Evaluation of the pharmacokinetics of liposomal amphotericin B and analysis of the relationship between pharmacokinetics, efficacy and safety in patients with hematological diseases.

INTRODUCTION: This study aimed to identify factors responsible for changes in blood concentrations of a liposomal formulation of amphotericin B (AMPH-B, L-AMB) and analyze the relationships between blood concentrations and efficacy or toxicity. METHODS: L-AMB was administered to 30 patients being treated for hematological diseases. AMPH-B plasma concentrations were determined right before the initiation (Cmin) and at the end (Cmax) of infusion on at least 1 day, beginning on Day 3 of L-AMB treatment. The relationships of Cmin divided by dose (C/D ratio) to body weight, age, hepatic function, renal function, serum albumin, C-reactive protein (CRP), response, hypokalemia, and renal impairment were evaluated. RESULTS: C/D ratio was not correlated with age, hepatic function, renal function, or serum albumin. Body weight adjusted C/D ratio was negatively correlated with CRP. Cmax and Cmin were compared between responders and non-responders, those with or without hypokalemia, and those with or without renal impairment. A higher Cmax in patients with hypokalemia was the only significant difference seen. CONCLUSIONS: The negative correlation between CRP and plasma concentrations was likely caused by higher distribution of L-AMB from the blood to infected tissue in patients with a greater degree of infection, with a resulting decrease in plasma concentrations. AMPH-B plasma concentrations were not related to response. Higher Cmax of AMPH-B were observed in patients with hypokalemia, but no relationship between plasma concentration and renal toxicity was observed, suggesting that AMPH-B plasma concentrations appear to be minimally related to PD when used as L-AMB.

Clinical Impact of Melphalan Pharmacokinetics on Transplantation Outcomes in Children Undergoing Hematopoietic Stem Cell Transplantation.

Melphalan is widely used for hematopoietic stem cell transplantation (HSCT) conditioning. However, the relationship between its pharmacokinetic (PK) and transplantation outcomes in children has not been thoroughly investigated. We prospectively analyzed the relationship between melphalan area under the curve (AUC) and transplantation outcome and examined the development of a predictive model for melphalan clearance in children. This study included 43 children aged 0 to 19 years who underwent HSCT following a melphalan-based conditioning regimen from 2017 to 2021. In univariable analysis, high-melphalan AUC resulted in a significantly lower cumulative incidence of acute graft-versus-host disease and a higher cumulative incidence of thrombotic microangiopathy, although no significant difference was observed in survival. Regression analysis of a randomly selected derivation cohort (n = 21) revealed the following covariate PK model: predicted melphalan clearance (mL/min) = 6.47 × 24-h urinary creatinine excretion rate (CER, g/day) × 24-h creatinine clearance rate (CCR, mL/min) + 92.8. In the validation cohort (n = 22), the measured melphalan clearance values were significantly correlated with those calculated based on the prediction equation (R2 = 0.663). These results indicate that melphalan exposure may be optimized by adjusting the melphalan dose according to CER and CCR.

Association between the pharmacokinetics of rabbit anti-thymocyte globulin and acute graft-versus-host disease in patients who received haploidentical hematopoietic stem cell transplantation.

Anti-thymocyte globulin (ATG) is an important prophylactic drug against acute graft-versus-host disease (aGVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). This study analyzed the pharmacokinetics of rabbit ATG 2.5 mg/kg and its effect against aGVHD in 24 patients undergoing unmanipulated haplo-HSCT. All patients had hematological malignancies not in remission. The median absolute lymphocyte count (ALC) before rabbit ATG administration was 9.5/µL (range 0-41/µL). The grade ≥ II aGVHD group had a significantly lower median rabbit ATG concentration on days 0 (C0) and 7 (C7) and areas under the curve on days 0-7 (AUC0-7) and 0-32 (AUC0-32) than the grade 0-I aGVHD group. Among the four parameters, C0 was the most optimal for predicting aGVHD according to the receiver-operating characteristic (ROC) analysis (area under the ROC curve 0.893; 95% confidence interval 0.738-1.000). The high C0 (≥ 27.8 µg/mL) group had significantly lower cumulative incidence of grade ≥ II aGVHD on day 100 than the low C0 (< 27.8 µg/mL) group (13.8% vs. 88.9%, p < 0.001). In haplo-HSCT, the C0 of rabbit ATG is a good predictor of grade ≥ II aGVHD, even though ALC before rabbit ATG administration is not a predictor of aGVHD.

