Association between Proton Pump Inhibitors, Immune Checkpoint Inhibitors, and Acute Kidney Injury: A Nested Case-Control Study.

BACKGROUND: An association between proton pump inhibitor (PPI) use and an increased risk of acute kidney injury (AKI) has been confirmed. This study aimed to evaluate the effects of PPI use on the risk of AKI in patients with cancer who were administered immune checkpoint inhibitors (ICIs), a class of drugs used in cancer treatment, and in those who were not. METHODS: We used a database provided by the Health, Clinic, and Education Information Evaluation Institute, which included demographic data, diagnoses, prescriptions, and laboratory results. We conducted a nested case-control study of 38,930 patients with cancer who were new PPI or ICI users and had no history of AKI before cohort entry. The odds ratio (OR) for AKI was estimated using conditional logistic regression models. RESULTS: During a mean follow-up of 8.3 months, 5,870 cases of AKI were identified (incidence rate, 21.9/100 person-years). Compared to never or past PPI use without ICI use, the adjusted ORs of AKI for current PPI use without ICI use, past or never PPI use with prior ICI use, current PPI use with prior ICI use were 1.82 (95% CI, 1.67 to 2.00), 1.47 (95% CI, 1.17 to 1.86), or 2.13 (95% CI, 1.42 to 3.20), respectively. The risk of AKI in patients treated with both PPIs and ICIs was not higher than the additional or multiplication of the risks in those who were treated with PPIs or ICIs alone. CONCLUSIONS: This study reinforces the association between PPIs and ICIs use and the increased risk of AKI. Although the interaction between the two drug classes was not detected, these findings highlight the need for careful monitoring and evaluation of kidney function in patients treated with PPIs and ICIs.

Model-Informed Dosing Optimization of Tacrolimus for Concomitant Administration with Itraconazole to Japanese Lung Transplant Recipients.

BACKGROUND: Tacrolimus is an immunosuppressant administered to patients undergoing lung transplantation. Itraconazole is often concomitantly used with tacrolimus to prevent fungal infections and increase tacrolimus concentration. However, the pharmacokinetics of tacrolimus in Japanese lung transplant recipients and the effect of itraconazole on its pharmacokinetics have not been adequately evaluated. Population pharmacokinetic analysis was conducted to develop an optimal dose adjustment method for use upon itraconazole initiation in Japanese lung transplant recipients. METHODS: This study comprised Japanese lung transplant recipients whose blood tacrolimus and itraconazole concentrations were measured between January 2017 and December 2019. A nonlinear mixed-effects modeling program was used to explore the covariates of tacrolimus pharmacokinetics and effects of concomitant itraconazole use. Using the model, the optimal initial tacrolimus dose was calculated and a dose adjustment method comprising concomitant itraconazole use was developed. RESULTS: A total of 1693 tacrolimus trough blood concentrations and 85 itraconazole trough plasma concentrations were obtained from 43 patients. Postoperative day, albumin level, and administration route were extracted as covariates for tacrolimus pharmacokinetics. The drug-drug interaction between tacrolimus and itraconazole could be predicted more accurately by considering the concentration-dependent inhibition of itraconazole. The optimal initial tacrolimus dose was 2.0 mg twice daily for tube and 1.5 mg twice daily for oral administration. To maintain the target concentration, the tacrolimus dose was reduced by 60% upon itraconazole initiation. CONCLUSIONS: This study is the first to use population pharmacokinetic analysis to assess the interaction between tacrolimus and itraconazole in patients who underwent lung transplantation. These results provide useful insights for optimizing the initial tacrolimus dose for concomitant itraconazole use.

Subjective symptoms are triggers for the detection of immune checkpoint inhibitor-induced interstitial lung disease and associate with disease severity: a single-center retrospective study.

