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Although dietary potassium restriction is an acceptable approach to hyperkalemia prevention, it may be insufficient for outpatients with chronic kidney disease (CKD). Most outpatients with CKD use community pharmacies owing to the free access scheme in Japan. The MieYaku-CKD project included a community pharmacist-led nutritional intervention for dietary potassium restriction, with the goal of determining its efficacy for patients' awareness of potassium restriction and serum potassium levels in outpatients with CKD. This was a five-community pharmacy multicenter prospective cohort study with an open-label, before-and-after comparison design. Eligible patients (n = 25) with an estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 received nutritional guidance from community pharmacists. The primary outcome was a change in serum potassium levels at 12 weeks post-intervention. The eligible patients' knowledge, awareness, and implementation of potassium restriction were evaluated using a questionnaire. The median value of serum potassium was significantly reduced from 4.7 mEq/L before to 4.4 mEq/L after the intervention [p < 0.001, 95% confidence interval (CI): 0.156–0.500], with no changes in eGFR (p = 0.563, 95% CI: -2.427–2.555) and blood urine nitrogen/serum creatinine ratio (p = 0.904, 95% CI: -1.793–1.214). The value of serum potassium had a tendency of attenuation from 5.3 to 4.6 mEq/L (p = 0.046, 95% CI: 0.272–1.114) in the eGFR < 30 mL/min/1.73 m2 group. A questionnaire revealed that after the intervention, knowledge and attitudes regarding dietary potassium restriction were much greater than before, suggesting that the decrease in serum potassium levels may be related to this nutritional guidance. Our findings indicate that implementing a dietary potassium restriction guidance program in community pharmacies is feasible and may result in lower serum potassium levels in outpatients with CKD. [ABSTRACT FROM AUTHOR]

Aim: Sorafenib is used as a first-line treatment for advanced hepatocellular carcinoma (HCC). However, hepatic arterial infusion chemotherapy (HAIC) has also gained acceptance, but only in Japan. We explored the role of body composition as a factor affecting the survival benefit of HAIC compared to sorafenib for the treatment of advanced HCC. Methods: We conducted a retrospective study using the clinical records of 133 patients with advanced HCC treated either with HAIC or sorafenib. Prior to treatment induction, skeletal muscle index and visceral fat area (VFA) were measured at the third lumbar vertebral and umbilical levels, respectively, using computed tomography. Muscle depletion and high-VFA (H-VFA) were defined using published cut-offs. We analyzed clinical parameters, including body composition as prognostic factors. Results: In the HAIC group, multivariate analysis identified a positive response to HAIC (hazard ratio [HR], 0.438; p = 0.022), and conversion from HAIC to sorafenib (HR, 0.374; p = 0.008) as favorable prognostic factors for survival. In contrast, tumor number < 7 (HR, 0.475; p = 0.008), absence of extra-hepatic spread (HR, 0.511; p = 0.015), absence of muscle depletion (HR, 0.555; p = 0.044), and H-VFA (HR, 0.483; p = 0.015) were studied in the sorafenib group. Conclusions: Body composition was identified as a prognostic factor for patient survival after treatment with sorafenib, but not for HAIC, and may be used as a biomarker when selecting between HAIC or sorafenib treatment of patients with advanced HCC. Additionally, conversion to sorafenib in patients receiving HAIC could improve survival regardless of response status. [ABSTRACT FROM AUTHOR]

