Published papers

Venetoclax-azacitidine chemotherapy is a key treatment for older or medically unfit patients with acute myeloid leukemia (AML). As venetoclax is metabolized via cytochrome P450 3 A, dose adjustments are required when combined with antifungal agents. However, data on venetoclax concentrations and their impact on safety and efficacy remain limited. This study analyzed the association between venetoclax trough levels and treatment outcomes in 152 AML patients (median age: 70 years). The median trough level was 1,518 ng/mL (range: 60–11,328 ng/mL), with significant interindividual variability, even after adjusting for antifungal use. High venetoclax trough levels were significantly associated with elevated creatinine and total bilirubin levels. Patients with trough levels below 1857.3 ng/mL had lower rates of hematologic toxicity during the first treatment cycle (92.9% vs. 100%, P = 0.041). In the second cycle, hematologic toxicity was lower in patients with concentrations below 1,299.3 ng/mL (68% vs. 90%, P = 0.009). In the treatment-naïve group, trough levels above 1857.3 ng/mL were associated with a higher composite complete remission rate (77.3% vs. 47.8%, P = 0.042). These findings highlight the need for venetoclax dose optimization based on drug levels to improve both safety and efficacy in AML treatment.

医薬品情報を利活用した癌薬物療法に対する薬学的介入として、薬剤師がタクロリムスとアプレピタントの薬物相互作用に着目し薬学的支援を行った、皮膚筋炎併発胃癌患者の症例(70代男性)について報告した。薬剤師が収集した既知情報、文献的考察および定量評価結果を医師に示し、医師と治療レジメンおよび制吐療法を協議した。その結果、本患者が男性であること、および年齢が70代であり、催吐性リスクが必ずしも高くないことに鑑み、アプレピタントの使用は必須でないと判断された。これらの協議内容を踏まえ、総合的に判断した。その結果、制吐療法としてアプレピタントを使用せず、SOX療法を施行することが決定された。その結果、化学療法開始後の嘔気はコントロール可能な範囲であり、タクロリムスのアドヒアランスに影響はなかった。本症例のように、エビデンスや情報が少ないケースであっても、薬剤師が相互作用という単一的要因だけでなく、特定の背景を有する患者側に起因する複数の因子を同時に考慮し、情報収集、評価、提案およびモニタリングを行うことが、安全で適切な化学療法の提供つながることが示唆された。

PURPOSE: Bevacizumab (BV) is an effective therapeutic antibody utilized in various cancers. Serum BV concentration can be a factor that potentially affects its therapeutic efficacy. Although proteinuria could affect BV pharmacokinetics, its influence was not evaluated in the previous population pharmacokinetic (PopPK) studies. Because BV can cause proteinuria as an adverse event, the present study aimed to develop a PopPK model in patients with proteinuria and to evaluate the influence of proteinuria on BV pharmacokinetics. METHODS: This prospective cohort study enrolled 70 Japanese cancer patients newly starting BV, and 368 concentration samples from these patients were analyzed. Serum BV concentrations were measured at several time points including at the onset of proteinuria. PopPK analysis was conducted using a non-linear mixed-effects modeling program. A two-compartment model was used to estimate total body clearance (CL). RESULTS: Serum BV concentrations divided by the dose per body weight and dosing interval tended to be lower in patients with higher urinary protein to creatinine ratio (UPCR). The covariate analysis showed that increasing BV CL was associated with decreasing serum albumin concentration and increasing body weight and UPCR. The simulated median trough concentrations of BV in patients with Common Terminology Criteria for Adverse Events grades 1, 2, and 3 proteinuria were decreased by 12.0%, 20.6%, and 31.5%, respectively, compared to those in patients with grade 0. CONCLUSION: We successfully established a PopPK model incorporating UPCR to predict serum BV concentrations in patients with proteinuria. Our study provides additional insights to better understand BV pharmacokinetics.

