Abnormally Elevated Blood Tacrolimus Level Following the Concomitant Use of Nirmatrelvir/Ritonavir With Extended-Release Tacrolimus in a Post-lung Transplant Patient: A Case Report and a Literature Review.

Although nirmatrelvir/ritonavir (NMV/r) reportedly increases blood levels of tacrolimus (TAC) due to CYP3A4 inhibition and other factors, reports on the use of NMV/r in combination with tacrolimus hydrate extended-release capsules (TAC-ER) in lung transplant patients are limited. Herein, we present a case with post-lung transplantation of elevated blood trough levels of TAC after concomitant use of NMV/r. A woman in her 60s had undergone lung transplantation. She had coronavirus disease 2019 (COVID-19) and was co-administered NMV/r and TAC-ER, with the trough level controlled at approximately 4 µg/mL. Upon the co-administration of NMV/r and TAC-ER, the patient developed diarrhea and vomiting and was hospitalized. TAC-ER was discontinued on day 6, and TAC level was measured on day 8 and had risen above 100 ng/mL. This level gradually decreased to 17.8 ng/mL on day 11 and 2.4 ng/mL on day 15; therefore, TAC-ER was resumed at 2.5 mg/day. On day 18, the TAC level was 5.2 ng/mL, which was within the target range, and the patient was discharged on day 19. This is the first report of a post-lung transplant patient co-administered TAC-ER with NMV/r, who showed abnormally high blood TAC levels above the detection limit. In patients using TAC-ER after lung transplantation, it may be useful to confirm that the TAC blood level is below the effective therapeutic range before resuming TAC-ER safely.

Effectiveness and safety of the simulation-based first-dose design of voriconazole.

BACKGROUND: We investigated whether the initial voriconazole (VRCZ) dosing design, as determined using simulation software with a population pharmacokinetic model of Japanese patients, impacts the effectiveness and safety when compared with VRCZ initiation according to the package insert. METHODS: In this single-center retrospective observational study, we employed records from Tosei General Hospital (a 633-bed hospital), dated April 2017 to September 2023. Eligible patients were divided into the software-based simulation group, comprising patients administered initial VRCZ dosage adjustment by pharmacists using software-based simulation, and the standard therapy group, whose dosage was administered by a physician following the package insert recommendations without simulation. The primary objective of this study was to determine the efficacy of VRCZ first-dose design in reducing the incidence of hepatotoxicity and visual symptoms. RESULTS: The median ages of enrolled participants (n = 93) were 75 (68-79) and 72 (65-78) years in the software-based simulation and standard therapy groups, respectively. Regardless of formulation, initial trough concentrations were lower in the VRCZ software-based first dosage adjustment group and higher rate within the appropriate range (1-4 µg/mL). The incidence of all-grade hepatotoxicity or visual symptoms was significantly lower in the software-based simulation group. The log-rank test revealed a significant impact on the occurrence of ≥grade 2 hepatotoxicity in the software-based first dosage adjustment group compared to that in the standard therapy group. CONCLUSIONS: The initial VRCZ dosing design using simulation software improved the achievement of appropriate initial trough concentrations and resulted in fewer occurrences of hepatotoxicity (≥grade 2) when compared with the standard therapy.

Cost-effectiveness of nirmatrelvir/ritonavir for high-risk adult outpatients with COVID-19 in Japan.

INTRODUCTION: This study aimed to evaluate the cost-effectiveness of nirmatrelvir/ritonavir (Nir/Rit) for adult outpatients with COVID-19 from the perspective of a Japanese public healthcare payer. METHODS: A cost-effectiveness simulation was conducted comparing Nir/Rit for the outpatient treatment of high-risk COVID-19 patients to best supportive care (BSC) without antiviral or antibody drugs. The analytical model was divided into two phases: the treatment phase, lasting 35 days from the start of COVID-19 treatment, and the post-treatment phase. Patients who survived the treatment phase were assumed to follow a general population survival curve. Expected costs and expected quality-adjusted life years (QALYs) for both BSC and Nir/Rit were calculated for ages 40 to 80 to obtain the incremental cost-effectiveness ratio (ICER). The robustness of the results was evaluated through deterministic and probabilistic sensitivity analysis (PSA). RESULTS: The ICERs for patients aged 40, 50, 60, 70, and 80 were 18,854,276 Japanese Yen (JPY)/QALY, 8,482,034 JPY/QALY, 4,976,612 JPY/QALY, 2,636,096 JPY/QALY, and 1,597,783 JPY/QALY, respectively. In the deterministic sensitivity analysis, both the mortality risk during the treatment phase and the relative mortality risk with Nir/Rit had a high impact on ICER across all ages. In the PSA, when the willingness-to-pay (WTP) threshold was set at 5 million JPY/QALY, the probability of the ICER being below the WTP threshold was 0%, 0.2%, 45.4%, 99.9%, and 100% at ages 40, 50, 60, 70, and 80, respectively. CONCLUSION: Nir/Rit is cost-effective for older individuals aged 60 and over but not for younger age groups.

