As cancer chemotherapy is often associated with several severe adverse effects, clinical pharmacists have to play a major role in its safety management. The author has studied the expression mechanism and risk factors of chemotherapy-induced adverse reactions and presents the major findings in this review. 1) Photodegradation of dacarbazine produces allyl radicals which cause DNA damage and can induce genotoxicity in the clinical setting. To prevent photodegradation, dacarbazine should be protected from UV light. 2) The risk factors for zoledoronic acid-induced hypocalcemia are considered to be an albumin-adjusted serum calcium concentration less than 9.5 mg/dL before zoledoronic acid administration and concomitant use of corticosteroids, whereas for prostate cancer which results in osteoblastic bone metastasis, the risk of this adverse reaction is reduced. 3) Drug interaction between bortezomib and itraconazole could increase the risk of bortezomib-induced peripheral neuropathy and thrombocytopenia. 4) Carboplatin-induced hypersensitivity reactions often occur after 8 cycles of a carboplatin based regimen, and the risk of such reactions is increased in patients with a carboplatin free interval > 13 months and carboplatin dose > 650 mg. These findings may provide useful information for the prevention and management of chemotherapy-induced adverse reactions. In addition, this kind of problem-based research aiming to establish clinical evidence could be recommended as an activity for oncology and hematology pharmacy specialists.
The immunosuppressive antimetabolites mycophenolate mofetil and mizoribine are widely used in combination with a calcineurin inhibitor for organ transplantation and autoimmune diseases. However, administering these antimetabolites at fixed doses often causes bone marrow toxicity or cytomegalovirus antigenemia. This review summarizes our findings from research in the clinical setting regarding evidence-based pharmaceutical care with antimetabolites in which therapeutic drug monitoring is used. (1) The contribution of enterohepatic recirculation to the plasma disposition of mycophenolic acid (MPA) in lupus nephritis patients was similar to that in tacrolimus-treated kidney transplant recipients. MPA’s pharmacokinetics in lupus nephritis were characterized by higher clearance most likely due to better renal function. (2) The renal clearance of MPA was higher in cyclosporine- than tacrolimus-treated kidney transplant recipients. The renal clearance ratio of MPA to creatinine was much higher than that for the unbound fraction of MPA. These pharmacokinetic data indicated the presence of renal tubular secretion in the urinary excretion process. (3) Concomitant metal cations decreased the MPA concentration in tacrolimus- but not cyclosporine-treated kidney transplant recipients. This interaction may depend on the amount of biliary-excreted MPA glucuronide. (4) The concentrative nucleoside transporter 1 (CNT1) genetic polymorphism G565A affected the bioavailability of mizoribine in kidney transplant recipients. CNT1 G565A may be a reason for inter-individual differences in the plasma disposition of mizoribine. (5) The plasma disposition of MPA and its metabolites affected inosine 5’-monophosphate dehydrogenase activity in erythrocytes. 5’-monophosphate dehydrogenase activity might be a useful marker of long-term exposure to MPA. The findings in this review should help achieve optimal dosing for antimetabolites through therapeutic drug monitoring in clinical practice.
Pharmacists can play a significant role in medical care by helping to ensure the proper use of drugs, and a knowledge of pharmacokinetics is indispensable for this. Therapeutic Drug Monitoring (TDM) is a pharmacy practice that involves the full use of such knowledge. Practical training in TDM in pharmacist education should thus be an optimal way acquiring skill in applying pharmacokinetics knowledge in the clinical setting. However, in the Model Core Curriculum for practical training at hospitals implemented in 2010, there is only 1 specific behavioral objective (SBO) concerning TDM, and only 1 day is given to training on TDM. With this in mind, we developed an original experience-based TDM curriculum that includes 5-days of practical training. The curriculum was introduced for students in the 2010 pharmaceutical internship to evaluate its components. All students who took our curriculum considered that the 1-day of TDM training stipulated in the Model Core Curriculum was not sufficient, and that around 5 days of training, the period we have set, would be necessary. They also indicated a high level of satisfaction with it, viewing the training components as appropriate. These findings suggest that our curriculum would be effective.
In 2006, bortezomib, a proteasome inhibitor, was approved for the treatment of patients with refractory or relapsed multiple myeloma. In the domestic clinical trial on bortezomib, which was limited in scale, therapy with it caused serious adverse effects such as interstitial pneumonia and acute lung injuries. Thus, in order to determine whether bortezomib is safe and effective, we investigated its adverse effects during the treatment period and compared them with those described in the bortezomib interview form. We investigated the reasons for extension of interval and discontinuation. Administration of this medicine resulted in adverse effects such as peripheral neuropathies and decrease in the platelet count that were dose-limiting factors. Furthermore, as bortezomib is a substrate for CYP3A4, we investigated its interaction with itraconazole. The reasons for extension of interval and discontinuation were mainly studied (87 % of the investigation). In particular, a remarkable decrease in the platelet count and a high incidence of peripheral neuropathy of grade 3 or higher were noted, making continuation of the treatment difficult. Further, combination therapy with bortezomib and itraconazole significantly increased the incidence of peripheral neuropathy. This suggests that caution is needed when combining bortezomib and itraconazole.