薬物血中濃度モニタリング(TDM)は抗菌薬,抗てんかん薬,免疫抑制薬などの個別化医療に大きく貢献してきた.抗体医薬品は免疫原性を有し血中濃度の個人差も現れることから,TDMの導入が期待されている.近年,関節リウマチ患者におけるインフリキシマブ血中濃度評価が承認された.しかし,低分子医薬品と同じように有効域を目指した投与設計を行うわけではなく,どのように実臨床で活用していくかの課題が残る.従来のproactive TDMに加えて,イベント発生時に行うreactive TDMという考え方も生まれ,抗体医薬品TDMの新しい考え方か展開されていく.また,抗体医薬品の革新的な分析手法の開発や,バイオトランスフォーメーションのエビデンスも蓄積されており,さらなる研究展開が進んでいる.本稿では,抗体医薬品のTDMの現状と今後の展望を概説するとともに,抗体医薬品の測定法の開発についてもも述べる.(著者抄録)

がん化学療法における薬物相互作用はときにがん化学療法の効果や副作用に影響をもたらすことがある。我々は移植後リンパ増殖性疾患患者に対し、シクロホスファミド、ピンクリスチン、プレドニゾロン併用療法(CVP療法)を施行するにあたり、抗がん薬、抗真菌薬および免疫抑制薬の相互作用による有害反応を回避するため、感染予防目的に投与したアゾール系抗真菌薬の変更および一時的休薬、免疫抑制薬の精密な投与設計を行うことで化学療法を完遂できた症例を経験した。これまでに免疫抑制薬、抗真菌薬を併用し、薬物相互作用を検討しつつ、がん化学療法を安全に施行した報告は少ない。今回の知見は、免疫抑制療法施行中という特殊条件下にある患者で、がん化学療法の副作用および合併症を制御しながら化学療法を施行するうえで有用と考えられる。(著者抄録)

ボリコナゾール(voriconazole:以下、VRCZ)はチトクロームP450(cytochrome P450:以下、CYP)を介した併用薬剤との相互作用が多数報告されている。一方、併用薬中止後のVRCZ投与量や血中濃度の推移、および副作用を詳細に記述した報告は限られる。今回、CYP誘導作用を有するレテルモビル(letermovir:以下、LMV)中止後に、VRCZのトラフ値が著明に上昇した症例を経験した。40歳代の女性で、造血幹細胞移植後にLMVとVRCZの投与を開始した。VRCZのトラフ値は1.1～1.9μg/mLで推移していたが、LMV中止7日後に視覚障害、29日後に肝障害を認め、33日後にトラフ値が9.0μg/mLに上昇していた。LMV中止後は、酵素誘導解除に伴うCYP発現量の減少により、VRCZ血中濃度が上昇する可能性が高いため、きめ細やかなモニタリングが必要と考えられる。(著者抄録)

Breastfeeding is important for the mental and physical health of mothers and newborn babies. The amount of ethyl loflazepate, an antidepressant drug, excreted into breast milk is not well clarified. Here, we measured the plasma and breastmilk levels of ethyl loflazepate in two lactating women on the third day after delivery and their breastfed infants on the fourth day after birth. The metabolite in plasma and breastmilk was measured by liquid chromatography/mass spectrometry. The metabolite concentrations in the respective milks of case 1 were 35.1 ng/mL (relative infant dose was 2.3％) and the metabolite concentrations of case 2 were 35.0 ng/mL (relative infant dose was 3.9％). The metabolite concentrations in mothers’ and infants’ plasma of case 1 were 128.9 ng/mL (mother), 67.5 ng/mL (infant). The metabolite concentrations in mothers’ and infants’ plasma of case 2 were 99.9 ng/mL (mother), 28.2 ng/mL (infant). Adverse drug symptoms, such as respiratory disorder and drowsiness, were observed in the case 1 infant from immediately after birth to day 2 and in the case 2 infant from immediately after birth until discharge on day 8. The present case report can contribute to the pharmacotherapy in pregnant and postpartum women with depression.

