Definitive chemoradiotherapy with paclitaxel for locally advanced esophageal squamous cell carcinoma in older patients (PARADISE-1): a phase I trial.

BACKGROUND: In older patients, esophageal squamous cell carcinoma (ESCC) is difficult to treat using standard therapies, including surgery and cisplatin-based chemoradiotherapy. Paclitaxel (PTX) has radiosensitizing activity. We conducted a phase I trial of PTX combined with radiotherapy to establish a standard therapy for locally advanced ESCC in older patients. METHODS: Enrollment was conducted at six centers in Japan from April 2016 to September 2019. The participants were aged ≥ 70 years, had locally advanced ESCC, and were intolerant to surgery or unwilling. A fixed 60-Gy radiation dose was administered in 30 fractions. PTX dosing levels started at 30 mg/m2 weekly for 6 weeks. Depending on the number of DLTs, the dose was set to be increased by 10 mg/m2 or switched to biweekly. A geriatric assessment was performed before treatment using the Geriatric-8 screening tool. The primary endpoint was dose-limiting toxicity (DLT). RESULTS: We enrolled 24 patients (6 per group); DLT was observed in one (grade 4 hypokalemia), one (grade 3 aspiration), two (grade 3 radiodermatitis, grade 3 esophageal hemorrhage), and two (grade 3 anorexia, grade 5 pneumonitis) patients in the weekly PTX 30, 40, 50, and 60 mg/m2 groups, respectively. All adverse events, except death in the 60 mg/m2 group, showed reversible improvement, and the safety profile was considered acceptable. The 2-year survival and complete response rates were 40.0% and 54.2%, respectively. There was a significant difference in survival between favorable and unfavorable Geriatric-8 scores. CONCLUSIONS: The recommended PTX dose with concomitant radiation was determined to be 50 mg/m2 weekly. Phase II trials at this dose are underway.

Pharmacodynamic Model-Based Safety Management of Eribulin-Induced Myelosuppression in Patients With Breast Cancer.

BACKGROUND: Neutropenia is a major dose-limiting toxicity of cancer chemotherapy. Semimechanistic mathematical models have been applied to describe the time course of neutrophil counts. The objectives of this study were to develop a mathematical model describing changes in neutrophil counts during eribulin treatment, to apply the empirical Bayes method to predict the probability of developing neutropenia ≥ grade 3 during eribulin treatment in each patient, and to propose the implementation of this mathematical tool in clinical practice for individual safety management. METHODS: The present model analysis and subsequent external evaluation were performed using the data of 481 patients with breast cancer, previously obtained from a postmarketing surveillance (training set) and a phase 2 clinical study (validation set). The model we previously reported (Kawamura et al 2018) was modified to improve its predictive capability. The individual time course of neutrophil changes during the treatment period was predicted by the empirical Bayes method using the observed neutrophil counts at baseline and the first measurement after the first eribulin dose. To evaluate the predictability of this method, the predicted neutrophil counts were compared with those of the observed values. RESULTS: The developed model provided good individual predictions, as indicated by the goodness-of-fit plots between the predicted and observed neutrophil counts, especially for a lower neutrophil count range. Days required to reach the nadir after the dose were also well-predicted. The sensitivity, specificity, and accuracy of the prediction of neutropenia grade ≥3 were 76%, 53%, and 71%, respectively. CONCLUSIONS: We developed a mathematical method for predicting and managing the risk of neutropenia during eribulin treatment. This method is generally applicable to other cases of chemotherapy-induced neutropenia and can be a new practical tool for individual safety management.

Evaluation of clinical validity of an S-1 dosage formula based on renal function using data of the SPIRITS and the G-SOX trials.

