Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Simulation of Piperacillin/Tazobactam for Dosing Optimization in Late Elderly Patients with Pneumonia.

The aim of this study was to develop a population pharmacokinetic model for piperacillin (PIPC)/tazobactam (TAZ) in late elderly patients with pneumonia and to optimize the administration planning by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. PIPC/TAZ (total dose of 2.25 or 4.5 g) was infused intravenously three times daily to Japanese patients over 75 years old. The plasma concentrations of PIPC and TAZ were determined using high-performance liquid chromatography and modeled using the NONMEM program. PK/PD analysis with a random simulation was conducted using the final population PK model to estimate the probability of target attainment (PTA) profiles for various PIPC/TAZ-regimen-minimum-inhibitory-concentration (MIC) combinations. The PTAs for PIPC and TAZ were determined as the fraction that achieved at least 50% free time > MIC and area under the free-plasma-concentration-time curve over 24 h ≥ 96 µg h/mL, respectively. A total of 18 cases, the mean age of which was 86.5 ± 6.0 (75-101) years, were investigated. The plasma-concentration-time profiles of PIPC and TAZ were characterized by a two-compartment model. The parameter estimates for the final model, namely the total clearance, central distribution volume, peripheral distribution volume, and intercompartmental clearance, were 4.58 + 0.061 × (CLcr - 37.4) L/h, 5.39 L, 6.96 L, and 20.7 L/h for PIPC, and 5.00 + 0.059 × (CLcr - 37.4) L/h, 6.29 L, 7.73 L, and 24.0 L/h for TAZ, respectively, where CLcr is the creatinine clearance. PK/PD analysis using the final model showed that in drug-resistant strains with a MIC > 8 µg/mL, 4.5 g of PIPC/TAZ every 6 h was required, even for the patients with a CLcr of 50-60 mL/min. The population PK model developed in this study, together with MIC value, can be useful for optimizing the PIPC/TAZ dosage in the over-75-year-old patients, when they are administered PIPC/TAZ. Therefore, the findings of present study may contribute to improving the efficacy and safety of the administration of PIPC/TAZ therapy in late elderly patients with pneumonia.

Clonality analysis performed using human androgen receptor assay in a rare case of undifferentiated thymic carcinoma coexisting with type AB thymoma.

We report a very rare case of combined thymic carcinomas: undifferentiated thymic carcinoma coexisting with type AB thymoma. The precise mechanism underlying the coexistence of these tumors remains unknown. Therefore, we used clonality analysis to ascertain whether the two tumors were clonally related. A 63-year-old woman with thyroid cancer visited our hospital. Chest computed tomography also revealed an anterior mediastinal tumor. The patient was treated with total thyroidectomy and surgery for mediastinal tumors together with left upper lobe partial resection. The mediastinal tumor was pathologically diagnosed as undifferentiated thymic carcinoma coexisting with type AB thymoma. Multiple pulmonary metastases were detected in the patient and stage IV disease was diagnosed. The tumor was treatment-resistant, and the patient received fourth-line chemotherapy. We conducted clonality analysis using an improved human androgen receptor gene-amplification assay that involves random X-chromosome inactivation through methylation, followed by methylated gene-specific PCR amplification after sample DNA digestion with HpaII, a methylation-sensitive restriction enzyme. Clonality analysis demonstrated identical X-chromosome inactivation in cells present in both thymoma and thymic carcinoma areas, and thus revealed clonal proliferation. The two lesions in the patient might have arisen through the transformation of a preexisting thymoma into a more malignant lesion.

Evaluation of a pharmacokineticpharmacodynamic approach using software to optimize the carbapenem antibiotic regimen.