Direct oral anticoagulants (DOACs) exert their anticoagulant effects by directly inhibiting thrombin and factor Xa; however, it is important to consider the interactions of DOACs with concomitant medications as some medication may increase the risk of bleeding. Selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs) have been reported to reduce platelet aggregation and increase the risk of bleeding. However, there is little evidence regarding the interaction between DOACs and SSRIs or SNRIs in Japanese patients. Therefore, the aim of our study was to investigate the background of bleeding in Japanese patients using SSRIs or SNRIs in combination with DOACs. Seventeen patients who took DOACs in combination with SSRIs or SNRIs between January 2016 and December 2019 at Kyoto University Hospital were included in the study. The observation period was 6 months after commencing DOAC administration and 6 months after of the commencement of SSRI or SNRI administration; moreover, the pre- and post-treatment examinations were performed to assess the changes for each patient. There was no incidence of major bleeding when only DOAC was used, but four of the seventeen patients (23.5％) had major bleeding when antidepressants were administered in addition to DOACs. Known bleeding risk factors such as hypertension, liver dysfunction, smoking history, cancer, peptic ulcer, and thrombocytopenia were not identified as risk factors for major bleeding in this study.

We retrospectively analyzed the effectiveness of posaconazole (tablet and infusion formulations) and its correlation with blood concentration in preventing invasive fungal infections (IFIs) in 360 patients who underwent allogeneic hematopoietic stem cell transplant (allo-HSCT) between 2010 and 2023. A total of 61 patients received posaconazole, 102 received micafungin, and 197 received fluconazole for primary prophylaxis. By day 100 post-transplant, the cumulative incidence of IFIs was significantly lower with posaconazole (5.0%) compared with fluconazole (14.4%) or micafungin (16.9%). Multivariate analysis showed that the risk of IFIs was significantly higher with fluconazole/micafungin than with posaconazole (hazard ratio 4.04, 95% CI 1.17–13.94, P = 0.027). This difference was most notable among patients with lymphoid malignancies (P = 0.053) and those undergoing repeat transplantation (P = 0.024). There were no significant differences in overall survival, non-relapse mortality, or mortality from IFI. Mean blood levels of posaconazole dropped to 0.57 μg/mL two weeks after allo-HSCT, coinciding with the observation of most IFIs in the posaconazole group shortly after transplant. Posaconazole appears to be more effective than fluconazole or micafungin as primary prophylaxis against IFIs in allo-HSCT recipients.

2012年は薬剤師の臨床業務にとって極めて大きな転機であった。すなわち、六年制薬学教育を受けた薬剤師の誕生と、薬剤師の病棟専任に対する診療報酬加算の実施の2つである。しかし、これら2つの転機が薬剤師の臨床業務の質に影響を及ぼしたかの評価はされていない。そこで、併用薬剤との相互作用が多いリファンピシンに焦点を絞り、病棟薬剤師がその処方に適切に介入できていたかを調査し、薬剤師の病棟業務の質を評価した。2012年(加算前)、2013年(加算直後)、2018年(加算5年後)において、該当薬剤の処方を病棟薬剤師が認識した割合は、調査年を追うごとに増加した。薬学的介入のなかで適切な提案ができている割合は、それぞれ75.0、87.5および86.6%であった。これらの結果から、病棟薬剤師業務加算の実施は、薬剤師の病棟業務の質的向上に寄与していると考えられる。一方で、薬学教育年数の延長が及ぼす効果を評価するために、卒後4年以内の病棟薬剤師の四年および六年制教育課程修了者について精査したところ、六年制修了者のほうが有意に処方介入度合いが高かった。このことから卒業直後は教育年数の延長効果が認められることが示唆された。しかし、今回の調査のみで、六年制薬学教育を修了した薬剤師の質を測ることは困難であり、今後様々な角度からの調査が必要である。(著者抄録)