Intraocular penetration of liposomal amphotericin B after intravenous injection in inflamed human eyes.

PURPOSE: To determine the intraocular penetration of amphotericin B (AMPH-B) after an intravenously injection of liposomal amphotericin B (L-AMB) in inflamed human eyes. METHODS: Seven eyes of 5 patients with fungal eye diseases (endophthalmitis in 6 eyes and keratitis in 1 eye) were treated with intravenous injections of 100-250 mg/day of L-AMB. Samples of blood, corneal button, aqueous humor, and vitreous humor were collected and assessed for AMPH-B. RESULTS: The AMPH-B level in the cornea (604.0 µg/g) of the case with fungal keratitis exceeded the minimum inhibitory concentration. However, the levels in the aqueous and vitreous humors of the cases with fungal endophthalmitis were lower, e.g., 0.02 ± 0.01 µg/ml (0.09% of serum level) in the aqueous humor and 0.05 ± 0.08 µg/ml (0.17% of serum level) in the vitreous humor. CONCLUSIONS: The AMPH-B levels administered intravenously were very low in the aqueous and vitreous humors. Our findings indicate that intravenous L-AMB can be considered only for patients with mild endogenous fungal endophthalmitis, e.g., isolated chorioretinitis without vitreous extensions.

Pharmacokinetics of intravenous busulfan as condition for hematopoietic stem cell transplantation: comparison between combinations with cyclophosphamide and fludarabine.

Busulfan (Bu) has been used in combination with fludarabine (Flu; BuFlu) or cyclophosphamide (Cy; BuCy) as conditioning for allogeneic hematopoietic stem cell transplantation (HSCT). This multi-institutional prospective study compared pharmacokinetic (PK) parameters of Bu between BuFlu and BuCy. Plasma Bu concentrations were measured by high-performance liquid chromatography at the first dose of the first and fourth days of intravenous Bu administrations (total of 16 doses of 0.8 mg/kg). Thirty-seven patients were evaluable (BuFlu, N = 18; BuCy, N = 19). The median age was significantly higher in BuFlu. In BuFlu, the median area under the blood concentration-time curve of Bu on the fourth day was 1183 µmol min/L (range 808-1509), which was significantly higher than that on the first day [1095 µmol min/L (range 822-1453), P < 0.01]. In contrast, such differences were not observed in BuCy. Consistently, there was a significant decrease in the clearance of Bu on the fourth day as compared with the first day in BuFlu. These results suggest that the PK of Bu was altered during the co-administration of Flu, which was not the case with Cy. A large-scale study is required to evaluate the significance of the differences in the PK of Bu between the conditionings on HSCT outcomes.

Effect of Prophylactic Post-transplant Ponatinib Administration on Outcomes in Patients With Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia.

BACKGROUND: The objective of the present retrospective study was to evaluate the effect of ponatinib administration as maintenance therapy on the outcomes after allogeneic hematopoietic stem cell transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. PATIENTS AND METHODS: We retrospectively analyzed the data from 34 consecutive patients treated at our institution from January 2008 to June 2019. We had administered post-transplant tyrosine kinase inhibitors preemptively before December 2017. Thereafter, we had initiated the prophylactic use of post-transplant ponatinib. The initial ponatinib dose was 15 mg/d. Ponatinib plasma trough levels were measured using the liquid chromatography-tandem mass spectrometry method 8 days after the first administration and subsequently. RESULTS: Nine patients received ponatinib maintenance. The 2-year overall survival and leukemia-free survival in the ponatinib maintenance group tended to be better than that in the non-ponatinib group (100% vs. 70.5%, P = .10; and 100% vs. 50.8%, P = .02, respectively). In the first 7 of the 9 consecutive patients, the median plasma concentration after ponatinib administration (15 mg/d) was 15.6 ng/mL (range, 4.8-23.3 ng/mL). Although the treatment schedule for 1 patient was altered because of adverse effects (elevation of serum amylase and neutropenia), ponatinib administration was continued for all the patients, except for 1 patient with molecular relapse. One patient developed a transient elevation of serum lipase. No patient presented with any arterial occlusive events. CONCLUSION: Our results have indicated that the strategy of ponatinib maintenance after allogeneic hematopoietic stem cell transplantation is safe, efficacious, and promising.