BACKGROUND: The aim of this study was to evaluate clinical validity of the S-1 dosage formula based on body surface area (BSA) and creatinine clearance (CLcr) to achieve the target area under the concentration-time curve of 5-FU, which we had developed and refined in each prospective pharmacokinetic study. METHODS: The recommended dose determined by the refined formula was assessed using data of the SPIRITS (S-1 vs. S-1 plus cisplatin [SP]) and the G-SOX (SP vs. S-1 plus oxaliplatin [SOX]) trials. Nine hundred and thirty-eight patients in these trials were classified into three groups according to their actual S-1 starting doses compared with the recommended doses (under-dosed, recommended dose). RESULTS: The patients in the under-dosed group in both trials showed similar tendencies: male, younger, higher BSA, and higher CLcr. The incidence of any grade neutropenia was significantly greater in the over-dosed group compared with the equal-dosed group in the S-1 and the SOX arms. The hazard ratios (HR) of overall survival (OS) (under-dosed vs. equal-dosed) were 1.361 (S-1 arm), 1.259 (SP arm) in the SPIRITS trial, and 1.381 (SOX arm), 0.999 (SP arm) in the G-SOX trial. Multivariate analysis in all the patients demonstrated that OS of the over-dosed group was equivalent (HR 1.002, 95% confidence interval [CI] 0.850-1.182, p = 0.980) and that of the under-dosed group was inferior (HR 1.267, 95% CI 1.005-1.597, p = 0.045) to the equal-dosed group. CONCLUSIONS: It is suggested that the refined S-1 dosage formula can recommend optimal dose in terms of safety and efficacy.

Prospective evaluation and refinement of an S-1 dosage formula based on renal function for clinical application.

In patients with impaired renal function, S-1-related toxicities increase due to higher exposure of 5-fluorouracil (5-FU). Our previous pharmacokinetic study in 16 cancer patients with various renal functions developed an S-1 dosage formula based on individual creatinine clearance (CLcr) and body surface area (BSA). To evaluate and refine the formula, this prospective study was conducted. Thirty-three patients with various renal functions received S-1 for 4 weeks at doses determined by the nomogram derived from the previously developed formula. A series of blood samples were collected after the first dose to calculate the area under the concentration-time curve (AUC) of 5-FU. Thirty patients with BSA of 1.14-1.84 m2 and CLcr of 23.8-96.4 mL/min were assessable for pharmacokinetics. The observed daily AUC ranged from 712.6 to 2868.7 ng·h/mL, and 18 patients achieved the target AUC (1447.8 ± 545.4 ng·h/mL). Three patients experienced S-1-related grade 3 adverse events during the first course. In the population pharmacokinetic analysis from the combined data of 46 patients in this study and the previous study, sex was identified as a statistically significant covariate for 5-FU clearance. Hence, the refined formula includes sex as an additional factor: Recommended daily dose = target AUC × (14.5 + 8.23 × SEX [0 for female and 1 for male] + 0.301 × CLcr) × BSA. Revised nomograms for recommended daily doses derived from the refined formula can be used in clinical practice to achieve the target AUC ensuring efficacy and safety of S-1.

Population Pharmacokinetics of Voriconazole in Patients With Invasive Aspergillosis: Serum Albumin Level as a Novel Marker for Clearance and Dosage Optimization.

BACKGROUND: Voriconazole (VRCZ) is an antifungal triazole recommended as an effective first-line agent for treating invasive aspergillosis. OBJECTIVES: To develop a population pharmacokinetic model of VRCZ and trough concentration-based dosing simulation for dynamic patient conditions. METHODS: The authors combined plasma VRCZ data from intensive sampling, and retrospective trough concentration monitoring for analysis. Nonlinear mixed-effects modeling with subsequent model validation was performed. The recommended dosage regimens were simulated based on the developed model. RESULTS: The study participants included 106 patients taking oral VRCZ. A linear one-compartment model with first-order elimination and absorption best described the observed data. The CYP2C19 phenotypes did not influence the pharmacokinetic parameters. Serum albumin (SA) levels and gamma-glutamyl transferase significantly correlated with the VRCZ clearance rate, whereas the actual body weight influenced the volume. A visual predictive check showed good consistency with the observed data, whereas SA levels across the treatment course correlated with linear clearance, irrespective of the CYP2C19 phenotype. Patients with SA levels ≤30 g/L had lower linear clearance than that in patients with SA levels >30 g/L. Dosing simulation based on the developed model indicated that patients with SA levels of ≤30 g/L required a lower daily maintenance dose to attain the therapeutic trough level. CONCLUSIONS: SA level was identified as a novel marker associated with VRCZ clearance. This marker may be a practical choice for physicians to perform therapeutic drug monitoring and optimize VRCZ dosage.

Pharmacodynamic analysis of eribulin safety in breast cancer patients using real-world postmarketing surveillance data.