京都大学医学部附属病院では、2019年11月より抗インフルエンザ薬を対象に適正使用指針(フォーミュラリ)を導入した。これまで、フォーミュラリ導入に関する過去の研究では医療経済を指標に検討されてきた。本研究では、医薬品の適正使用に焦点を当てて、フォーミュラリ導入の効果を検討した。2018年12月〜2019年1月および2019年12月〜2020年1月に抗インフルエンザ薬が投与された331名を対象とした。各薬剤の使用割合は導入前後によって、オセルタミビル:47.2→72.2%、ザナミビル:2.2→4.0%、ラニナミビル:19.4→7.3%、ペラミビル:19.4→16.5%、バロキサビル:11.6→0%に変化した。不適切投与は導入前後において21.6%から1.3%へ有意に低下した。1人当たりの薬剤費用は3,391円から2,685円へと減少した。フォーミュラリの導入は、医療経済だけでなく適正使用にも貢献することが明らかとなった。(著者抄録)

服薬されずに破棄される医薬品(残薬)とともに、臨床的に必要以上の薬剤が処方される「ポリファーマシー」が社会問題視されている。本研究では、病棟薬剤師の持参薬確認と服薬計画提案による、他職種の業務負担軽減効果およびポリファーマシー改善効果を検証した。持参薬確認業務により、内科・外科の医師および看護師ともに、患者1人あたりの持参薬確認にかかる業務時間が4.1〜8.5分短縮した。調査期間中の入院患者数694人のうち約9割に持参薬があり、平均持参薬数は6.8種類であった。そのうち17.1%の患者に対して病棟薬剤師による服薬計画変更提案がされ、74.8%の提案が医師に受け入れられた。薬剤の中止提案が最も多く、平均服用薬剤数は6.78種から6.71種へと有意に減少した。病棟薬剤師による持参薬の服薬計画提案が、医師および看護師の負担軽減とポリファーマシー改善に貢献すると考えられる。(著者抄録)

Everolimus has recently been used to prevent graft rejection in liver transplantation and reduces the incidence of kidney dysfunction caused by calcineurin inhibitors. In this study, a population pharmacokinetic analysis was conducted to improve the individualization of everolimus therapy. Japanese post-liver transplant patients whose blood everolimus concentrations were measured between March 2018 and December 2020 were included in this study. A nonlinear mixed-effect modeling program was used to explore covariates that affect everolimus pharmacokinetics. Individual everolimus pharmacokinetic parameters estimated by the post-hoc Bayesian analysis using the final model were compared with the tacrolimus dose per trough concentration (D/C) ratio in each patient. The final model was extrapolated to pediatric liver transplant patients for external evaluation. A total of 937 concentrations from 87 adult patients were used in the model-building process. Everolimus clearance was significantly affected by the estimated glomerular filtration rate, concomitant use of fluconazole, sex, as well as total daily dose of everolimus (TDM effect). The estimated individual apparent clearance of everolimus by the post-hoc Bayesian analysis was moderately correlated with the D/C ratio of tacrolimus in each patient (R2 = 0.330, p < 0.0001). The estimation accuracy in pediatric patients was considerably high, except for one infant out of 13 patients. In conclusion, population pharmacokinetic analysis clarified several significant covariates for everolimus pharmacokinetics in liver transplant patients. Everolimus pharmacokinetics moderately correlated with tacrolimus pharmacokinetics and could be extrapolated from adult to pediatric patients by body size correction, except for infants.

