Prevalence of therapeutic drug monitoring and adherence to imatinib in chronic myeloid leukemia in Japan.

OBJECTIVE: The effectiveness of imatinib, a tyrosine kinase inhibitor recommended for the treatment of chronic myeloid leukemia, is associated with high adherence and trough plasma imatinib concentrations of ~ 1,000 ng/mL. However, adherence and therapeutic drug monitoring (TDM) for imatinib have hardly been reported. This study evaluated the prevalence of TDM and adherence to imatinib for chronic myeloid leukemia in Japan. MATERIALS AND METHODS: Monthly insurance claims data for ~ 5.6 million individuals aged 20 - 74 years between June 1, 2005 and December 31, 2017 were studied. Patients with at least one prescription for imatinib were included to calculate adherence and the annual mean prevalence of TDM for imatinib. RESULTS: A total of 498 patients with 9,620 prescriptions of imatinib were included. After 2013, the number of imatinib prescriptions and the number of patients treated with imatinib were over 1,000 and 200, respectively. The mean annual prevalence of TDM for imatinib was 12.2% (95% confidence interval (CI), 8.1 - 16.1%). Antihyperuricemic drugs and steroids increased the likelihood of TDM. The medication possession ratio for assessment of adherence was 93.5% (95% CI: 91.8 - 95.5%). The annual mean prevalence of TDM for imatinib was low, although adherence was high. CONCLUSION: To encourage the measurement of plasma concentrations of imatinib in clinical settings, adding a package insert, a summary of product characteristics, and a patient information leaflet regarding the implementation of TDM is justified and warrants further attention.

Voriconazole concentration is inversely correlated with corticosteroid usage in immunocompromised patients.

BACKGROUND: Voriconazole (VRCZ) is a broad-spectrum antifungal agent that can be administered both orally and intravenously. A high level of intra- and interindividual variability in serum drug therapeutic concentrations has been reported. We analyzed the influence of corticosteroid use on serum VRCZ concentration by assessing the correlation between corticosteroid dose and VRCZ trough level. METHODS: Immunocompromised patients treated with VRCZ with or without corticosteroid use from June 2010 to March 2017 (6 years and 8 months) were reviewed in our institute. VRCZ and the corticosteroids were administered orally or intravenously. Corticosteroid treatment was considered as "concurrent" only if it was administered within 3 days before or after the initiation of VRCZ. All corticosteroids were converted to a prednisolone-based dosage according to their anti-inflammatory effect (relative glucocorticoid activity). VRCZ concentration was measured at the trough point on the day of steady state. RESULTS: A total of 85 samples were obtained from 38 patients. The medical records of 23 women and 15 men, with a median age of 61 years (range: 35-86), were reviewed. Twenty-one patients (55.3%, 21/38) received chemotherapy, and 28 (73.7%, 28/38) received corticosteroid therapy. The average and median daily doses of corticosteroids were 59.2 and 89.8 mg, respectively (range: 0.714-377). VRCZ concentration was inversely correlated with corticosteroid dose (r = -.26). The VRCZ concentration was significantly decreased in the corticosteroid user compared to nonuser (P = .013). We evaluated the association of VRCZ concentration and corticosteroid dose in 3 patients among our cohorts for whom more than 5 points of data were available. Intraindividual analysis revealed the trough level of VRCZ concentration decreased as the corticosteroid dose increased. The patients' underlying diseases were hematological diseases (n = 25) and immunological diseases (n = 13). Among accrual patients, no patients were undergoing stem cell transplantation, and no patients were treated with known confounders such as calcineurin inhibitors or phenytoin. CONCLUSIONS: VRCZ might be metabolized by an enzyme induced by corticosteroid treatment; therefore, intraindividual variation in VRCZ metabolism should be considered prior to concurrent treatment, especially for patients with hematological malignancies treated with corticosteroids.

Developing population pharmacokinetic parameters for high-dose methotrexate therapy: implication of correlations among developed parameters for individual parameter estimation using the Bayesian least-squares method.