Safety Evaluation of Remdesivir for COVID-19 Patients with eGFR < 30 mL/min without Renal Replacement Therapy in a Japanese Single-Center Study

There are limited reports on the safety of remdesivir for patients with severe kidney disease. We investigated the safety of remdesivir administration for COVID-19 patients with estimated glomerular filtration rate (eGFR) <30 mL/min. This single-center retrospective study was conducted between March 2020 and April 2022 at Tosei General Hospital, Japan. Propensity score matching was performed between patients with eGFR ≤ 30 mL/min and eGFR >30 mL/min with remdesivir administration. The primary outcome was 30-day mortality after the first administration. Adverse events, including development of acute kidney injury (AKI), liver function disorder, anemia, and thrombocytopenia 48 h after the end of remdesivir administration, were evaluated. After propensity score matching, 23 patients were selected from each group. There were no differences in the 30-day mortality (risk ratio [RR] 1.00; 95% confidence interval [CI] 0.18−5.56). Development of AKI and liver function disorder was not statistically different between the two groups (RR 1.05; 95% CI 0.96−1.14 and RR 0.48; 95% CI 0.04−5.66, respectively). There was no trend toward a significant increase in adverse events in the eGFR < 30 mL/min group and severe renal dysfunction had little effect on the safety of remdesivir treatment.

Cost-effectiveness analysis of olanzapine in four-drug antiemetic therapy in Japanese patients treated with highly emetogenic cisplatin-containing chemotherapy.

BACKGROUND: Olanzapine has been shown to have an additive effect on the three-drug antiemetic therapy consisting of aprepitant, palonosetron, and dexamethasone, in a highly emetogenic cisplatin-containing chemotherapy. Although olanzapine may be more economical than aprepitant or palonosetron, an adequate cost-efficacy analysis has not been conducted. METHODS: We conducted a cost-utility analysis to evaluate the cost-effectiveness of olanzapine use in four-drug antiemetic therapy among Japanese patients. We simulated model patients treated with highly emetogenic cisplatin-containing chemotherapy and developed a decision-analytical model of patients receiving triple antiemetic therapy with or without olanzapine in an inpatient setting. The cost and probabilities of each treatment were calculated from the perspective of the Japanese healthcare payer. The probabilities, utility value, and other costs were obtained from published sources. One-way and probabilistic sensitivity analyses were conducted to examine the influence of each parameter on the model and the robustness of a base-case analysis. Threshold analysis was conducted to determine the cost of olanzapine that would make the incremental cost-effectiveness ratio (ICER) equivalent to the threshold ICER). The threshold incremental cost-effectiveness ratio was set at 5 million Japanese Yen (JPY) per quality-adjusted life-year (QALY) gained. RESULTS: The cost was 10,238 JPY in the olanzapine regimen and 9719 JPY in the non-olanzapine regimen. The QALY gained were 0.01065 QALYs and 0.01029 QALYs in the olanzapine and non-olanzapine regimen, respectively. The incremental cost of the olanzapine regimen relative to the non-olanzapine regimen was 519 JPY, and the incremental QALYs were 0.00036 QALY, resulting in an ICER of 1,428,675 JPY per QALY gained. In the one-way sensitivity analysis, the results were most sensitive to the utility value of incomplete control. The probabilistic sensitivity analysis revealed the probability that the ICER was below the willingness-to-pay, and the incremental QALYs was positive was 96.2%. The calculated cost of olanzapine per 5 mg that would make the incremental cost-effectiveness ratio equivalent to the threshold incremental cost-effectiveness ratio was calculated to be 475 JPY. CONCLUSIONS: Olanzapine was cost-effective in the four-drug antiemetic therapy for Japanese patients treated with highly emetogenic cisplatin-containing chemotherapy.