Infliximab (IFX) therapy has considerably improved the treatment of rheumatoid arthritis (RA). However, some patients still do not respond adequately to IFX therapy, or the efficacy of the treatment diminishes over time. Although previous studies have reported a relationship between serum IFX levels and therapeutic efficacy, the potential applications of IFX therapeutic drug monitoring (TDM) in clinical practice remain unclear. The purpose of this study was to investigate the potential applications of IFX TDM by analyzing a Japanese cohort database. Data were collected retrospectively from the Kyoto University Rheumatoid Arthritis Management Alliance cohort between January 1, 2011, and December 31, 2018. Serum IFX levels were measured using a liquid chromatography-tandem mass spectrometer. Out of the 311 RA patients that used IFX, 41 were eligible for the analysis. Serum IFX levels were significantly higher in responders than in non-responders. An optimal cut-off value was determined to be 0.32 μg/mL based on a receiver operating characteristic curve. At the IFX measurement point, a better therapeutic response was observed in the high IFX group (n = 32) than in the low IFX group (n = 9). Conversely, at the maximum effect point, when DAS28-ESR was the lowest between IFX introduction and measurement points, there were no differences in responder proportions between the low and high IFX groups. IFX primary ineffectiveness could be avoided with appropriate dose escalation without blood concentration measurement in clinical practice. In conclusion, IFX TDM could facilitate the identification of secondary non-responders and in turn, proper IFX use.

Background:Levetiracetam, a second-generation antiepileptic drug, is frequently used for managing partial-onset seizures. About 70% of the administered dose is excreted in urine unchanged, and dosage adjustment is recommended based on the individual's renal function. In this study, a population pharmacokinetic model of levetiracetam was developed using routinely monitored serum concentration data for individualized levetiracetam therapy.Methods:Patients whose serum concentrations of levetiracetam at steady-state were routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were enrolled. The influence of patient characteristics on levetiracetam pharmacokinetics was evaluated using the nonlinear mixed-effects modeling (NONMEM) program.Results:A total of 583 steady-state concentrations from 225 patients were used for the analysis. The median patient age and estimated glomerular filtration rate (eGFR) were 38 (range: 1-89) years and 98 (15-189) mLmin(-1)1.73 m(-2), respectively. Serum concentration-time data of levetiracetam were well described by a 1-compartment model with first-order absorption. Oral clearance was allometrically related to the individual body weight and eGFR. An increase in the dose significantly increased oral clearance. No improvement in model fit was observed by including the covariate of any concomitant antiepileptic drugs. The population mean clearance for an adult weighing 70 kg and with a normal renal function was 4.8 and 5.9 L/h for 500 mg bis in die (bid) and 1500 mg bid, respectively.Conclusions:Oral clearance allometrically related with body weight and eGFR can well predict the routine therapeutic drug monitoring data from pediatric to aged patients with varying renal function. Dosage adjustments based on renal function are effective in controlling the trough and peak concentrations in similar ranges.

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is used to suppress GvHD in patients undergoing hematopoietic stem cell transplantation (HCT). The purpose of this study was to construct a population pharmacokinetic and pharmacodynamic model in HCT patients for individualized MPA therapy. Blood samples were obtained from 49 HCT patients after starting MMF therapy. Population pharmacokinetic and pharmacodynamic parameters were obtained using the program NONMEM. MPA was described via a one-compartment model with a first-order elimination, and 30.9% of MPA glucuronide (MPAG) was found in the enterohepatic circulation. Inosine-5Œ-monophosphate dehydrogenase (IMPDH) activity was modeled as a maximal inhibitory model with a half-maximal inhibitory concentration (IC50) of 3.59 μg/mL against MPA concentrations. Simulations based on the obtained pharmacokinetic and pharmacodynamic parameters revealed that decreased creatinine clearance increases the MPAG concentration followed by an increased MPA concentration therefore, IMPDH activity decreases. Diarrhea decreases the enterohepatic circulation of MPAG and consequently reduces MPA concentration. The IC50 for MPA exhibited a positive association with C-reactive protein. Dosage adjustment based on plasma MPA concentration is required especially for patients with renal dysfunction and/or diarrhea.