Bayesian estimation enables the individual pharmacokinetic parameters of the medication administrated to be estimated using only a few blood concentrations. Due to wide inter-individual variability in the pharmacokinetics of methotrexate (MTX), the concentration of MTX needs to be frequently determined during high-dose MTX therapy in order to prevent toxic adverse events. To apply the benefits of Bayesian estimation to cases treated with this therapy, we attempted to develop an estimation method using the Bayesian least-squares method, which is commonly used for therapeutic monitoring in a clinical setting. Because this method hypothesizes independency among population pharmacokinetic parameters, we focused on correlations among population pharmacokinetic parameters used to estimate individual parameters. A two-compartment model adequately described the observed concentration of MTX. The individual pharmacokinetic parameters of MTX were estimated in 57 cases using the maximum likelihood method. Among the available parameters accounting for a 2-compartment model, V1, k10, k12, and k21 were found to be the combination showing the weakest correlations, which indicated that this combination was best suited to the Bayesian least-squares method. Using this combination of population pharmacokinetic parameters, Bayesian estimation provided an accurate estimation of individual parameters. In addition, we demonstrated that the degree of correlation among population pharmacokinetic parameters used in the estimation affected the precision of the estimates. This result highlights the necessity of assessing correlations among the population pharmacokinetic parameters used in the Bayesian least-squares method.

Effects of angiotensin II AT1-receptor blockade on high fat diet-induced vascular oxidative stress and endothelial dysfunction in Dahl salt-sensitive rats.

We examined the effects of angiotensin II AT1-receptor blockade with olmesartan on high fat (HF) diet-induced vascular oxidative stress and endothelial dysfunction in normal salt (NS) diet-fed Dahl salt-sensitive (DSS) rats. Treatment with NS + HF diet (32% crude fat, 0.3% NaCl) for 20 weeks significantly increased blood pressure in DSS rats. NS + HF diet-fed DSS rats also showed higher plasma levels of thiobarbituric acid-reactive substances, aortic superoxide production, and mRNA levels of p22(phox) and gp91(phox) in aortic tissues than NS diet-fed DSS rats. Furthermore, acetylcholine-induced vasorelaxation of aorta from NS + HF diet-fed DSS rats was significantly reduced. In NS + HF diet-fed DSS rats, treatment with olmesartan medoxomil (10 mg/kg per day, p.o.) and hydralazine (25 mg/kg per day, p.o.) similarly decreased blood pressure. However, in these animals, only olmesartan normalized plasma levels of thiobarbituric acid-reactive substances, vascular superoxide in aortic tissues, and acetylcholine-induced vasorelaxation. These data indicate that HF diet-induced hypertension is associated with vascular oxidative stress and endothelial dysfunction in NS diet-treated DSS rats. Inhibition of angiotensin II AT1 receptors may elicit beneficial effects on HF-induced hypertension and vascular injury in subjects that have genetically enhanced sodium-sensitive blood pressure.

Erythroid recovery affects tacrolimus levels after engraftment during stem cell transplantation.

Tacrolimus is commonly used in stem-cell transplants (SCT) for prophylaxis of graft-versus-host disease and is continuously administered throughout transplantation. The dose of tacrolimus is frequently decreased to maintain a desired concentration during the recovery of hemocytes after engraftment. If parameters which affect tacrolimus clearance are identified, it is of clinical use to estimate concentrations and aid dosing. The objective of this study was to identify which hematologic parameters affect tacrolimus clearance. Seventeen consecutive Japanese patients with hematological malignancies who received allogeneic SCT between March 2004 and January 2007 were enrolled in this study. Their steady-state concentrations were routinely measured and standardized as the concentration/dose (C/D) ratio ((ng/mL)/(mg/kg/d)). Multivariate analysis was performed to identify which hemocyte parameters affected the C/D ratio. Of the 13 patients, gradual dose reduction was required to combat elevated tacrolimus concentrations. The mean post-engraftment C/D ratio was higher than the pre-engraftment C/D ratio in each patient. The mean C/D ratio for all patients after engraftment was 1.56-fold higher (p=0.00004, range: 1.04-3.03) than that before engraftment. The variation ratio was calculated by dividing the C/D ratio by that on the engraftment day. Multivariate analysis revealed that the reticulocyte (RET) level (×10(3) count/µL) was the sole parameter influencing this ratio, and both parameters were expressed as: Variation ratio=0.004×RET+1.0. RET recovery of patients could influence the C/D ratio and tacrolimus clearance was affected by recipient original red blood cells, but not that of transfused red blood cells.

[Case of encephalopathy seemingly caused by tacrolimus at blood concentration near the upper limit of therapeutic range].