BACKGROUND: Interstitial lung disease (ILD) is one of the most common fatal immune-related adverse events (irAEs). ILD development adversely affects the continuation of anticancer drug therapy, including immune checkpoint inhibitor (ICI) therapy and prognosis. There are no established useful clinical indicators for the early detection of ILD. Furthermore, the factors that lead the attending physician to suspect ICI-induced ILD (ICI-ILD) remain unclear. This study aimed to investigate the ICI-ILD detection based on subjective symptoms and their relationship with disease severity in patients receiving anti-PD-1/PD-L1 antibody. METHODS: This was a retrospective observational study. We enrolled the patients who received anti-PD-1/PD-L1 antibody at Kyoto University Hospital between September 2014 and April 2021. Patients who developed ICI-ILD were stratified into two distinct groups based on factors that triggered the suspicion of ILD development. The "Subjective symptoms" group was defined as patients in whom ILD was detected based on subjective symptoms. Conversely, the "Routine examinations" group was defined as patients in whom ILD was suspected based on scheduled routine examinations. The severity of ILD in each group was assessed and its association with changes in the respiratory symptoms was examined. RESULTS: Of 926 patients who received anti-PD-1/PD-L1 antibody, 51 patients (5.5%) developed ICI-ILD. The incidence of ICI-ILD in patients with lung cancer was significantly higher than that in patients with other cancers (P < 0.001). Among the patients with ICI-ILD, 27 patients (52.9%) were classified into the "Subjective symptoms" group. The "Subjective symptoms" group exhibited a significantly higher proportion of Grade 3-5 ICI-ILD cases than the "Routine examinations" group (76.2% vs. 23.8%, P = 0.010). At the last visit, before the suspected onset of ILD, 21 of the 27 patients (77.8%) had no symptoms or no change in the respiratory symptoms. CONCLUSION: Subjective symptoms triggered the suspicion of Grade 3-5 ICI-ILD. Enhanced monitoring and patient education could be essential for the early detection of ICI-ILD because ILD may develop rapidly. Our findings might help to manage ICI-ILD in clinical practice.

Development of a 3-dimensional organotypic model with characteristics of peripheral sensory nerves.

We developed a rat dorsal root ganglion (DRG)-derived sensory nerve organotypic model by culturing DRG explants on an organoid culture device. With this method, a large number of organotypic cultures can be produced simultaneously with high reproducibility simply by seeding DRG explants derived from rat embryos. Unlike previous DRG explant models, this organotypic model consists of a ganglion and an axon bundle with myelinated A fibers, unmyelinated C fibers, and stereo-myelin-forming nodes of Ranvier. The model also exhibits Ca2+ signaling in cell bodies in response to application of chemical stimuli to nerve terminals. Further, axonal transection increases the activating transcription factor 3 mRNA level in ganglia. Axons and myelin are shown to regenerate 14 days following transection. Our sensory organotypic model enables analysis of neuronal excitability in response to pain stimuli and tracking of morphological changes in the axon bundle over weeks.

Influence of ensitrelvir or nirmatrelvir/ritonavir on tacrolimus clearance in kidney transplant recipients: a single-center case series.

BACKGROUND: Among the oral antivirals used for treating patients with mild-to-moderate novel coronavirus disease 2019 (COVID-19), nirmatrelvir/ritonavir (NMV/RTV) and ensitrelvir (ESV) are inhibitors of cytochrome P450 (CYP) 3A, and therefore, can cause drug-drug interactions with concomitant medications. Tacrolimus (TAC), a substrate of CYP3A4/5, is administered for a long period to prevent rejection after kidney transplantation. TAC should be discontinued while using NMV/RTV because blood TAC levels significantly increase when these drugs are concomitantly administered. However, the influence of ESV on blood TAC levels has not yet been reported, and the management of TAC doses during the use of ESV remains unclear. CASE PRESENTATION: We experienced three kidney transplant recipients with COVID-19, whose blood trough levels of TAC increased by the concomitant use of NMV/RTV or ESV. In two patients administering NMV/RTV, blood trough levels of TAC increased more than tenfold after combination therapy, whereas in one patient administering ESV, TAC level increased approximately threefold. CONCLUSIONS: These cases suggest that TAC administration should be discontinued during NMV/RTV treatment to maintain blood TAC levels within the therapeutic range, and a reduced TAC dose is sufficient during ESV treatment.

A case of successful contribution of therapeutic drug monitoring of valganciclovir as the prophylaxis against cytomegalovirus infection in a lung transplant recipient.

