Application of a hemodialysis clearance prediction model using quantitative structure-pharmacokinetic relationship analysis.

Hemodialysis (HD) is a method used to remove biogenic substances or blood components that cause disease and some drugs used by patients to treat their diseases. Therefore, dosing schedule must be planned according to HD clearance (CLHD ) when medical treatment is provided to patients receiving HD. We aimed to clarify the physical properties (eg, octanol-water partition coefficient and molecular electronegativity) or pharmacokinetic parameters (eg, volume of distribution) of compounds affecting CLHD and to construct a mathematical model to predict CLHD . The analysis covered individual CLHD data for nine compounds from the literature. The molecular descriptors which are physical properties or pharmacokinetic parameters were calculated using the structural formula of each compound, and searched for factors related to CLHD among the calculated 148 molecular descriptors. Nonlinear mixed-effects model analysis with CLHD as objective variable and molecular descriptors as explanatory variable was conducted to examine the factor affecting CLHD and develop a model for predicting CLHD . The logarithm of the brain/blood partition coefficient was detected as a factor affecting CLHD . The predictive accuracy of CLHD using the constructed mathematical model with the logarithm of the brain/blood partition coefficient as explanatory variable was adequate.

[Evaluation of Antibiotics for the Treatment of Bacteremia Due to Extended-spectrum ß-Lactamase-producing Escherichia coli].

Recently, extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli has been more frequently isolated from blood specimens than in the past. In this study we investigated a panel of therapeutic agents used to treat 37 patients with ESBL-producing E. coli bacteremia. Antimicrobial agents administered as definitive therapy displayed higher efficacy rates than when empiric therapy was administered (efficacy rates, 95.7% vs. 62.5%). The success rate of carbapenem was 95.8% (23/24) in patients with ESBL-producing E. coli bacteremia. In addition, the success rate of cefmetazole against ESBL-producing E. coli sensitive to this drug was 87.5% (7/8). In conclusion, patients at high risk of infection due to ESBL-producing E. coli should be empirically treated with carbapenem antibiotics. In addition, cefmetazole may be a treatment option for patients with ESBL-producing E. coli bacteremia.

[Relationship between the effectiveness and dose of micafungin in the treatment of candidemia].

The Guidelines for Management of Deep-seated Mycoses 2007 recommend the use of micafungin as a first-line agent for the treatment of candidemia. On the package insert, the recommended dose of micafungin is 50 mg/d. However, the Guidelines recommend a micafungin dose of 100-150 mg/d. In the present study, we evaluated the relationship between the effectiveness and dose of micafungin in 42 patients with candidemia who underwent treatment with micafungin. We found that the efficacy rate of micafungin at a dose of 50 mg/d was 40%, whereas that at ≥100 mg/d was 87.5%. Moreover, the treatment was more effective in patients who received ≥100 mg/d of micafungin as compared to those who received 50 mg/d of micafungin. Furthermore, we assessed the efficacy of micafungin according to the Candida species. Among all patients, the efficacy rate of micafungin was found to be lower in patients infected by Candida parapsilosis as compared to those infected by other Candida species. However, among the patients who received ≥100 mg/d of micafungin, the efficacy rate in patients infected by Candida parapsilosis was equivalent to that of patients who were infected by other Candida species. Thus, based on the results of the present study, the optimal micafungin dose for the treatment of candidemia appears to range from 100 to 150 mg/d, as recommended by the Guidelines.

[Assessment of risk factors for adverse events due to pemetrexed in patients with reduced renal function].

Pemetrexedis a key drug in the first and second -line therapy for non-small-cell lung cancer. It exhibits an increased area under the plasma drug concentration-time curve, and it has a prolonged half -life when administered to patients with reduced renal function, resulting in a high frequency of neutropenia. Accordingly, pemetrexed is administered to these patients with caution. Herein, we retrospectively investigated the background characteristics of patients with a creatinine clearance rate (Ccr) of<45 mL/min, who experienced severe adverse events due to pemetrexed. Thirty-eight patients with a Ccr of <45 mL/min were administered pemetrexed. Of these patients, 13 (34%) developed severe adverse events (≥Grade 3) such as neutropenia, thrombocytopenia, and nausea. Multiple logistic regression analysis revealed that a Ccr of <30 mL/min (p= 0.033) and the concomitant use of non-steroidal anti-inflammatory drugs (p=0.012) were significant risk factors for adverse events. Therefore, whenever possible, pemetrexed administration should be avoided in patients with a Ccr of <30 mL/ min and in those receiving concomitant non-steroidal anti-inflammatory drugs.

Analysis of risk factors for severe adverse events of chemotherapy with pemetrexed and comparison of adverse event occurrence according to renal function.

Various factors, including renal function and the combination of nonsteroidal anti-inflammatory drugs, influence the pharmacokinetics of pemetrexed. In this study, we aimed to determine the risk factors for severe adverse events associated with pemetrexed administration. We retrospectively examined the medical records of 82 patients who received pemetrexed. Multiple logistic regression analysis indicated that a creatinine clearance (CCr) of less than 45 mL/min and administration of pemetrexed as early-line treatment were significant risk factors. We then retrospectively compared the adverse events associated with pemetrexed between patients with normal renal function (CCr≥45 mL/min) and those with impaired renal function (CCr<45 mL/min). With regard to hematological toxicity, the frequency of occurrence of grade 3 neutropenia was significantly higher among patients with a CCr of <45 mL/min. With regard to non-hematological toxicity, the frequency of occurrence of grade 2 or higher nausea was significantly higher among patients with a CCr of <45 mL/min. However, the efficacy of pemetrexed did not differ significantly between the 2 groups. Our findings suggest that, for patients with a decline in renal function (CCr <45 mL/min), attention must be paid to the possibility of serious adverse events such as neutropenia and nausea when considering the administration of pemetrexed.

[Adverse events during pemetrexed administration caused by concomitant nonsteroid anti-inflammatory therapy].

Pemetrexed, a folate metabolic antagonist, is considered to be effective against plural mesotheliomas, non-small cell lung cancer, and especially for non-squamous cell cancer. However, it has been reported to have adverse interactions with nonsteroid anti-inflammatory drugs(NSAIDs). In the present study, we compared the incidence of adverse events between patients receiving pemetrexed therapy with and without concomitant NSAID administration. No significant difference in the incidence of hematotoxic events of Grade 3 or worse was observed. As for the incidence of non-hematotoxic events, the increase in the amount of creatinine, namely a severe adverse effect of Grade 2 or more, was significantly higher in the combined therapy group (p=0.018). No other significant differences were noted for other adverse events. A creatinine increase to Grade 2 or greater developed significantly earlier in the combined group(median value, 12.7 courses; p=0.0063). Our results suggest that renal dysfunction may easily develop as a result of continued pemetrexed administration combined with NSAID therapy. Therefore, it is necessary to take precautions against adverse side effects such as renal dysfunction when combining pemetrexed with NSAID therapy, by conducting periodic examinations.