Background: Transcatheter arterial infusion chemotherapy (TAI) using a combination of iodized oil (lipiodol) and degradable starch microspheres (DSMs) has been reported to be superior to TAI with either lipiodol or DSMs separately for the treatment of hepatocellular carcinoma (HCC), based on the results of a prospective randomized study. In the study reported here, we investigated the predictors influencing response and survival in HCC patients receiving TAI using lipiodol and DSMs. Methods: A total of 50 HCC patients [Child-Pugh A/B, 34/16 patients; maximum tumor size 2.9 cm (mean); tumor number <5/≥5 = 29/21 patients] were administered a mixture of cisplatin and lipiodol, followed by the injection of DSMs. Results: According to the criteria of the Liver Cancer Study Group of Japan, the response [complete response (CR) + partial response (PR)] rate and CR rate were 72 and 38%, respectively [CR, 19 patients; PR, 17; stable disease, 9; progressive disease, 5]. The 1-, 2-, 3-, and 4-year cumulative survival rates were 85, 67, 41, and 35%, respectively, and the median survival time was 32.6 months. Multivariate analysis identified tumor number <5 nodules [odds ratio 10.651, 95% confidence interval (CI) 2.168-52.317; P = 0.004] as an independent predictor of response and des-γ-carboxyprothrombin level <100 mAU/mL [hazard ratio (HR), 0.268, 95% CI 0.091-0.786, P = 0.017] and therapeutic effect CR or PR (HR 0.255, 95% CI 0.099-0.659; P = 0.005) as independent predictors of survival. Conclusion: Transcatheter arterial infusion chemotherapy using lipiodol and DSMs might be considered as a potential intervention in HCC patients, especially those with tumors of <5 nodules. [ABSTRACT FROM AUTHOR]

Abstract: Background: A drug interaction between oral tacrolimus (TAC) and lansoprazole (LAN) has been reported in patients with CYP2C19 hetero/homozygous mutations and the CYP3A5 *3/*3 genotype. A PubMed search (implemented March 16, 2011) using search terms drug interaction, tacrolimus, and lansoprazole failed to identify drug interactions in CYP3A5 extensive metabolizers and parenterally administered TAC. Objective: The purpose of this study was to report a case of drug interaction between intravenously administered TAC and LAN in a patient being treated with voriconazole (VCZ) and harboring CYP2C19 and CYP3A5 heterozygous mutations. Case Summary: An 18-year-old Japanese man weighing 53 kg with an anaplastic large cell lymphoma received continuous IV administration of TAC as post-transplantation prophylaxis against graft-versus-host disease (GVHD) after an allogeneic bone marrow transplantation (BMT). He began receiving IV LAN 60 mg/d and VCZ 400 mg/d initiated the day before BMT. His blood TAC concentrations were within the range of 9–16 ng/mL from post-BMT day 5 to 26. The engraftment of the donor''s hematopoietic cells was observed on day 17. The LAN dose was reduced to 15 mg/d PO on day 26, and the blood TAC concentration subsequently decreased to 6.6 ng/mL, with GVHD-related symptoms emerging on day 28. Consequently, the plasma VCZ concentration also decreased from 5.0 ng/mL to 2.5 ng/mL after reducing the LAN dose. VCZ was switched to liposomal amphotericin B on day 48. Thereafter, the blood TAC concentration decreased to 4.4 ng/mL on day 51. Ultimately, the patient died on day 77 because of the recurrence and progression of lymphoma. Other drugs taken were acyclovir, ursodeoxycholic acid, cefepime, meropenem, vancomycin, lenograstim, and dopamine hydrochloride. The genotyping analyses using the pre-BMT and post-engraftment (day 33) samples indicated that both were CYP2C19 *1/*2, CYP3A5 *1/*3 and CYP2C9 *1/*1. The calculated Drug Interaction Probability Score between TAC and LAN was 6, indicating a probable interaction. TAC and VCZ concentrations were measured by an affinity column-mediated immunometric assay and HPLC, respectively. Mutant alleles were examined using the multiplex extension of unlabeled oligonucleotide primers with fluorescently labeled dideoxynucleoside triphosphates. Conclusions: In a BMT patient with CYP2C19 and CYP3A5 heterozygous mutations, blood TAC concentration decreased after reducing the LAN dose, which appeared to be caused by a reduction in plasma VCZ concentration. [Copyright &y& Elsevier]