We report a case of encephalopathy seemingly caused by tacrolimus (FK506) in spite of blood concentration near the upper limit of therapeutic range. A 26-year-old man received FK506 to prevent acute graft-versus-host disease after hematopoietic stem cell transplantation. He underwent an intravenous injection of FK506 the day before transplantation (day -1). He developed headache, hypertension, nausea and vomiting from day 2 to day 3. A computed tomography scan showed a low density area with unclear border in the bilateral cerebellar hemispheres. Thereafter, these symptoms improved with discontinuation of FK506, which was strongly suggestive of encephalopathy caused by FK506. The blood concentration of FK506 at the onset of encephalopathy was 21.7 ng/mL. Although this value was slightly higher than the standard therapeutic range (10-20 ng/mL), it was within clinically acceptable range in the early stage after stem cell transplantation. This indicates that even if the blood concentration of FK506 is within the therapeutic range, encephalopathy may develop. In summary, although the blood concentration of FK506 is useful as an indicator for prevention of encephalopathy, we propose careful monitoring not only of the blood concentration but also clinical status for the detection of initial symptoms and prevention of aggravation.

Pharmacokinetics of prophylactic micafungin in very-low-birth-weight infants.

We evaluated the use of micafungin as a prophylaxis in very-low-birth-weight infants. Micafungin was first administered to 25 very-low-birth-weight infants 12 to 24 hours after birth at a dose of 1 mg/kg/d. the apparent volume of distribution, the apparent elimination rate constant, the elimination half-life, and the total body clearance (mean +/- SD) were 0.76 +/- 0.28 L/kg, 0.12 +/- 0.041 1/h, 6.7 +/- 2.2 h, and 0.089 +/- 0.047 L/kg/h, respectively.

[Infection treatment caused by multiple-drug-resistant Pseudomonas aeruginosa in a patient undergoing allogeneic hematopoietic stem cell transplantation].

Infections caused by multiple-drug-resistant Pseudomonas aeruginosa (MDRP) are a clinically significant problem. We reported here the effective use of combination therapy in a patient with infection caused by MDRP according to an interventional treatment strategy suggested by a pharmacist. The patient was a 70-year-old male who underwent allogeneic hematopoietic stem cell transplantation. On day 45 after transplant, MDRP was newly isolated from urine, but the diagnosis at that time was colonization. On day 61, the patient developed a fever (> or =38.0 degrees C). In addition, laboratory data showed that C-reactive protein (CRP) was also increased. At the medical team conference, the pharmacist proposed the following treatment strategy for this infection. Aztreonam and amikacin were intravenously administered at doses of 2 g/day and 800 mg/day, respectively. The subsequent clinical course was well controlled, but the infection recurred and was aggravated. Aztreonam and ciprofloxacin were then intravenously administered at doses of 4 g/day and 600 mg/day, respectively, resulting in the alleviation of fever in the patient as well as a decrease in CRP and disappearance of MDRP isolates from urine on day 67; that is, MDRP infection was consequently well controlled. In conclusion, the combination therapy between aztreonam and amikacin, or ciprofloxacin may be clinically useful for severe infections of MDRP in compromised hosts.

[Preventive effects of newquinolones for endogenous infection in patients receiving allogeneic hematopoietic stem cell transplantation--comparison between bone marrow transplantation, peripheral blood stem cell transplantation, and cord blood transplantation].

We performed a retrospective study to examine the preventive effects of newquinolones for endogenous infection in patients receiving various allogeneic hematopoietic stem cell transplantation including bone marrow transplantation (BMT), peripheral blood stem cell transplantation (PBSCT), and cord blood transplantation (CBT). Forty-nine patients were enrolled. Ciprofloxacin or norfloxacin was orally administered for intestinal sterilization from day -14 until engraftment. As a result, the period from transplantation until engraftment was significantly longer in CBT group than in BMT group. The febrile index (the ratio of the febrile (> or =38.0 degrees C) period during neutropenia (< or =500 cells/mm(3)) and C-reactive protein (CRP)-positive index (the ratio of CRP-positive (> or =2.0 mg/dl) period during neutropenia) were comparable among the three groups. In addition, no gram-negative bacteria in stool was isolated in the three groups; that is, an endogenous infection of gram-negative bacteria, a potential pathogen, was well controlled by newquinolones. We should be careful when interpreting the results of this small study; however, newquinolones are clinically effective for endogenous infection of gram-negative bacteria in patients receiving not only BMT, but also PBSCT and CBT.

Preventive effects of low-dose dexamethasone for delayed adverse events induced by carboplatin-based combination chemotherapy.