The objective of this study was to assess possible interaction between kurosu (japanese unpolished rice vinegar) and Pglycoprotein (P-gp), using rhodamine 123 (Rho-123) and glibenclamide (GB) as known P-gp substrates. The absorption of the drugs was investigated using an in situ loop technique. Three 10-cm loops were created in the rat small intestine - in the duodenal, jejunal, and ileal regions. Then, a test solution was introduced into each loop and its disappearance rate after 30 min was determined. In the presence of kurosu, Rho-123 absorption markedly increased in the 3 regions. Although the lipophilicity of GB was greater than that of tolbutamide (TB), GB absorption was much less than that of TB in the 3 regions, which implied that an efflux transporter restricted GB absorption. However, typical P-gp inhibitors such as verapamil and cyclosporin A slightly increased GB absorption. Also, the enhancing effect of kurosu on GB absorption was limited. The present results suggest that some components of kurosu are capable of strongly interfering with P-gp function in the intestine and increasing the absorption of P-gp substrates. Our data also imply that an efflux transporter other than P-gp is involved in the low absorption of GB.
High-dose methotrexate (MTX) therapy is used to treat cancers such as acute leukemia, malignant lymphoma, and osteosarcoma. Serum MTX levels are usually measured in order to prevent adverse effects and make a schedule for leucovorin rescue in this therapy. TDx® analyzer (TDx®, Abbott), the device currently used for measurement, provides dependable serum MTX measurements. However, the Viva-ETM system (Viva-ETM, Siemens) which has recently started to be used for analysis cannot determine levels <0.30 μmol/L. Since this makes serum MTX levels 72 h after MTX administration uncertain, we investigated methods of improving the detection limit of serum MTX levels with Viva-ETM, and evaluated the validity of its clinical application. The sample volume was increased from 3.0 to 9.0 μL to detect lower concentrations, and accuracy as well as intra- and interassay variability were evaluated. We also examined a correlation with TDx® measurements for low levels (< 0.30 μmol/L) in samples obtained 48 h and 72 h after MTX administration. A level of 0.04 μmol/L could be detected,making it possible to monitor serum MTX levels 72 h after MTX administration. The accuracy ( p = 0.78), intra-assay variability (coefficient of variation [C.V.], 1.8-15.1%), inter-assay variability (C.V., 1.48.6%) and correlation with TDx® (y = 1.11x + 0.01, r = 0.97) were reasonable for the clinical setting. In conclusion, these findings provide useful information for institutions where serum MTX levels are measured using Viva-ETM in patients receiving MTX treatment.
In a retrospective study, pharmacists attended medical interviews and examinations conducted by a doctor and carried out follow-up interviews by telephone, to lessen the risk factors for hand-foot skin reactions (HFSR) caused by sorafenib in advanced hepatocellular carcinoma patients and improve treatment adherence for the drug. The study was conducted to assess the effectiveness of pharmacist intervention. The medical records and risk assessment sheets of 48 hepatocellular carcinoma patients who received sorafenib from June 2009 to May 2010 were reviewed. There were 45 male and 3 female patients, with a median age of 70.5 (range 37-83) yrs. The Eastern Cooperative Oncology Group performance status was 0, 1 and 2 in 37, 10 and 1 patients, respectively. The incidence of HFSR was 73%(35/48), and the maximum grade of HFSR was 0, 1, 2 and 3 in 13, 7, 23 and 5 patients, respectively. The mean number of risk factors for HFSR was significantly reduced after pharmacist intervention as compared with that before (3.5 ± 2.1 vs. 1.4 ± 1.3, p<0.001). Non-adherence to sorafenib was observed in 17 patients (35%), but treatment adherence improved for all of these patients after pharmacist intervention. Therefore, pharmacist intervention mitigated risk factors for HFSR and resolved the problem of non-adherence to treatment in patients with advanced hepatocellular carcinoma.
We prepared dried thyroid rectal suppositories for the treatment of thyroid papillary adenocarcinoma in patients with hypothyroidism in response to clinicians’ requests. The suppositories had a content of 50 mg or 100 mg and were prepared using dried thyroid powder and hard fat. The initial daily dose of 100 mg, which was given as a single dose in the morning, could be increased on the basis of thyroid stimulating hormone (TSH) levels, as required. In addition, an oral dose of levothyroxine sodium hydrate 150 μg could be switched to a dose of 300 mg of dried thyroid rectal suppositories in this patient. These results suggested that the dose of dried thyroid rectal suppositories for the treatment of hypothyroidism should be titrated for individual patients based on TSH levels.