calibration curve was linear over the concentration range (0.05-5 µg/mL) with a coefficient of determination of 0.99999. The accuracy of the assay ranged from -4.35% to 0.98%, and recovery was >96.04%. The measurement time was 9 min. These findings confirm the effectiveness of this HPLC-UV method for cabozantinib quantification in human plasma, which is sufficiently simple for use for monitoring patients in clinical settings.

Factors contributing to carboplatin blockade and interruption in its route of administration in paclitaxel-carboplatin therapy.

The interruption of anticancer infusion processes in patients undergoing chemotherapy may affect their quality of life and the efficacy and safety of the therapy. We experienced several interruptions of carboplatin infusion in multiple patients receiving paclitaxel-carboplatin combination therapy. Therefore, we investigated the causes of these interruptions. The filter and catheter surfaces were evaluated by scanning electron microscopy. Moreover, using a texture analyzer, the mechanical strengths of catheter-attached syringes were compared pre- and post-administration. We observed that the syringe pushing force requirement was higher following dripping failure. However, precipitates were not evident on the filter surfaces, regardless of the dripping failure route. In this case, some of the drug adhered to the catheters' surfaces and interrupted the carboplatin titration. Consequently, in patients receiving combination therapy with paclitaxel and carboplatin, and experiencing interruptions in carboplatin infusion, attention should be paid to the catheter.

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.

Determination of Venetoclax Concentration in Plasma Using High-Performance Liquid Chromatography.

Venetoclax is an oral B-cell lymphoma-2 protein inhibitor. It is a key drug for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia. However, venetoclax is administered at a fixed dose, irrespective of body surface area or weight. Furthermore, the plasma concentration of venetoclax varies widely between individuals and is influenced by diet. Therefore, individualized dosing using therapeutic drug monitoring (TDM) may help to optimize treatment in clinical practice. In this study, we aimed to develop a simple method to determine venetoclax concentrations in plasma. The analysis required the extraction of a 50-µL plasma sample and precipitation of proteins using acetonitrile extraction. Venetoclax and the internal standard (12.5-µg/mL ibrutinib) were separated by high-performance liquid chromatography (HPLC). The calibration curve was linear over the plasma venetoclax concentration range 0.25-10 µg/mL with a coefficient of determination (r2) of 0.9999. The coefficients of intra-day and inter-day validation were 0.8-4.1% and 1.3-3.3%, respectively. The assay accuracy was -2.8 to 1.6%, and the recovery was >97.2%. These results demonstrate a very simple, novel and sensitive HPLC-UV-based method for determining the concentration of plasma venetoclax, and confirm its applicability to the TDM of venetoclax in a clinical setting.

CEFAZOLIN PROPHYLACTIC EFFICACY ON PROSTHETIC JOINT INFECTION AFTER PRIMARY HIP ARTHROPLASTY.

Objective: Perioperative deep prosthetic joint infection (PJI) is a serious postoperative complication of total hip arthroplasty (THA). We aimed to compare the efficacy of cefazolin administered within 24 and 48 h of primary THA for PJI prophylaxis. Methods: In this retrospective study, 720 patients were divided into two groups depending on whether cefazolin was administered as a single injection of 2 g twice daily within 24 (24-h group) or 48 h of surgery and the following day (48-h group). Sex, age at surgery, body mass index, co-existing diseases, blood test data, and PJI risk factors were evaluated. Results: The 24- and 48-h groups included 364 and 356 patients, respectively. Diabetes mellitus was the most common risk factor for PJI in both groups. The corresponding incidence of perioperative deep PJI following primary THA was 0.55% and 0.28% in the 24- and 48-h groups, respectively. There was no significant difference in patient background characteristics between the groups. Conclusions: Cefazolin administration within 24 h of primary THA may be appropriate for perioperative deep PJI. Level of Evidence II; Retrospective study .

Objetivo: A infecção de prótese articular (IPA) perioperatória profunda é uma grave complicação pós-operatória da artroplastia total de quadril (ATQ). Este estudo buscou comparar a eficácia da cefazolina administrada dentro de 24 e 48 horas após ATQ para profilaxia de IPA. Métodos: Neste estudo retrospectivo, 720 pacientes foram divididos em dois grupos, que receberam cefazolina em uma injeção de 2g duas vezes por dia nas primeiras 24 e 48 horas (grupos de 24 e 48 horas), respectivamente. Foram avaliados sexo, idade na data da cirurgia, índice de massa corporal, comorbidades, testes sanguíneos e fatores de risco para IPA. Resultados: Os grupos de 24 e 48 horas incluíram, respectivamente, 364 e 356 pacientes. O fator de risco para IPA mais comum nos dois grupos foi o diabetes mellitus. A incidência de IPA perioperatória profunda após ATQ foi, respectivamente, de 0,55% e 0,28% nos grupos de 24 e 48 horas. Não houve diferença significativa nas características gerais dos pacientes entre os dois grupos. Conclusão: A administração de cefazolina dentro de 24 horas após ATQ primária pode ser adequada para IPA perioperatória profunda. Nível de Evidência II; Estudo retrospectivo .