BACKGROUND: Ganciclovir and its prodrug, valganciclovir, are first-line agents for cytomegalovirus infection prophylaxis after lung transplantation. Although valganciclovir prophylaxis is known to result in severe leukopenia as an adverse effect, dosage adjustment based on therapeutic drug monitoring (TDM) of ganciclovir concentration is not generally implemented in clinical practice. CASE PRESENTATION: In this report, we describe the case of a female in her fifties after lung transplantation who successfully maintained valganciclovir prophylaxis under TDM with a minimal occurrence of severe leukopenia. Valganciclovir administration was initiated at a conventional dose of 450 mg/day on postoperative day 43 but was reduced to 450 mg/2 days on postoperative day 69 because of a decrease in white blood cell count and an increase in trough ganciclovir concentration. Subsequently, the valganciclovir dose adjustment was switched from label-indicated renal function-guided dosing to TDM-based dosing, targeting a trough level of 300-800 ng/mL. This target range was determined through deliberations with infectious disease specialists and pharmacists based on previously reported data. The TDM-based dose adjustment successfully prevented cytomegalovirus reactivation without causing significant adverse effects. Valganciclovir prophylaxis was completed on postoperative day 256, and the patient was transferred to another hospital for rehabilitation. CONCLUSIONS: The findings of the present case suggest that TDM-based dosing could be helpful for clinicians in optimizing the prophylactic administration of valganciclovir in patients undergoing lung transplantation.

Real-Time Particle Emission Monitoring for the Non-Invasive Prediction of Lung Deposition via a Dry Powder Inhaler.

Although inhalation therapy represents a promising drug delivery route for the treatment of respiratory diseases, the real-time evaluation of lung drug deposition remains an area yet to be fully explored. To evaluate the utility of the photo reflection method (PRM) as a real-time non-invasive monitoring of pulmonary drug delivery, the relationship between particle emission signals measured by the PRM and in vitro inhalation performance was evaluated in this study. Symbicort® Turbuhaler® was used as a model dry powder inhaler. In vitro aerodynamic particle deposition was evaluated using a twin-stage liquid impinger (TSLI). Four different inhalation patterns were defined based on the slope of increased flow rate (4.9-9.8 L/s2) and peak flow rate (30 L/min and 60 L/min). The inhalation flow rate and particle emission profile were measured using an inhalation flow meter and a PRM drug release detector, respectively. The inhalation performance was characterized by output efficiency (OE, %) and stage 2 deposition of TSLI (an index of the deagglomerating efficiency, St2, %). The OE × St2 is defined as the amount delivered to the lungs. The particle emissions generated by four different inhalation patterns were completed within 0.4 s after the start of inhalation, and were observed as a sharper and larger peak under conditions of a higher flow increase rate. These were significantly correlated between the OE or OE × St2 and the photo reflection signal (p < 0.001). The particle emission signal by PRM could be a useful non-invasive real-time monitoring tool for dry powder inhalers.

Investigation of severe acute respiratory syndrome coronavirus 2 infection status in solid organ transplant recipients treated with tixagevimab/cilgavimab.

INTRODUCTION: Tixagevimab and cilgavimab (T/C) are neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be used to prevent SARS-CoV-2 infection in solid organ transplant (SOT) recipients. However, their neutralizing activity against recent variants was reduced, raising concerns regarding the emergence of breakthrough coronavirus diseases 2019 (COVID-19). This study aimed to investigate the status of the COVID-19 breakthrough after T/C administration. METHODS: We retrospectively investigated breakthrough COVID-19 in SOT recipients administered T/C at Kyoto University Hospital, Japan, from November 2022 to March 2023. Patients were monitored for 6 months after T/C administration. SARS-CoV-2 infection was diagnosed using polymerase chain reaction or antigen tests. The monthly incidence rates of SARS-CoV-2 infection were calculated using the person-time method. RESULTS: T/C were administered to 67 SOT recipients (liver, 16; lung, 36; and kidney, 15), of whom five were infected with SARS-CoV-2. All five cases were classified as mild, and none of these patients required admission to the intensive care unit (ICU) or died. All infected individuals tested positive for SARS-CoV-2 after March 2023, when T/C-resistant subvariant strains became predominant. The monthly incidence rate of SARS-CoV-2 infection, calculated using the person-time method, suggested an increasing trend. CONCLUSIONS: During the T/C-resistant variant epidemic, SARS-CoV-2 infections were identified even after T/C administration, suggesting that the prophylactic effects of T/C were invalid. Therefore, emerging variants must be carefully monitored and characterized to determine appropriate antiviral strategies, such as the use of suitable neutralizing antibodies.