OBJECTIVE: Meropenem (MEPM) and doripenem (DRPM), whose antipseudomonal activity is more potent than that of other carbapenem antimicrobials, were used in the study. Monte Carlo simulation of drug concentrations was performed to develop an administration plan for MEPM and DRPM that takes into account the pharmacokinetics (PK)-pharmacodynamics (PD) of MEPM and DRPM and the renal function of each patient. Drug administration plans were proactively applied to patients with pneumonia to determine the usefulness of the method by assessing treatment efficacy and safety. METHODS: Patients with healthcareassociated pneumonia and an indication for MEPM or DRPM chemotherapy underwent drug administration in accordance with the MEPM and DRPM treatment plan developed by the PK-PD software applications. The primary efficacy endpoints were the clinical and bacteriological efficacy of the drugs agains pneumonia. The safety of the antimicrobials was assessed based on abnormal laboratory findings and the seizure disorders in accordance with the criteria for safety evaluation of antimicrobial agents. RESULTS: This study examined 12 and 11 patients in the MEPM and DRPM group, respectively; however, 3 DRPM patients were excluded due to the administration of anti-methicillin-resistant Staphylococcus aureus drugs after the initiation of DRPM treatment. MEPM and DRPM drug administration was determined to be safe and effective in all patients. CONCLUSIONS: The present results suggest that the Monte Carlo simulation-based PK-PD software is an effective tool for planning individualized antimicrobial chemotherapy with carbapenem in accordance with the PK-PD theory of antimicrobials. It is also possible to propose safe and effective drug administration plans for patients with healthcare-associated pneumonia.

Comparison of clinical management of young and elderly asthmatics by respiratory specialists and general practitioners.

BACKGROUND: Asthmatic death in the elderly is a serious problem worldwide. Differences in clinical skill between respiratory specialists (RS) and general practitioners (GP) are important in asthma control. The aim of this study was to compare asthma management between RS and GP. METHODS: A cross-sectional survey was carried out in Shimane, Japan, in February 2009 using a questionnaire about patient background, treatment, asthma control test (ACT) and adherence to treatment. We secured the cooperation of 48 clinics (39 private clinics and 9 general hospitals). Asthmatics were divided into the elderly and young groups, and also into the RS and GP groups. RESULTS: Clinical data of 779 patients were available for analysis. Elderly patients constituted 464 (RS group: 192, GP group: 272), while those of the young group were 315 (RS group: 207, GP group: 108). RS prescribed inhaled corticosteroids (ICSs) to their elderly and young patients more than GP. The total ACT score was higher in young RS group than in young GP group, but no such difference was noted in the elderly. Despite more asthma-related symptoms, the ACT showed that elderly GP asthmatics used fewer rescue inhalers than elderly RS. Self-assessment was higher in elderly GP than elderly RS asthmatics. Adherence to therapy was better in elderly patients than young patients. CONCLUSIONS: Elderly asthmatics treated by GPs underestimated the severity of their asthma and asthmatics seen by GPs were undertreated. The results stress the need to engage patients in educational activities, to adhere to guidelines, and to improve the coordination between GP and RS.

Clinical usefulness of testing for UDP glucuronosyltransferase 1 family, polypeptide A1 polymorphism prior to the inititation of irinotecan-based chemotherapy.

An association between UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) polymorphisms and irinotecan-induced neutropenia has been previously reported. In this study, we assessed the clinical usefulness of testing for UGT1A1 polymorphisms prior to the initiation of irinotecan-based chemotherapy, as this remains a controversial subject. A total of 136 lung cancer patients who were treated with a combination of nedaplatin and irinotecan as initial chemotherapy were assessed. Following exclusion of patients exhibiting low UGT1A1 enzyme activity, 70 patients were treated after UGT1A1 polymorphism testing (test group) and 66 patients were treated without UGT1A1 polymorphism testing (non-test group). We retrospectively analyzed and compared the adverse events between the test and the non-test groups and observed no reduction in hematological or non-hematological toxicities in the test group compared to that in the non-test group. Of the 9 patients with grade 4 or 5 non-hematological toxicity, 6 patients had febrile neutropenia (FN). All the patients with FN were aged >70 years. The incidence of adverse events was significantly higher among patients aged >70 years compared to that among younger patients. In conclusion, in patients treated with nedaplatin and irinotecan combination chemotherapy, UGT1A1 polymorphism testing prior to the initiation of chemotherapy did not reduce the incidence of adverse events. Therefore, UGT1A1 polymorphism testing alone may not be sufficient to predict the occurrence of severe adverse events and it may be more important to effectively manage adverse events, particularly in elderly patients.

Nephrotoxicity induced by piperacillin­tazobactam in late elderly Japanese patients with nursing and healthcare associated pneumonia.