Cost-effectiveness analysis of pegfilgrastim in patients with non-small cell lung cancer receiving ramucirumab plus docetaxel in Japan.

PURPOSE: The dose-limiting factor of ramucirumab plus docetaxel (RAM + DTX) in patients with non-small cell lung cancer (NSCLC) is febrile neutropenia (FN), which has a high incidence in Asians. This study aimed to evaluate the cost-effectiveness of pegfilgrastim (Peg-G) in patients with NSCLC receiving RAM + DTX in Japan. METHODS: We simulated model patients treated with RAM + DTX in Japan and developed a decision-analytical model for patients receiving Peg-G prophylaxis or no primary prophylaxis. The expected cost, quality-adjusted life-year (QALY), and incremental cost-effectiveness ratio (ICER) of each treatment were calculated from the perspective of a Japanese healthcare payer. The willingness-to-pay (WTP) threshold was set at 45,867 United States dollars (USD) (5 million Japanese yen) per QALY gained. The probabilities, utility values, and other costs were obtained from published sources. Deterministic sensitivity analysis (DSA) and probabilistic analysis were conducted to evaluate the effect of each parameter and robustness of the base-case results. RESULTS: The expected cost and QALYs were 20,275 USD and 0.701 for Peg-G prophylaxis and 17,493 USD and 0.672 for no primary prophylaxis, respectively. The ICER was calculated to be 97,519 USD per QALY gained. The results were most sensitive to FN risk with Peg-G. When FN risk with no primary prophylaxis exceeded 51% or the cost of Peg-G was less than 649 USD per injection, the ICER was below the WTP threshold. The probabilistic analysis revealed a 9.1% probability that the ICER was below the WTP threshold. CONCLUSION: Peg-G is not cost-effective in patients with NSCLC receiving RAM + DTX in Japan.

Influence of Change of Full-Time Equivalents on Post-prescription Review with Feedback Interventions in an Antimicrobial Stewardship.

Few studies have investigated the influence of more full-time equivalents (FTEs) of infectious disease (ID) pharmacists on the likelihood of a post-prescription review with feedback (PPRF) intervention. This study focused on this in community hospitals before and after the Japanese medical reimbursement system was revised to introduce antimicrobial stewardship (AS) fees. We collected data for two periods: before (April 2017 to March 2018) and after (April 2018 to March 2019) AS fee implementation. The efficacy of the PPRF by the ID pharmacist was assessed based on the usage of broad-spectrum antimicrobials in days of therapy (DOT) per 100 patient-days. Further, we generated the susceptibility rate for antimicrobial-resistant organisms. The number of PPRF drugs was 2336 (2596 cases) before AS fee implementation and 2136 (1912 cases) after implementation. The overall monthly FTE for AS for an ID pharmacist increased from [median (interquartile range; IQR)] 0.34 (0.33-0.36) to 0.63 (0.61-0.63) after AS fee implementation. The DOT of the broad-spectrum antibiotics decreased from 10.46 (9.61-12.48) to 8.68 (8.14-9.18). The DOT of carbapenems and quinolones decreased significantly from 4.11 (3.69-4.41) to 3.07 (2.79-3.22) and 0.96 (0.61-1.14) to 0.37 (0.19-0.46), respectively (p < 0.05). Furthermore, the rate of levofloxacin (LVFX)-susceptible Pseudomonas (P.) aeruginosa improved from 71.5 to 84.8% (p < 0.01). We observed that increasing the FTE of ID pharmacists influences the DOTs of broad-spectrum antibiotics; a higher FTE contributes to fewer DOTs. Further, the susceptibility of P. aeruginosa to meropenem and LVFX increased as the FTE increased.

Visualization of Kinase Inhibition-Related Adverse Events Using the Japanese Adverse Drug Event Report Database.