Population Pharmacokinetic Modeling of Posaconazole in Japanese Patients Receiving Fungal Prophylaxis.

BACKGROUND: Posaconazole is a vital drug to treat and prevent invasive fungal infections. Several factors, such as sex, body weight, total serum proteins, dietary intake, and severe mucositis, affect posaconazole pharmacokinetics (PKs). However, the relevance of other factors that affect the PKs of posaconazole in hematopoietic stem cell transplantation (HSCT) is unknown. This study explored factors influencing the PKs of posaconazole in HSCT recipients and nontransplant patients with hematological diseases. METHODS: The authors conducted a single-institution, retrospective study. Forty-two Japanese inpatients receiving oral posaconazole tablets as prophylaxis for fungal infections were enrolled in this study. A one-compartment model with first-order absorption was used as the structural pharmacokinetic model. A population PK (PopPK) analysis was performed using a nonlinear mixed-effects modeling program, using a first-order conditional estimation method with interactions. Perl-speaks-NONMEM and R were used to evaluate the goodness of fit and visualize the output. RESULTS: In 29% of the enrolled patients, the serum concentration of posaconazole was <0.5 mcg/mL, considered the effective range. PopPK analysis revealed that the patient had undergone HSCT within 1 year, diarrhea occurred more than 5 times a day, and aspartate aminotransferase were covariates that influenced apparent clearance (CL/F). The CL/F of posaconazole was 1.43-fold higher after HSCT and 1.26-fold higher during diarrhea. CONCLUSIONS: PopPK analysis revealed that HSCT, diarrhea, and aspartate aminotransferase were factors associated with the CL/F of posaconazole. The trough concentration of posaconazole may be below the therapeutic range in a few patients with diarrhea and/or after HSCT. As invasive fungal infections in patients with hematologic diseases can be life-threatening, therapeutic drug monitoring of posaconazole is strongly recommended, and patients should be carefully monitored.

Potential treatment option of rivaroxaban for breastfeeding women: A case series.

The use of direct oral anticoagulants (DOACs) in breastfeeding women is currently challenging due to limited safety data for breastfeeding infants, and there have been no previous studies on the drug concentration in breastfeeding infants. We treated 2 patients (one case was twin pregnancy) with venous thromboembolisms in breastfeeding women administered rivaroxaban at our institution. Blood samples from the mothers and breastmilk samples were collected at time 0 and 2 h after the rivaroxaban administration, breastfeeding was conducted 2 h after the rivaroxaban administration, and blood samples from the infants were collected 2 h after breastfeeding (4 h after maternal rivaroxaban administration). The milk-to-plasma (M:P) ratios were 0.27 in Case 1 and 0.32 in Case 2. The estimated relative infant dose (RID) was 0.82 % in Case 1 Children 1 and 2, and 1.27 % in Case 2. The rivaroxaban concentration in the infant plasma was below the lower limit of quantification in all infants. In addition, even in the high-exposure case simulation based on 5 days of breastfeeding in Case 2, the infant plasma concentration level was below the lower limit of quantification. At 3 months of follow-up, breastfeeding was continued, and all infants grew and developed without any health problems including bleeding events. The current case series showed that there were no pharmacokinetic or clinical concerns for breastfeeding women or breastfed infants, and provides support for rivaroxaban as a safe treatment option for these patients.

Comparison of safety and effectiveness between etanercept biosimilar LBEC0101 and reference in patients with rheumatoid arthritis in real-world data using the KURAMA cohort.