Survey of Anaphylaxis during Rasburicase Re-Administration in Patients with Hematological Malignancies Using a Japanese Claims Database.

Management of tumor lysis syndrome (TLS) associated with cancer chemotherapy for malignant tumors is important because of its potentially fatal course. The use of rasburicase, a recombinant urate oxidase, is recommended for TLS; however, because rasburicase is an enzymatic drug, one should be cautious of anaphylaxis during administration. Using claims data in Japan, we investigated the rate of rasburicase re-administration and the occurrence of anaphylaxis during re-administration in patients with hematopoietic malignancies in a multicenter setting. Re-administration of rasburicase was defined as administration after an interval of 21 days from the first dose. Of 373 patients, 18 were re-administered rasburicase (re-administration rate: 4.8%). No patient developed anaphylaxis. The median number of days from the first to the last dose of rasburicase was 256.5 days (interquartile range: 138.8-455.8 days). The median daily dose was 7.5 mg (4.5-11.3 mg), and the median total dose was 33.8 mg (19.1-64.1 mg). This claims database analysis revealed that the re-administration rate of rasburicase was low in Japanese patients with hematopoietic malignancies, suggesting that rasburicase was being used appropriately, and that associated anaphylaxis was not observed.

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.

Utility of therapeutic drug monitoring of venetoclax in acute myeloid leukemia.

The favorable outcomes of venetoclax-based regimens in older adults with acute myeloid leukemia (AML) may result in its regimen becoming the standard treatment. However, the dosage of venetoclax is fixed, irrespective of body surface area (BSA) or weight. Therefore, individualized dosing using therapeutic drug monitoring (TDM) may help optimize treatment in a safe and effective manner. Twelve patients with AML who received venetoclax-based treatment were enrolled in this study. Blood samples were collected before venetoclax administration, and the minimum plasma concentration (Cmin) was evaluated. The concentration of venetoclax was evaluated using a simple, sensitive, and cost-effective assay using high-performance liquid chromatography, as described previously. The median age was 74 (70-85) years. Ten patients received venetoclax in combination with azacitidine and one patient received low-dose cytarabine (LDAC). The patients BSA ranged from 1.345 to 1.912 m2 (median 1.543). The dose of venetoclax was 400 mg with azacitidine, and 600 mg with LDAC. In four patients who were taking CYP3A4 inhibitors, venetoclax was reduced to 50 mg according to the prescribing information. The Cmin ranged from 0.39 to 2.49, and the patient taking itraconazole showed highest Cmin regardless of the reduction of venetoclax. Most patients showed higher Cmin compared to the data from previous clinical trials, and BSA and venetoclax concentrations showed a negative correlation. Many Asian AML patients > 75 years old are petite and receive CYP3A4 inhibitors. Therefore, the TDM of venetoclax may be useful.

Safety of linezolid, rifampicin, and clindamycin combination therapy in patients with prosthetic joint infection.

We investigated adverse events in patients with prosthetic joint infections receiving combination therapy with linezolid, rifampicin, and clindamycin for ≥ 7 days. Twenty-two patients were evaluated. The combination therapy was administered for 15.5 (7-29) days at dosages of 1200, 450, and 450-1200 mg/day for linezolid, rifampicin, and clindamycin, respectively. Adverse events (gastrointestinal, eye, and skin disorders; liver damage; myelosuppression; hyponatremia, and others) were recorded. The incidence rates of leukopenia, neutropenia, anemia, thrombocytopenia, and hyponatremia were 36.4%, 31.8%, 40.9%, 18.2%, and 18.2%, respectively. Common Terminology Criteria for Adverse Events version 5.0 Grade 3 neutropenia, anemia, and hyponatremia were observed. The incidence rate of myelosuppression was higher following combination therapy compared with that previously reported following single-drug administration. All patients were discharged after the infection was under control. It is important to monitor these adverse events during combination therapy with the aforementioned agents; these conditions may be relieved by discontinuing linezolid.

Invasive Fungal Disease in Patients with Chronic Lymphocytic Leukemia in Japan: A Retrospective Database Study.

Invasive fungal disease (IFD) is an important cause of morbidity and mortality in patients with hematological malignancies. As chronic lymphocytic leukemia (CLL) is a rare hematological malignancy in Japan, IFD incidence in Japanese patients with CLL is unclear. This study aimed to investigate IFD incidence in Japanese patients with CLL. This retrospective cohort study used data of patients with CLL registered between April 2008 and December 2019 in the Medical Data Vision database (n = 3484). IFD incidence after CLL diagnosis in the watch-and-wait (WW) and drug therapy (DT) groups was 1.5% and 9.2%, respectively. The most common type of IFD was invasive aspergillosis (28.1%). Cox proportional hazards multivariate analysis revealed that DT (hazard ratio [HR]: 2.13) and steroid use (HR: 4.19) were significantly associated with IFD occurrence. IFD incidence was significantly higher in the DT group than in the WW group (log-rank p < 0.001); however, there was no significant between-group difference in the time to IFD onset or the type of IFD (p = 0.09). This study determined the incidence of IFD in patients with CLL during WW. Physicians should monitor for IFD, even among patients with CLL undergoing the WW protocol.