INTRODUCTION: Small molecule tyrosine kinase inhibitors (TKIs) inhibit not only the target kinase but also various kinases as off-target inhibitors not mentioned in the package insert. However, there are no reports that comprehensively examine the relationship between adverse events and kinase affinity. OBJECTIVE: In this study, we combined basic data and clinical data to visualize the relationship between kinase affinity and adverse events, which will be useful for the management of adverse events in clinical practice. METHODS: We targeted TKIs that have been used domestically and for which the dissociation constant was obtained as reported by Davis et al. Adverse event data recorded in the Japanese Adverse Drug Event Report (JADER) database provided by the Pharmaceuticals and Medical Devices Agency between April 2004 and January 2018 were used. We calculated the reporting rates of the Standardized MedDRA Queries (SMQ) for the adverse events of interest and visualized the correlation coefficients with kinase affinity. We used the adverse events associated with VEGFR2 and EGFR to assess their validity. RESULTS: We found a correlation among known kinase-related adverse events, suggesting that the methodology may be used as a signal detection method to generate hypotheses for clinical and basic research. CONCLUSION: Our comprehensive analysis of the kinase affinity of TKIs in this study, which was based on basic TKI kinase affinity data and the clinical data of the reporting rates, suggested that our comprehensive analysis method is useful for generating hypotheses about possible causal relationships between pharmacological effects and adverse events.

Identification of target small molecule tyrosine kinase inhibitors that need monitoring and clinical application of protocol for early detection of cancer therapeutics-related cardiac dysfunction using signal detection: An investigation of real world data.

PURPOSE: In order to detect cancer therapeutics-related cardiac dysfunction (CTRCD) early, we identified which drugs were to be monitored using signal detection and the package insert, and created and applied a protocol to address this. METHODS: Adverse event data recorded in the Japanese Adverse Drug Event Report (JADER) database between April 2004 and January 2018 were used. Among small molecule tyrosine kinase inhibitors that are not described in the serious side-effects section of the package insert despite signal detection, tyrosine kinase inhibitors with severe side-effects in the background of cases reported by JADER database were selected to be monitored in clinical practice. We applied our findings clinically by creating a protocol to detect CTRCD early. All cases at Tosei General Hospital where the target tyrosine kinase inhibitors were administered from when they were first released in November 2019 were included. We compared the results from before and after we began the protocol to clarify its effects. RESULTS: We found that CTRCD was not described in the serious side-effect section of the package inserts for Bosutinib, Alectinib, and Osimertinib even though CTRCD signals were detected for them. Therefore, it is possible that we may have previously overlooked CTRCD. When we applied our protocol using Osimertinib as the target drug, we were able to detect CTRCD early in 5/21 (24%) patients. CONCLUSIONS: It was clarified that the drug identification method used in this study for early detection of adverse events leads to early detection of adverse events when applied clinically.

Efficacy of baloxavir marboxil on household transmission of influenza infection.

BACKGROUND: Baloxavir marboxil (baloxavir) is a new anti-influenza virus agent that is comparable to oseltamivir phosphate (oseltamivir). Since the efficacy of baloxavir in preventing household transmission of influenza is not well established, we compared the secondary household influenza virus transmission rates between patients on baloxavir vs oseltamivir. METHODS: Between October 2018 and March 2019, we enrolled index patients (diagnosed with influenza and treated with baloxavir or oseltamivir) and household members. The secondary attack rate of household members was compared between index patients treated with baloxavir vs oseltamivir. Risk factors of household transmission were determined using multivariate logistic analyses. RESULTS: In total, 169 index patients with influenza type A were enrolled. The median age was 27.0 (interquartile range; 11-57) years. The number of index patients treated with baloxavir and oseltamivir was 49 and 120, respectively. The secondary attack rate was 9.0% (95% confidence interval [CI]: 4.6-15.6) in the baloxavir group and 13.5% (95% CI: 9.8-17.9) in the oseltamivir group. In the multivariate analysis, independent risk factors were 0-6 years of age (odds ratio [OR] 2.78, 95% CI: 1.33-5.82, p < 0.01) and not being on baloxavir treatment. (OR: 0.63, 95% CI: 0.30-1.32, p = 0.22). CONCLUSION: The household secondary attack rate of influenza was comparable in patients treated with baloxavir vs oseltamivir. Therefore, baloxavir can be used as an alternative therapy to oseltamivir in reducing household transmission of influenza. TRIAL REGISTRATION: Patients in this study were retrospectively registered. https://www.tosei.or.jp/clinical/pdf/2_influenza.pdf.