OBJECTIVES: Biosimilars are anticipated to be widely used in the treatment of rheumatoid arthritis (RA), owing to their cost efficiency; LBEC0101 was the first etanercept (ETN) biosimilar approved in Japan. However, there are limited real-world data comparing its safety and effectiveness with those of a reference product. METHODS: This study used data from the Kyoto University Rheumatoid Arthritis Management Alliance cohort, including patients with RA who received ETN therapy-ETN reference product (ETN-RP) or LBEC0101-between 2015 and 2021. Serum ETN levels were measured using liquid chromatography-tandem mass spectrometry. RESULTS: The 1-year continuation rates of ETN-RP and LBEC0101 were 58.7% and 74.4%, respectively. Effectiveness of treatment was evaluated in 18 patients; both products significantly reduced the 28-joint RA disease activity score and erythrocyte sedimentation rate (DAS28-ESR). Moreover, to determine equivalence, we analysed 11 patients who switched from ETN-RP to LBEC0101; the DAS28-ESR and serum ETN levels before and after switching were not significantly different. CONCLUSIONS: This real-world cohort study confirmed that the biosimilar of ETN, LBEC0101, was comparable to the reference product in terms of continuation rate, effectiveness at initiation of introduction, and effect persistence before and after switching in clinical practice.

[Management of high-alert medications by clinical pharmacological approaches].

During the past decade, many high-alert medications have been developed and used in clinical practice. Particularly, in the pharmacotherapy of high-alert medications with large individual differences, more attention is needed. To achieve appropriate and individualized pharmacotherapy, there are many issues to be addressed from a clinical pharmacology perspective, such as enhanced monitoring and prior risk identification. This paper is focusing on the therapeutic drug monitoring of molecularly targeted anticancer drugs, and the provision of real-world evidence based on the clinical implementation of pharmacogenetic testing.

Low serum concentrations of bevacizumab and nivolumab owing to excessive urinary loss in patients with proteinuria: a case series.

PURPOSE: Proteinuria can cause interindividual variability in the pharmacokinetics of therapeutic antibodies and may affect therapeutic efficacy. Here, we measured the serum and urinary concentrations of bevacizumab (BV) and nivolumab (NIVO) in patients with proteinuria and reported a case series of these patients. METHODS: Thirty-two cancer patients who received BV every 3 weeks or NIVO every 2 weeks between November 2020 and September 2021 at Kyoto University Hospital were enrolled in this study. The serum and urinary concentrations of BV and NIVO were measured using liquid chromatography-tandem mass spectrometry. RESULTS: We divided the BV-treated patients and the NIVO-treated patients into two groups based on the urine protein-creatinine ratio (UPCR): UPCR 1 g/g or higher (BV, n = 9; NIVO, n = 3) and UPCR less than 1 g/g (BV, n = 14; NIVO, n = 6). Serum concentrations of the therapeutic antibodies adjusted by their doses were significantly lower in both BV- and NIVO-treated patients with UPCR 1 g/g or higher compared to those with less than 1 g/g. In patients with UPCR 1 g/g or higher, urinary concentrations of the therapeutic antibodies adjusted by their serum concentrations and urinary creatinine concentrations tended to increase. CONCLUSION: This case-series study suggests a possibility of reduction in serum concentrations of BV and NIVO in patients with proteinuria by urinary excretion of these drugs.

Development of extended pharmacokinetic models for propofol based on measured blood and brain concentrations.

Propofol's pharmacokinetics have been extensively studied using human blood samples and applied to target-controlled infusion systems; however, information on its concentration in the brain remains scarce. Therefore, this study aimed to simultaneously measure propofol plasma and brain concentrations in patients who underwent awake craniotomy and establish new pharmacokinetic model. Fifty-seven patients with brain tumors or brain lesions who underwent awake craniotomy were sequentially assigned to model-building and validating groups. Plasma and brain (lobectomy or uncapping margins) samples were collected at five time-points. The concentration of propofol was measured using high-performance liquid chromatography. Population pharmacokinetic analysis was conducted through a nonlinear mixed-effects modeling program using a first-order conditional estimation method with interactions. Propofol's brain concentrations were higher than its plasma concentrations. The measured brain concentrations were higher than the effect site concentrations using the previous models. Extended models were constructed based on measured concentrations by incorporating the brain/plasma partition coefficient (Kp value). Extended models showed good predictive accuracy for brain concentrations in the validating group. The Kp value functioned as a factor explaining retention in the brain. Our new pharmacokinetic models and Kp value can predict propofol's brain and plasma concentrations, contributing to safer and more stable anesthesia.