Myeloablative intravenous busulfan-containing regimens for allo-HSCT in AML or MDS patients over 54 years old: combined results of three phase II studies.

An optimal pretransplant conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in older adults has not been established. Three prospective multicenter phase II studies were conducted, in which 142 patients older than 54 years (median age, 61 years; range 55-70 years) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) received a myeloablative dose of intravenous busulfan (ivBu, 12.8 mg/kg) along with fludarabine (180 mg/m2) ± low dose total body irradiation for allo-HSCT between September 2009 and February 2013. A total of 103 AML and 39 MDS patients including 21 related bone marrow (BM) or peripheral blood (PB), 50 unrelated BM, and 71 unrelated cord blood (UCB) transplantation were enrolled. Grade 3 or greater toxicities were observed in 105 patients. Neutrophil engraftment was achieved in 70 out of the 71 related PB/BM or unrelated BM recipients, and 61 out of the 71 UCB recipients. The cumulative incidence rates of relapse and non-relapse mortality after 2 years were 24.0 and 24.1%, respectively. The overall and event-free survival rates at 2 years were 53.3 and 47.4%, respectively. The myeloablative dose of ivBu was well tolerated without increased toxicity-related mortality in older adults who underwent allo-HSCT with any donor source.

Nafamostat mesilate inhibits linezolid metabolism via its antioxidant effects.

Patients who undergo renal replacement therapy often exhibit a high plasma linezolid concentration. Linezolid is metabolized via oxidation. Nafamostat mesilate has antioxidant effects and is frequently used as an anticoagulant during renal replacement therapy. We aimed to investigate the effect of nafamostat mesilate on plasma linezolid concentration. We examined whether the co-administration of linezolid and nafamostat had any effect on plasma linezolid concentration. Mice were randomly allocated to two groups (n = 18/group): linezolid (100 mg kg-1 , subcutaneous injection) + nafamostat (30 mg kg-1 , intraperitoneal injection) and linezolid + saline. At 5 hours, the linezolid concentration was significantly higher in the linezolid + nafamostat co-administration group than that in the linezolid + saline group (20.6 ± 9.8 vs 3.6 ± 1.2 µg/mL, respectively P < .001). The antioxidant effects of nafamostat may inhibit linezolid metabolism, resulting in the adverse event of high linezolid concentration if both are administered concurrently during renal replacement therapy.

In vitro Evaluation of Linezolid and Doripenem Clearance with Different Hemofilters.

INTRODUCTION: Renal replacement therapy (RRT) is widely used in the treatment of septic acute kidney injury. However, little is known about how the adsorption properties of hemofilters used in RRT affect antibiotic concentration. Because a cytokine-adsorption membrane is frequently used in RRT, it is important to determine the antibiotic adsorption capacity of this membrane. OBJECTIVE: The present study aimed to investigate the antibiotic adsorption capacity of different hemofilter membranes by in vitro experiments using 2 antibacterial agents (linezolid and doripenem). METHODS: We performed experimental hemofiltration in vitro using polyacrylonitrile (AN69ST), polymethylmethacrylate (PMMA), and polysulfone (PS) hemofilters for 1,440 min. The test solution was a 1,000-mL substitution fluid containing 30 µg/mL linezolid and 120 µg/mL doripenem. We measured drug concentrations at the inlet, outlet, and filtrate ports of the hemofilters for 1,440 min and calculated the sieving coefficient (SC) and adsorption rate (Ra) of the drugs onto the hemofilters. RESULTS: The amount of linezolid adsorbed onto AN69ST, PMMA, and PS membranes was decreased relative to that in the control group at 15 min (p < 0.05). However, no SC for linezolid was obtained thereafter. The Ra of linezolid onto AN69ST, PMMA, and PS membranes was higher than that in the control group (p < 0.05). In contrast, no significant differences were observed in the concentrations and Ra values of doripenem adsorbed onto AN69ST, PMMA, and PS membranes compared with those in the control group. CONCLUSIONS: Doripenem was not adsorbed onto PMMA, PS, and AN69ST membranes. Linezolid was adsorbed onto PMMA, PS, and AN69ST membranes, but only temporarily, and this did not affect drug bioavailability.