Efficacy of prolonged tapered and pulsed vancomycin regimen on recurrent Clostridioides difficile infection in the Japanese setting: a case control study.

BACKGROUND: According to the Clinical Practice Guidelines for Clostridioides difficile, oral vancomycin is to be used in vancomycin tapered and pulsed regimen (VCM-TP) for recurrent Clostridium difficile infection (CDI). However, data on the efficacy of VCM-TP in Japanese patients with recurrent CDI are scarce. To address this gap, we investigated the efficacy of VCM-TP and performed a case-controlled study to assess the risk factors associated with treatment failure in these patients. FINDINGS: We conducted this study on all patients who were administered VCM-TP for recurrent episodes of CDI between January 2008 and December 2018 at Tosei General Hospital. All patients had documented follow-ups within 90 days after completion of the VCM-TP. Data were obtained for comparative analysis of treatment success or failure. Thirty-six patients were eligible for this study, and treatment success was documented in 23 patients (63.9%) following VCM-TP treatment. Treatment success was documented in 22 of 30 (73.3%) patients who received the recommended therapy according to the Clinical Practice Guidelines. The frequency of patients treated with the recommended therapy was higher in the treatment success group (95.7%) than in the treatment failure group (61.5%) (OR: 13.75, 95% CI: 1.39-136.39, p = 0.016). Vancomycin-resistant enterococci culture tests were performed in 20 patients (55.6%), and all results were negative. CONCLUSIONS: Our findings suggest that VCM-TP is a good therapeutic option for recurrent CDI in Japanese patients. Furthermore, administration of the recommended VCM-TP is important for achieving a high rate of treatment success. Hence, antimicrobial stewardship teams should support the implementation of recommended VCM-TPs.

Effectiveness of pharmaceutical support by pharmacists in urinary care teams.

To facilitate timely removal of urinary catheters and promote self-voiding among inpatients, urinary care teams have been established in some Japanese medical institutions. However, direct evidence of the effectiveness of pharmacist intervention in urinary care teams is limited. We evaluated the efficacy of pharmaceutical support by a pharmacist in a urinary care team. Between September 2017 and August 2018, 84 patients met the criteria for initiating continuous intervention. Patients with (20 cases) and without (8 cases) adoption of pharmaceutical support (initiation or discontinuation of treatment for dysuria) were scored for urinary function (including degree of independence of urination and score of lower urinary tract disorder) and for urinary situation. Comparative analysis results showed that pharmacist intervention in the adoption cases resulted in significantly improved scores for urinary function than in non-adoption cases. Similarly, pharmaceutical support resulted in improved overall urinary situation in the patients (85.0% of adoption cases compared to 37.5% of the non-adoption cases). The most common pharmaceutical support was a recommendation to discontinue drugs that induce dysuria (65.0% of the cases). Taken together, our findings suggested that pharmacists are important members of urinary care teams.

Ethylene signaling pathway and MAPK cascades are required for AAL toxin-induced programmed cell death.

Programmed cell death (PCD), known as hypersensitive response cell death, has an important role in plant defense response. The signaling pathway of PCD remains unknown. We employed AAL toxin and Nicotiana umbratica to analysis plant PCD. AAL toxin is a pathogenicity factor of the necrotrophic pathogen Alternaria alternata f. sp. lycopersici. N. umbratica is sensitive to AAL toxin, susceptible to pathogens, and effective in Tobacco rattle virus-based virus-induced gene silencing (VIGS). VIGS analyses indicated that AAL toxin-triggered cell death (ACD) is dependent upon the mitogen-activated protein (MAP) kinase kinase MEK2, which is upstream of both salicylic acid-induced protein kinase (SIPK) and wound-induced protein kinase (WIPK) responsible for ethylene (ET) synthesis. ET treatment of MEK2-silenced N. umbratica re-established ACD. In SIPK- and WIPK-silenced N. umbratica, ACD was compromised and ET accumulation was not observed. However, in contrast to the case of MEK2-silenced plants, ET treatment did not induce cell death in SIPK- and WIPK-silenced plants. This work showed that ET-dependent pathway and MAP kinase cascades are required in ACD. Our results suggested that MEK2-SIPK/WIPK cascades have roles in ET biosynthesis; however, SIPK and WIPK have other roles in ET signaling or another pathway leading to cell death by AAL toxin.