Comparison of the safety and cost-effectiveness of nebulized liposomal amphotericin B and amphotericin B deoxycholate for antifungal prophylaxis after lung transplantation.

INTRODUCTION: Fungal infection after lung transplantation can lead to poor clinical outcome, for which lung transplant recipients require prophylaxis. One of the antifungal agents used after lung transplantation is nebulized amphotericin B (AMB). Nebulized AMB causes adverse events such as dyspnea and airway irritation, and long-term use leads to high economic costs. So far, prophylactic regimens employing AMB deoxycholate (AMB-d) and liposomal AMB (L-AMB) have been developed. This study compared the efficacy, safety, and cost of AMB-d and L-AMB. PATIENTS AND METHODS: Patients who underwent lung transplantation at Kyoto University Hospital from January 2021 to May 2023 were included in this study. Thirty-three patients received nebulized AMB-d, whereas 29 received nebulized L-AMB. RESULTS: Both regimens maintained comparable prophylactic efficacy regarding the development of fungal infection in the AMB-d and L-AMB groups (3.0% vs. 3.4%, P = 0.877). Patients treated with nebulized L-AMB experienced fewer respiratory-related adverse reactions than those treated with nebulized AMB-d (6.9% vs. 30.3%, P < 0.05), leading to a longer treatment duration with L-AMB than with AMB-d. Additionally, the daily cost of administering L-AMB was lower than that of administering AMB-d (3609 Japanese yen vs. 1792.3 Japanese yen, P < 0.05). DISCUSSION: These results suggest that nebulized L-AMB is safer and more cost-effective than nebulized AMB-d, with comparable efficacy.

Relationships of Proton Pump Inhibitor-Induced Renal Injury with CYP2C19 Polymorphism: A Retrospective Cohort Study.

Proton pump inhibitors (PPIs) have recently been reported to be linked with nephrotoxicity. PPIs are metabolized mainly or partly by cytochrome P450 2C19 (CYP2C19). However, the relationship between CYP2C19 genetic polymorphism and PPI-induced nephrotoxicity is unclear. In this study, we aimed to analyze the association between the time of occurrence of renal injury by PPIs, including lansoprazole, esomeprazole, rabeprazole, and vonoprazan, and CYP2C19 metabolizer status classified by CYP2C19 genotypes. Patients prescribed PPIs were reviewed in this retrospective cohort study. The primary outcome was the time to a 30% decrease in estimated glomerular filtration rate (eGFR) from baseline. In patients treated with lansoprazole, the time to a 30% decrease in eGFR for the CYP2C19 poor metabolizer (PM) group was significantly shorter than that for the non-PM group (hazard ratio for PM vs. non-PM, 2.43, 95% confidence interval, 1.21 to 4.87, P = 0.012). In contrast, in patients that received esomeprazole, rabeprazole, or vonoprazan, no significant differences were found in the time to a 30% decrease in eGFR between non-PM and PM groups. The adjusted hazard ratios for the time to a 30% eGFR decrease in patients treated with lansoprazole were significantly higher for CYP2C19 PM, hypertension, and a history of myocardial infarction. In conclusion, this retrospective study showed that CYP2C19 metabolizer status was associated with the time to a 30% eGFR decrease in patients treated with lansoprazole, but not with esomeprazole, rabeprazole, or vonoprazan.

Pharmacokinetics of GS-441524, the active metabolite of remdesivir, in patients receiving continuous renal replacement therapy: A case series.

Remdesivir plays a key role in the treatment of coronavirus disease in 2019 (COVID-19). Haemodialysis is sometimes required for hospitalised patients with COVID-19, and patients undergoing haemodialysis are at an increased risk of severe COVID-19. In the present study, we report the serum concentrations of GS-441524, the active metabolite of remdesivir, in four patients undergoing continuous renal replacement therapy (CRRT). Patient 1, a male aged 70s, received a loading dose of 200 mg remdesivir on day 1, followed by 100 mg remdesivir from day 2, according to the package insert as in non-haemodialysis patients. The mean trough serum concentration of GS-441524 was 783.5 ng/mL, which was approximately 7-fold higher than the mean for patients with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min. Patients 2-4 received a loading dose of 200 mg remdesivir on day 1, followed by 100 mg once every 2 days from day 2. The mean trough serum concentrations of GS-441524 were 302.2 ng/mL, 585.8 ng/mL and 677.3 ng/mL, respectively. These were 3 to 6-fold higher than the mean for patients with eGFR ≥60 mL/min. The target doses for patients 1, 2, 3, and 4 receiving CRRT were 13.6 mL/kg/h, 6.0-12.5 mL/kg/h, 20.1 mL/kg/h, and 15.1 mL/kg/h, respectively, using a polysulphone membrane. The package insert dose of remdesivir is an overdose for CRRT patients with a target dose of 10-20 mL/kg/h. In low-intensity CRRT, as in Japan, it may be necessary to extend the interval between the doses of remdesivir.