Effective plasma concentrations of itraconazole and its active metabolite for the treatment of pulmonary aspergillosis.

BACKGROUND: Itraconazole (ITCZ) is used to treat pulmonary aspergillosis, but findings regarding the range of effective plasma concentrations are often contradictory. This study attempted to determine effective plasma concentrations of ITCZ and its active metabolite hydroxyitraconazole (OH-ITCZ) by retrospectively analyzing their relationships to clinical efficacy. METHODS: The study included 34 patients with pulmonary aspergillosis treated using ITCZ (mean age, 70 years). Each patient was treated with 200 mg ITCZ once daily (mean duration of treatment: 384 days). Plasma concentrations of ITCZ and OH-ITCZ at trough levels from 7 to 889 days after the start of treatment were determined using high-performance liquid chromatography. Clinical efficacy was assessed through the improvement clinical symptoms. RESULTS: Fifteen patients were classified as effective group and the other 19 patients as non-effective group. Mean (±standard deviation) ITCZ trough plasma concentration was significantly higher in effective group (1254 ± 924 ng/mL) than in non-effective group (260 ± 296 ng/mL). Mean OH-ITCZ plasma concentration was significantly higher in effective group (1830 ± 1031 ng/mL) than in non-effective group (530 ± 592 ng/mL). Receiver operating characteristic curve analysis revealed the optimal cutoff for ITCZ trough plasma concentration was 517 ng/mL, and 86.7% of effective group showed concentrations exceeding this value. The optimal cutoff for total ITCZ + OH-ITCZ plasma concentration was 1025 ng/mL, and 93.3% of effective group showed a concentration exceeding this value. CONCLUSIONS: Our findings indicate that effective plasma concentration ranges for the treatment of pulmonary aspergillosis begin at an ITCZ trough plasma concentration of 500 ng/mL and a total ITCZ + OH-ITCZ plasma concentration of 1000 ng/mL.

Essential human resources for antimicrobial stewardship teams in Japan: Estimates from a nationwide survey conducted by the Japanese Society of Chemotherapy.

Implementation of antimicrobial stewardship programs (ASPs) with multidisciplinary antimicrobial stewardship teams (ASTs) is critical for appropriate antimicrobial use at healthcare facilities. Although the Japanese medical reimbursement system was revised to allow fees for ASP implementation, several concerns remain, including understaffing and enforcement of the recommendations on ASTs and ASPs in practice. Furthermore, there are no recommendations on full-time equivalents (FTEs) of the core members in ASTs in Japan. This committee report presents our recommendations on ASTs based on an analysis of the nationwide survey on implemented ASPs and staff FTEs at 1358 healthcare facilities conducted by the Japanese Society of Chemotherapy. Our report provides a directive for structural and financial support of ASTs and should aid in planning for the enhancement of AST practices and the organization of new ASTs.

Cyst infection in autosomal dominant polycystic kidney disease: penetration of meropenem into infected cysts.