This study aimed to clarify the efficacy, safety, and pharmacokinetics of piperacillin­tazobactam (PIPC­ TAZ) in late elderly Japanese patients. This is the first antimicrobial pilot study in late elderly patients with nursing and healthcare associated pneumonia. After PIPC­TAZ administration, PIPC concentrations in plasma were measured chromatographically and the pharmacokinetic parameters were estimated. Efficacy, safety, and bacteriological evaluations were also carried out. The mean age was 85.0 years old and most of the patients were late elderly. Chest X-rays, body temperature, white blood cell count, and C reactive protein all improved significantly, and a high efficacy ratio of 90.9% was observed. Serious nephrotoxicity was observed in 4 cases (18.2%) after administration of PIPC­TAZ. Creatinine clearance (meanS.D.) measured before PIPC­TAZ therapy was significantly lower in the nephrotoxicity group (32.54.4 mL/min) than in the non-nephrotoxicity group (46.116.7 mL/min), although the ages were not different between the 2 groups. In the pharmacokinetic parameters for PIPC, total clearance was slightly lower in the nephrotoxicity group than in the non-nephrotoxicity group. However, no significant difference was observed in plasma PIPC levels between the 2 groups. In patients with renal impairment, especially with a creatinine clearance of <40 mL/ min, renal impairment was found to be an influencing factor for severe nephrotoxicity following PIPC­TAZ administration. In conclusion, the results suggest that physicians should pay close attention in order to avoid possible toxicity, and that deliberate administration planning and careful follow-up are required in late elderly patients with comprised organ dysfunction.

¹8F-fluorodeoxyglucose uptake on positron emission tomography in mucinous adenocarcinoma.

BACKGROUND: The prognostic value of maximum standardized uptake value (maxSUV) on (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) is known for localized pulmonary adenocarcinoma, which is most commonly non-mucinous adenocarcinoma. We examined the validity of thin-section computed tomography (TS-CT) and FDG-PET findings in mucinous adenocarcinoma. MATERIALS AND METHODS: TS-CT and FDG-PET were performed on 25 patients with mucinous lung adenocarcinoma that was subsequently resected between January 2009 and March 2013. Based on the percentage reduction of maximum tumor diameter on the mediastinal window image compared with the diameter on the lung window image on TS-CT, tumors were classified as air-type (≥50%) or solid-type (<50%). All resected specimens were pathologically diagnosed according to the International Association for the Study of Lung Cancer (IASLC) classification, and the diameter of the pathological invasive area was assessed. RESULTS: Most mucinous adenocarcinomas were located in the lower lobe. All except two were classified as solid-type tumor on TS-CT. Multiple regression analysis revealed the correlation of maxSUV with pathological tumor size and diameter of pathological invasive area; these two parameters showed no significant correlation with each other (r=0.354, p=0.083). maxSUV was significantly lower for tumors with invasive area ≤5 mm than for tumors with invasive area >5mm (1.62 vs. 3.77, p=0.01), but no statistically significant difference was found in terms of other pathological invasive findings such as the presence of lymphatic or vascular invasion, pleural involvement, or predominant histological subtype. CONCLUSIONS: Most mucinous adenocarcinomas had appearances of solid-type tumor on TS-CT. maxSUV on FDG-PET indicates the pathological invasive area in mucinous adenocarcinoma as well as non-mucinous adenocarcinoma.

Efficacy and safety of piperacillin/tazobactam versus biapenem in late elderly patients with nursing- and healthcare-associated pneumonia.

Pneumonia is associated with an extremely high mortality rate in patients of late elderly age. Piperacillin/tazobactam and carbapenems are drugs of first choice for hospitalized patients with potentially resistant bacteria. We compared the efficacy and safety of piperacillin/tazobactam and biapenem. Among elderly patients with nursing- and healthcare-associated pneumonia, we extracted 53 patients treated with piperacillin/tazobactam and 53 patients treated with biapenem who were matched for sex, age, and severity of pneumonia. The average age was more than 80 years; most of the patients were middle- to oldest old in age. Although clinical efficacy was equally good, patients in the piperacillin/tazobactam group achieved significantly faster improvements on chest X-ray and body temperature on day 7. However, in the piperacillin/tazobactam group, nephrotoxicity frequently led to a need for a reduction in the dose or complete discontinuation of treatment. The average age of patients who developed significant nephrotoxicity was high, at 83.2 years. The biapenem group exhibited significantly better continuation of treatment than the piperacillin/tazobactam group. Toxicity profiles were different between the two groups. Hepatic toxicity was significantly higher in the biapenem group, whereas nephrotoxicity was significantly more common in the piperacillin/tazobactam group. Rate of decrease in bacteria was equally good between the two groups. Providing careful follow-up and conducting more detailed examinations, including studies to determine optimal dose and timing of administration, are necessary for the treatment of late elderly patients with numerous underlying diseases and potential organ dysfunctions.