Background: Topiramate is a second-generation antiepileptic drug used as monotherapy and adjunctive therapy in adults and children with partial seizures. A population pharmacokinetic (PPK) analysis was performed to improve the topiramate dosage adjustment for individualized treatment. Methods: Patients whose steady-state serum concentration of topiramate was routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were included in the model-building data. A nonlinear mixed effects modeling program was used to evaluate the influence of covariates on topiramate pharmacokinetics. The obtained PPK model was evaluated by internal model validations, including goodness-of-fit plots and prediction-corrected visual predictive checks, and was externally confirmed using the validation data from January 2015 to December 2015. Results: A total of 177 steady-state serum concentrations from 93 patients were used for the model-building analysis. The patients' age ranged from 2 to 68 years, and body weight ranged from 8.6 to 105 kg. The median serum concentration of topiramate was 1.7 mcg/mL, and half of the patients received carbamazepine coadministration. Based on a one-compartment model with first order absorption and elimination, the apparent volume of distribution was 105 L/70 kg, and the apparent clearance was allometrically related to the body weight as 2.25 L.h(-1).70 kg(-1) without carbamazepine or phenytoin. Combination treatment with carbamazepine or phenytoin increased the apparent clearance to 3.51 L.h(-1).70 kg(-1). Goodness-of-fit plots, prediction-corrected visual predictive check, and external validation using the validation data from 43 patients confirmed an appropriateness of the final model. Simulations based on the final model showed that dosage adjustments allometrically scaling to body weight can equalize the serum concentrations in children of various ages and adults. Conclusions: The PPK model, using the power scaling of body weight, effectively elucidated the topiramate serum concentration profile ranging from pediatric to adult patients. Dosage adjustments based on body weight and concomitant antiepileptic drug help obtain the dosage of topiramate necessary to reach an effective concentration in each individual.

OBJECTIVE: The objective of this study was to clarify the types and prevalence of, and the risk factors for, the adverse events that occur in patients receiving anti-dementia drugs. METHODS: A questionnaire survey was conducted. The respondents were pharmacists who were dispensing anti-dementia drugs. The pharmacists responded to questions about patients who were receiving anti-dementia drugs delivered to them at home by the pharmacists. The survey questions included questions about whether or not the patients experienced adverse reactions to the drugs, about the patients' background characteristics, about the numbers of drugs the patients were taking when the pharmacists first visited the patients at home, and about the pharmacists' assessments of the appropriateness of the use of the anti-dementia drugs. RESULTS: Data were collected on 3712 patients from 1673 pharmacies in a nationwide survey. Anti-dementia drugs had been prescribed to 863 of these patients; and 801 (92.8%) of these 863 patients were 75 years of age or older, and. confirmed adverse events occurred in 170 (21%) of these 863 patients. The most common adverse event was excitation/anxiety, at 45.1%. A multivariate analysis found that polypharmacy (10 or more types of drugs per day) (P = 0.030), inappropriate use (P = 0.002), and irregular medication use (P = 0.034) were risk factors. INTERPRETATION: In order to avoid adverse events when using anti-dementia drugs, doctors and pharmacists should carefully examine the prescribing of multiple medications, assess the applicability of the use of anti-dementia drugs, and investigate how to best manage patients' drug use.

Riboflavin (vitamin B2) plays a role in various biochemical oxidation-reduction reactions. Flavin mono nucleotide (FMN) and FAD, the biologically active forms, are made from riboflavin. Riboflavin transporters (RFVTs), RFVT1-31Slc52a1-3, have been identified. However, the roles of human (h)RFVTs in FMN and FAD homeostasis have not yet been fully clarified. In this study, we assessed the contribution of each hRFVT to riboflavin, FMN and FAD uptake and efflux using in vitro studies. The transfection of hRFVTs increased cellular riboflavin concentrations. The uptake of riboflavin by human embryonic kidney cells transfected with hRFVTs was significantly increased, and the efflux was accelerated in a time-dependent manner. However, the uptake and efflux of FMN and FAD hardly changed. These results strongly suggest that riboflavin, rather than FMN or FAD, passes through plasma membranes via hRFVTs. Our findings could suggest that hRFVTs are involved in riboflavin homeostasis in the cells, and that FMN and FAD concentrations are regulated by riboflavin kinase and FAD synthase.