BACKGROUND: Cyst infection is a common and serious complication of autosomal dominant polycystic kidney disease (ADPKD) that is often refractory. Carbapenems are frequently needed to treat to patients with refractory cyst infection, but little is known about the penetration of newer water-soluble carbapenems into cysts. This study investigated the penetration of meropenem (MEPM) into infected cysts in patients with ADPKD. METHODS: Between August 2013 and January 2014, 10 ADPKD patients (14 infected cysts) receiving MEPM at Toranomon Hospital underwent drainage of infected cysts and definite cyst infection was confirmed through detection of neutrophils by cyst fluid analysis. The serum concentration of MEPM was measured just after intravenous administration and was compared with that in fluid aspirated from infected cysts. RESULTS: In the patients undergoing cyst drainage, the mean serum MEPM concentration was 35.2 ± 12.2 µg/mL (range: 19.7 to 59.2 µg/mL, while the mean cyst fluid concentration of MEPM in the drained liver cysts (n = 12) or kidney cysts (n = 2) was 3.03 ± 2.6 µg/mL (range: 0 to 7.3 µg/mL). In addition, the mean cyst fluid/serum MEPM concentration ratio was 9.46 ± 7.19% (range: 0 to 18.8%). There was no relationship between the cyst fluid concentration of MEPM and the time until drainage after MEPM administration or between the cyst fluid/serum MEPM concentration ratio and the time until drainage. CONCLUSION: These findings suggest that MEPM shows poor penetration into infected cysts in ADPKD patients. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network (UMIN) as "Penetration of meropenem into cysts in patients with autosomal dominant polycystic kidney disease (ADPKD)", UMIN ID 000011292 on July 26th, 2013.

Breakthrough Exophiala dermatitidis infection during prophylactic administration of micafungin during second umbilical cord blood transplantation after graft failure.

Exophiala dermatitidis infections in patients with hematological malignancies are very rare. Our patient had a blood stream infection caused by E. dermatitidis following the second umbilical cord blood transplantation (UCBT) after graft failure during the first UCBT. To our knowledge, this is the first report describing a breakthrough fungal infection caused by E. dermatitidis during the prophylactic administration of micafungin (MCFG). Therefore, MCFG-treated patients should be monitored for breakthrough E. dermatitidis infection during hematopoietic stem cell transplantation.

Dasatinib and Prednisolone Induction Therapy for a Case of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with Dilated Cardiomyopathy Accompanied by Life-Threatening Ventricular Tachycardia.

A 56-year-old man being treated for dilated cardiomyopathy presented with epigastralgia. He was diagnosed with ventricular tachycardia and Philadelphia chromosome-positive acute lymphoblastic leukemia. After treating incessant ventricular tachycardia, we commenced induction therapy for leukemia with dasatinib and prednisolone to minimize toxicity towards cardiomyocytes and the cardiac conduction system. Although dasatinib was temporarily withheld because of a recurrence of ventricular tachycardia, we rechallenged dasatinib while using bisoprolol and amiodarone and achieved a complete hematological response three weeks later. Although drug interactions between dasatinib and amiodarone were of concern, the blood concentration of each drug remained within the safe range after concomitant use, and there were no adverse cardiac effects such as QT prolongation after rechallenging dasatinib. Induction therapy with dasatinib and prednisolone may be an acceptable therapeutic option for Philadelphia chromosome-positive acute lymphoblastic leukemia with severe cardiac complications.

Clinical Application of the Dried Blood Spot Method in the Measurement of Blood Busulfan Concentration.

The dried blood spot (DBS) method, which is a simple technique for blood sample processing involving the placement of a drop of whole blood onto filter paper, has been used recently in clinical pharmacology to determine blood concentrations of various drugs. This study examined the feasibility of the clinical application of the DBS method for individual busulfan dose adjustments. Pharmacokinetic (PK) parameters of blood samples for busulfan measurements determined using the DBS method were compared with those using plasma separation (the conventional method). Blood samples were collected from patients receiving i.v. busulfan as a conditioning regimen before allogeneic hematopoietic stem cell transplantation at Toranomon Hospital, Japan. Samples collected 2, 4, and 6 hours after the start of the first drip infusion were processed by DBS or the conventional method. The area under the blood concentration-time curve (AUC) and other PK parameters were calculated to compare the 2 methods. Divergence of <20% in each parameter was considered acceptable. The divergence range for each parameter was as follows: blood concentration at 2 hours after the start of drip infusion, .6 to 8.2%; at 4 hours, .3 to 10.0%; at 6 hours, .3 to 14.2%; and AUC0-∞, .0 to 10.3%. None of the PK parameters showed a divergence between the DBS method and the conventional method exceeding 20%, suggesting that both methods are well correlated. The clinical application of blood sample processing with the DBS method in the measurement of blood busulfan concentration may therefore be feasible, but further studies are needed to confirm these findings.