Purpose: The rate of hypersensitivity reactions in patients receiving carboplatin (CBDCA) has been reported to increase after multiple doses of the agent. However, risk factors for these onsets have not been well described. In this study, we investigated the contribution of the reported risk factors to the onset of CBDCA-related delayed hypersensitivity reactions. Methods: We reviewed the records of gynecologic cancer patients receiving CBDCA of more than 7 cycles in Mie University Hospital from March 2006 to July 2009. The patients were divided into two groups on the basis of whether hypersensitivity reactions developed (13 patients) or not (43 patients). Thereafter, the potential influences of the patients' characteristics on the development of CBDCA-related delayed hypersensitivity reactions were explored using logistic regression analyses. Results: The median CBDCA-free interval (10 months) in patients with hypersensitivity reactions was significantly higher than that (3 months) in patients without hypersensitivity reactions. Logistic regression analyses revealed a CBDCA-free interval >13 months (odds ratio 22.2, 95% confidence interval 2.57-192, p < 0.01) and a maximum dose of CBDCA > 650 mg (odds ratio 9.52, 95% confidence interval 1.04-93.9; p < 0.05) were significantly correlated with the incidence of CBDCA-related delayed hypersensitivity reactions. Conclusions: Careful attention should be paid to the onset of delayed hypersensitivity reactions for recurrent gynecologic cancer patients receiving CBDCA > 650 mg after an interval of more than 13 months from the previous CBDCA administration. [ABSTRACT FROM AUTHOR]

Aims: Genotype-guided dosing algorithms can explain about half of the interindividual variability in prothrombin time-international normalized ratio (PT-INR) under warfarin treatment. This study aimed to refine a published kinetic-pharmacodynamic model and guide warfarin dosage for an optimal PT-INR based on renal function., Methods: Using a retrospective cohort of adult patients (>20 years) who were administered warfarin and underwent PT-INR measurements, we refined the kinetic-pharmacodynamic model with age and the genotypes of cytochrome P450 2C9 and vitamin K epoxide reductase complex subunit 1 using the PRIOR subroutine in the nonlinear-mixed-effect modelling programme. We searched the significant covariates for parameters, such as the dose rate for 50% inhibition of coagulation (EDR 50 ), using a stepwise forward and backward method. Monte Carlo simulation determined a required daily dose of warfarin with a target range of PT-INR (2.0-3.0 or 1.6-2.6) based on the significant covariates., Results: A total of 350 patients with 2762 PT-INR measurements were enrolled (estimated glomerular filtration rate [eGFR]: 47.5 [range: 2.6-199.0] mL/min/1.73 m 2 ). The final kinetic-pharmacodynamic model showed that the EDR 50 changed power functionally with body surface area, serum albumin level and eGFR. Monte Carlo simulation revealed that a lower daily dose of warfarin was required to attain the target PT-INR range as eGFR decreased., Conclusions: Model-informed precision dosing of warfarin is a valuable approach for estimating its dosage in patients with renal impairment., (© 2023 British Pharmacological Society.)

Teicoplanin can cause acute kidney injury, but little is known about the risk of acute kidney injury when teicoplanin is co-administered with loop diuretics (a powerful diuresis), which can alter renal hemodynamics and glomerular filtration rate. We performed a signal detection analysis using a Japanese adverse event database to determine the additive impact of loop diuretics on acute kidney injury associated with teicoplanin. The dataset originated between April 2004 and August 2022. Disproportionality analysis was performed to detect the signals for acute kidney injury (the Standardized MedDRA Query) when co-administered teicoplanin or vancomycin (a positive control) with individual diuretics, including loop diuretics. Multivariate logistic regression analysis was tested to estimate the adjusted reporting odds ratio (aROR) and 95% confidence interval (95% CI). There were 147 and 515 events of acute kidney injury associated with teicoplanin and vancomycin, respectively. A significant positive signal for acute kidney injury when teicoplanin was co-administered with loop diuretics was present (aROR 4.83, 95% CI 3.52-6.61, p < 0.0001). Contrastingly, no significant signals were observed when vancomycin was co-administered with any diuretics. These findings suggest that co-administered loop diuretics may have an unfavorable effect on acute kidney injury while undertaking teicoplanin but not vancomycin., (© 2023. Springer Nature Limited.)