Association of direct oral anticoagulant and delayed bleeding with pharmacokinetics after endoscopic submucosal dissection.

BACKGROUND AND AIMS: Pharmacokinetic parameters, such as drug plasma level at trough, time to maximum plasma concentration (Tmax), and coagulation factor Xa (FXa) activity generally predict factors for the anticoagulant effects of direct oral anticoagulants (DOACs). Although GI bleeding is a major adverse event after endoscopic submucosal dissection (ESD), little is known about the association between post-ESD bleeding in patients taking DOACs and the pharmacologic parameters. This study aimed to evaluate pharmacologic risk factors for post-ESD bleeding in patients taking DOACs. METHODS: We prospectively evaluated the incidence of post-ESD bleeding in patients taking DOACs between April 2018 and May 2022 at 21 Japanese institutions and investigated the association with post-ESD bleeding and pharmacologic factors, including plasma concentration and FXa activity at trough and Tmax. RESULTS: The incidence of post-ESD bleeding was 12.8% (14 of 109; 95% confidence interval [CI], 7.2-20.6). Although plasma DOAC concentration and plasma level/dose ratio at trough and Tmax varied widely among individuals, a significant correlation with plasma concentration and FXa activity was observed (apixaban: correlation coefficient, -0.893; P < .001). On multivariate analysis, risk factors for post-ESD bleeding in patients taking DOACs were higher age (odds ratio [OR], 1.192; 95% CI, 1.020-1.392; P = .027) and high anticoagulant ability analyzed by FXa activity at trough and Tmax (OR, 6.056; 95% CI, 1.094-33.529; P = .039). CONCLUSIONS: The incidence of post-ESD bleeding in patients taking DOACs was high, especially in older patients and with high anticoagulant effects of DOACs. Measurement of pharmacokinetic parameters of DOACs may be useful in identifying patients at higher risk of post-ESD bleeding.

Trough ganciclovir concentration as predictor of leukopenia in lung transplant recipients receiving valganciclovir prophylaxis.

BACKGROUND: Valganciclovir is the first-line agent for Cytomegalovirus prophylaxis after lung transplantation. However, its use is associated with a relatively high risk of hematological toxicity. This study aimed to investigate the relationship between trough ganciclovir concentration and hematologic toxicity in lung transplantation patients receiving valganciclovir prophylaxis, and identify factors that affect ganciclovir pharmacokinetics in this population. METHODS: This prospective observational study included 24 lung transplant patients receiving valganciclovir prophylaxis. The cutoff value of trough ganciclovir concentration was estimated using receiver operating characteristic analysis in leukopenia grade 3 and higher. Population pharmacokinetic analysis was performed using a nonlinear mixed-effects modeling program. RESULTS: The trough ganciclovir concentration was significantly higher in the group with leukopenia grades 3 or higher than in the group with grades less than or equal to 2 (1605.7 ± 860.1 ng/mL [n = 3] vs. 380.5 ± 175.8 ng/mL (n = 21), p < .001). The cutoff value of trough ganciclovir concentration for predicting greater than or equal to grade 3 leukopenia was estimated as 872.0 ng/mL. Creatinine clearance and lung re-transplantation were found to have a significant impact on the total body clearance of valganciclovir. Ganciclovir clearance was decreased in patients with reduced creatine clearance or re-transplantation. CONCLUSION: These results suggest that higher ganciclovir trough concentrations are associated with an increased risk of leukopenia grade 3 or higher, and that creatinine clearance and lung re-transplantation affected the pharmacokinetics of ganciclovir.