Significance of monitoring trough plasma concentration levels for invasive fungal infection prophylaxis with itraconazole oral solution in patients with hematological malignancies: a prospective study.

In this prospective study, we examined the prophylactic effect of itraconazole oral solution (ITCZ-OS) against invasive fungal disease in hematologic malignancy patients. The participants were 36 patients, at least 16 years of age, with hematologic malignancies treated at our hospital. ITCZ-OS 200 mg/day was administered orally twice a day with a target trough plasma concentration of 350 ng/ml. If the patient did not achieve the target trough plasma concentration, the dose was increased. The success rate of achieving the target trough plasma concentration of ITCZ with a dose of 200 mg/day was 63.9%. During the observation period, 2 patients (5.6%) were diagnosed with possible invasive fungal disease according to the EORTC/MSG 2008 criteria. Adverse events were observed in 2 patients (5.6%). The results showed administration of ITCZ-OS while monitoring ITCZ trough plasma concentrations to be effective for preventing invasive fungal disease, and no serious adverse events occurred. Since predicting trough levels in response to ITCZ administrations is difficult, its measurement is necessary to maintain the prophylactic effect of ITCZ.

[Invasive Aspergillosis Accompanied by a Subcutaneous Nodular Lesion].

We report herein on a case of invasive aspergillosis accompanied by a subcutaneous nodular lesion. A 74-years-old male with myelodysplastic syndrome was hospitalized due to high fever and a painful subcutaneous nodule on the left thigh. Chest radiography and CT scans showed multiple nodular lesions of both lungs, and bacterial pneumonia was initially suspected. He was treated with meropenem, but the symptoms did not subside. Three days after admission, we found that ß-D-glucan levels were elevated at 52.6 pg/mL. He was treated with liposomal amphotericin B (L-AMB) for invasive fungal pneumonia, and the symptoms regressed thereafter. Excisional biopsy of the nodular lesion showed a cluster of septated and branching hyphae. Serum Aspergillus antigen tests and sputum fungal culture were negative, and the fungal species could not be identified. Thus, we performed in situ hybridization (ISH) and polymerase chain reaction (PCR) with the excised subcutaneous specimens, and as a result Aspergillus fumigatus infection was diagnosed. Invasive aspergillosis with a subcutaneous lesion is a rare case, and we found that treatment with L-AMB was effective. ISH, PCR and measurement of serum trough concentration of AMPH-B are useful in diagnosis and treatment.

Pharmacokinetics study of once-daily intravenous busulfan in conditioning regimens for hematopoietic stem cell transplantation.

In Japan, intravenous busulfan (ivBu) is usually given four times per day as an infusion at 0.8 mg/kg over 2 h. However, as this requires a midnight administration, a once-daily infusion of ivBu at 3.2 mg/kg over 3 h has been investigated as a more convenient and safer method. In this study, 20 Japanese patients received once-daily ivBu in conditioning regimens before allogeneic hematopoietic stem cell transplantation (HSCT), and blood samples were obtained just before, and 3, 3.5, 5, 7, 10, and 24 h after the initiation of ivBu infusion. The outcomes of HSCT were evaluated prospectively. The median area under the plasma concentration versus time curve (AUC) of Bu was 5272 µmol × min/L (range 3491-6284 µmol × min/L), and was similar to those in previous once-daily ivBu studies and to the estimated daily AUC in previous 4-times-daily ivBu studies. All of the patients but two, who died early due to infection, achieved neutrophil engraftment at a median of 25 days after transplantation. No patient was diagnosed with veno-occlusive disease according to the criteria established by Jones. No regimen-related toxicity was significantly associated with AUC. In conclusion, once-daily administration of ivBu has a stable pharmacokinetic profile, and was safely performed in Japanese patients.