We performed a retrospective study to examine the protective effect of low-dose dexamethasone (DEX) on delayed adverse events induced by carboplatin (CBDCA)-based combination chemotherapy in patients with thoracic tumors. Low-dose DEX (4-8 mg/day) was administered on day 1 and after, in addition to a serotonin 5-HT3 receptor antagonist. The acute adverse events (day 1) were well controlled in the patients with or without co-treatment of DEX. On the other hand, the delayed nausea, emesis, anorexia, and fatigue after day 2 failed to be controlled by 5-HT3 antagonist alone. Co-treatment with DEX significantly suppressed the grade of the delayed adverse events during days 2-10. The mean ratio of complete protection during days 2-10 were significantly higher in the DEX-treated group compared with the non-DEX-treated group. These results reveal that low-dose DEX is a clinically effective treatment for the prevention of delayed adverse events induced by CBDCA-based combination chemotherapy.

[Monitoring sheet covering long-term chemotherapy to predict individual adverse reaction patterns for patients with gynecologic chemotherapy].

Monitoring the adverse reaction patterns specific to individual patients is important to avoid subsequent reactions. Gynecologic cancer chemotherapy is often implemented repeatedly with an altered protocol during prolonged terms. The purpose of this study was to develop and assess the efficacy of a worksheet that pharmacists can use to analyze adverse reaction patterns in individual patients with gynecologic chemotherapy. The worksheet which we developed consisted of multiple sections. One section is for necessary drug information for the proper use of antineoplastic agents. Another section is for the following items recorded by the pharmacists: a) patients' basic information such as stage of disease and protocol, b) state of implementation and break of chemotherapy and supportive therapy on calendar, and c) laboratory data and symptoms. We arranged the last item below the calendar and enabled pharmacists to easily assess individual adverse reactions coupled with the treatment course. Reviews of the developed worksheet indicated that the worksheet led to the convenient detection of individual adverse reaction patterns and effective prevention of additional adverse reactions. This monitoring sheet covering long-term chemotherapy which was designed to predict individual adverse reaction patterns will improve the individualization and safety of gynecologic chemotherapy.

Change of the blood concentration of tacrolimus after the switch from fluconazole to voriconazole in patients receiving allogeneic hematopoietic stem cell transplantation.

The purpose of this study was to assess the impact by switching co-administered triazole antifungal agent from fluconazole (FCZ) to voriconazole (VCZ) on the blood concentration of tacrolimus (FK506) in patients receiving allogeneic hematopoietic stem cell transplantation. We performed a retrospective study presented as case reports. The blood concentration of FK506 was increased after the switch from FCZ to VCZ, resulting in increase of the concentration/dose (C/D) ratio of FK506. Thus, the mean C/D ratios of FK506 with oral administration was surprisingly increased over 4.5-fold after the switch. Therefore, it was necessary to reduce the FK506 dose when co-administered FCZ is switched to VCZ. We should be careful when interpreting the results of these case reports; however, in some patients, it is recommended that the dose of FK506 be reduced to one-fifth after the switch.

[Monitoring the side effects of cancer chemotherapy with patients--participation of patients in cancer therapy and sharing patient information].

The purpose of this study was to assess patient participation in cancer therapy and the sharing of patient information among the medical care team (physicians, nurses, pharmacists, and especially patients). We monitored the side effects of cancer chemotherapy with patients, and developed two support tools: One scored the points of subjective symptoms (fatigue, anorexia, nausea, etc) by patients, and the other recorded objective symptoms (clinical examination data) by pharmacists. It is most important that they attend each patient at their bedside. At this time, the trial was evaluated by questionnaire survey by inpatients receiving cancer chemotherapy (n=15). As a result, all patients (15/15) responded that this trial was necessary. This trial addressed the following: 1) increased communication between patients and medical staff concerning side effects (14/15), 2) increased interest in side effects (10/15), 3) when a patient tells medical staff about side effects, they act on it (10/15). None of the patients felt inconvenienced by scoring every day (0/15), or anxiety about side effects (0/15). Furthermore, all patients (15/15) responded that "participation of pharmacists in cancer chemotherapy" was necessary. This trial revealed no problems and suggested that patients related to the center of medical care. We should be careful in interpreting results of this small sized trial; however, the following conclusions should be reached: 1) introduction of monitoring side effects of cancer chemotherapy with patients, 2) develop communication among the medical care team.