Phase I clinical and pharmacokinetic study of bi-weekly carboplatin/paclitaxel chemotherapy in elderly patients with advanced non-small cell lung cancer.

AIM: We evaluated the pharmacokinetics and quality of life of elderly patients with advanced non-small-cell lung cancer (NSCLC) treated with bi-weekly carboplatin and paclitaxel chemotherapy, and determined the maximum tolerated dose (MTD) of this treatment. PATIENTS AND METHODS: Eligible patients had histologically- or cytologically-proven inoperable NSCLC, age of 70 years or older, no prior treatment, and Eastern Cooperative Oncology Group performance status 0-2. Paclitaxel was administered in combination with carboplatin under a bi-weekly schedule. We determined the plasma concentrations of both drugs during therapy. RESULTS: The median patient age was 80 years. Using carboplatin at AUC 3, the MTD of paclitaxel was 100 mg/m(2). Both hematological and non-hematological toxicities were mostly mild and manageable. Although paclitaxel is predominantly metabolized in the liver, clearance was decreased in patients with lower estimated glomerular filtration rate. CONCLUSION: Bi-weekly treatment, as described here, is feasible for elderly patients as a conventional regimen, particularly in the outpatient setting, due to its lower toxicity.

Evaluation of the efficacy and safety of biapenem against pneumonia in the elderly and a study on its pharmacokinetics.

Although biapenem is used in the treatment of pneumonia, the clinical data on elderly patients are yet insufficient. Therefore, the purpose of this study was evaluating the efficacy and safety of biapenem against pneumonia in the elderly and its pharmacokinetics. The subjects were patients 65 years of age or older with pneumonia. Biapenem (300 mg) was administered once to three times per day. For some cases, the drug concentrations in plasma were measured chronologically. The clinical efficacy was evaluated in reference to the improvement in subjective symptoms and objective opinion. The primary outcome was efficacy rate at the end of treatment. Biapenem was effective in 17 of 20 subject cases (85.0 %). Regarding safety, although 4 cases experienced hepatic dysfunction and 1 case had nausea, these effects were not severe in all cases and administration was continued. There was no deterioration of renal function associated with biapenem. In 13 cases in which the trough value of biapenem was measured, there were no unacceptable side effects and the trough values were generally low. It is believed that biapenem (300 mg once to three times a day), even when taken by elderly people, does not accumulate and that the dosage is safe and appropriate. The changes in the predicted concentrations calculated with the pharmacokinetic-pharmacodynamic (PK-PD) software, which is based on previously reported population pharmacokinetic parameters, and those in the measured concentrations approximately matched. It is useful to plan biapenem administration using the PK-PD software when performing antibiotic chemical treatment.

A retrospective analysis comparing the safety and efficacy of chemotherapy in elderly and non-elderly non-small-cell lung cancer patients.

AIM: The number of elderly patients with non-small-cell lung cancer (NSCLC) is increasing in Japan. We retrospectively analyzed and compared the safety and efficacy of chemotherapy in elderly and non-elderly NSCLC patients who received chemotherapy at Shimane University Hospital. METHODS: We carried out a retrospective analysis of survival in a series of 112 NSCLC patients treated from 2004 through 2009. We compared the data from the elderly group (≥ 70 years-of-age, 56 patients) with the non-elderly group (< 70 years-of-age, 56 patients) who had similar characteristics, such as sex and Eastern Cooperative Oncology Group performance status. We analyzed the patient characteristics, therapeutic regimen, dose intensity, toxicity and survival time in both groups. RESULTS: The patient characteristics were comparable between the two groups; however, there was a significant difference between the choice of first-line therapeutic regimen. A platinum-doublet regimen was more frequently used in the non-elderly population (39.3% vs 64.3% for the elderly patients vs the non-elderly patients, respectively; P < 0.01), whereas single agents and epidermal growth factor receptor-tyrosine kinase inhibitors were more frequent in the elderly population (26.8% vs 10.7%, 19.6% vs 7.1%; P < 0.05, respectively). The relative dose intensity was approximately 80% or higher for all regimens, and toxicity was acceptable. The median survival time was 24.4 months and 18.6 months in the elderly and non-elderly groups, respectively. CONCLUSION: This retrospective study suggests that elderly patients can safely receive effective chemotherapy similar to non-elderly patients under careful observation and management.