Background: The impact of cytochrome P450 3A5 (CYP3A5) genotype of recipients (intestine) as well as donors (graft liver) on the tacrolimus pharmacokinetics and the incidence of infectious complications was assessed in Japanese living-donor liver transplant (LDLT) adult recipients., Material/methods: Fifty-six patients were divided into 4 groups based on the CYP3A5 genotype (expression of *1 allele: expressor (EX) and non-expressor (NEX)) in each recipients (R) and donors (D), EX-R/EX-D (n=9), EX-R/NEX-D (n=7), NEX-R/EX-D (n=12) and NEX-R/NEX-D (n=28). Tacrolimus blood concentration and concentration/dosage ratio (C/D) were evaluated every week until 4 weeks and every month until 12 months after LDLT. The incidences of postoperative infectious complication, acute cellular rejection and tacrolimus adverse effect were compared., Results: The tacrolimus blood concentrations among 4 groups did not significantly differ at each follow-up time period. The C/Ds were significantly lower in EX-R/EX-D (median: 122.3 at 2 weeks) than in NEX-R/NEX-D (389.6 at 2 weeks) until 12 months. The C/Ds in EX-R/NEX-D (163.2 at 2 weeks) have been significantly lower than those in NEX-R/NEX-D until 6 months. Over 6 months, however, those in NEX-R/EX-D showed lower levels (84.1 at 8 months) than those in NEX-R/NEX-D (189.3 at 8 months). Additionally, logistic regression analysis showed that EX-R/EX-D had significantly higher risk for the development of infectious complications than NEX-R/NEX-D (odds ratio 8.67, p=0.03)., Conclusions: Preoperative assessment of CYP3A5 genotypes in both recipients and donors would be useful not only for predicting tacrolimus pharmacokinetics but also defining high-risk group of infectious complications after LDLT.

Study Objective: To investigate whether a drug interaction exists between bortezomib and the cytochrome P450 (CYP) 3A4 inhibitor itraconazole and/or the CYP2C19 inhibitor lansoprazole that results in increased severity of bortezomib-induced peripheral neuropathy and thrombocytopenia., Design: Retrospective medical record review., Setting: Hematology-oncology ward of a university-affiliated hospital in Japan., Patients: Six adults with relapsed multiple myeloma who received intravenous bortezomib plus oral dexamethasone as the first course of a 21-day cycle between July 2007 and December 2008. Four of the six patients were treated concomitantly with itraconazole or lansoprazole: two with itraconazole, one with lansoprazole, and one with both itraconazole and lansoprazole., Measurements and Main Results: Using the National Cancer Institute's Common Terminology Criteria for Adverse Events, we identified the presence and graded the severity of peripheral neuropathy and thrombocytopenia before and during each patient's first 21-day course of bortezomib plus dexamethasone therapy. All three patients who received itraconazole experienced new or worsening peripheral neuropathy; they also experienced grade 4 thrombocytopenia. The patient who received lansoprazole alone, as well as the two patients who did not receive itraconazole or lansoprazole, had no changes in either adverse effect. We also evaluated the relationship between peripheral neuropathy and bortezomib plus dexamethasone therapy by using the Naranjo adverse drug reaction probability scale, and a probable relationship was found. We further assessed whether a drug interaction between bortezomib and itraconazole and/or lansoprazole had occurred involving the CYP3A4 and/or the CYP2C19 pathways, respectively-resulting in increased severity of the bortezomib-induced peripheral neuropathy and thrombocytopenia-by using the Horn drug interaction probability scale. We found that the occurrence of this drug interaction was strongly supported., Conclusions: Itraconazole appears to exacerbate peripheral neuropathy and thrombocytopenia induced by bortezomib; however, the mechanism of this drug interaction is unknown. Clinicians should closely monitor for bortezomib-induced adverse effects when itraconazole, or any other potent CYP3A4 inhibitor, is administered concomitantly with bortezomib.