Postmarketing surveillance is useful to collect safety data in real-world clinical settings. In this study, we applied postmarketing real-world data on a mechanistic model analysis for neutropenic profiles of eribulin in patients with recurrent or metastatic breast cancer. Demographic and safety data were collected using an active surveillance method from eribulin-treated recurrent or metastatic breast cancer patients. Changes in neutrophil counts over time were analyzed using a mechanistic pharmacodynamic model. Pathophysiological factors that might affect the severity of neutropenia were investigated, and neutropenic patterns were simulated for different treatment schedules. Clinical and laboratory data were collected from 401 patients (5199 neutrophil count measurements) who had not received granulocyte colony-stimulating factor and were eligible for pharmacodynamic analysis. The estimated mean parameters were as follows: mean transit time = 104.5 h, neutrophil proliferation rate constant = 0.0377 h-1 , neutrophil elimination rate constant = 0.0295 h-1 , and linear coefficient of drug effect = 0.0413 mL/ng. Low serum albumin levels and low baseline neutrophil counts were associated with severe neutropenia. The probability of grade ≥3 neutropenia was predicted to be 69%, 27%, and 27% for patients on standard, biweekly, and triweekly treatment scenarios, respectively, based on virtual simulations using the developed pharmacodynamic model. In conclusion, this is the first application of postmarketing surveillance data to a model-based safety analysis. This analysis of safety data reflecting authentic clinical settings will provide useful information on the safe use and potential risk factors of eribulin.

The effects of advanced age and serum α1 -acid glycoprotein on docetaxel unbound exposure and dose-limiting toxicity in cancer patients.

AIM: α1 -Acid glycoprotein (AAG), which is a major binding protein of docetaxel, is considered to be a determinant for docetaxel pharmacokinetics. However, there are no reports about the impact of serum AAG on pharmacokinetics and pharmacodynamics in elderly patients treated with docetaxel. The aim of this prospective study was to elucidate the effects of advanced age and serum AAG on docetaxel unbound exposure and neutropenia, dose-limiting toxicity, in cancer patients. METHODS: Docetaxel was administered at 60 mg m-2 to 51 patients with non-small cell lung cancer, 17 of whom were ≥75 years of age. Pharmacokinetics, unbound fraction (fu), neutropenia, serum protein levels of AAG and albumin, as well as baseline absolute neutrophil count (ANC) were assessed during the first course. Population pharmacokinetic and pharmacodynamic analyses were performed to evaluate the influence of clinically relevant factors on docetaxel pharmacokinetics and neutropenia. RESULTS: Clearance of docetaxel and degree of fu were significantly associated with serum AAG level, but not with age. Area under the concentration-time curve of unbound docetaxel (fu·AUC) was significantly higher in patients aged ≥75 years (0.389 µg·h ml-1 , 95% CI; 0.329-0.448 µg·h ml-1 ) compared with patients aged <75 years (0.310 µg·h ml-1 , 95% CI; 0.268-0.352 µg·h ml-1 ). Percent decrease in ANC at nadir related to fu·AUC, and was dependent on baseline ANC. CONCLUSION: Regardless of ageing, serum level of AAG determines docetaxel unbound exposure and related dose-limiting toxicity. Serum AAG level and ANC at baseline appear to be predictive of neutropenia for patients of all ages following the administration of docetaxel.

Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study.

BACKGROUND: S-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-fluorouracil, 5-FU), 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. As renal dysfunction is known to increase exposure of 5-FU following S-1 administration, the incidence of severe adverse reactions is increased in patients with impaired renal function. However, no reliable information on its dose modification for patients with renal dysfunction has been provided. METHODS: We conducted a prospective pharmacokinetic study to develop an S-1 dosage formula based on renal function. Sixteen cancer patients with various degrees of renal function received a single dose of S-1 at 40 mg/m(2). A series of blood samples were collected at predefined times within 24 h to assess the plasma concentration profiles of 5-FU, 5-chloro-2,4-dihydroxypyridine, and tegafur. A mathematical model for the relationship between renal function and exposure of 5-FU was constructed by a population pharmacokinetic analysis. RESULTS: The clearance of 5-FU following S-1 administration was related to body surface area and creatinine clearance in the range 15.9-108.8 mL/min as estimated by the Cockcroft-Gault equation. The S-1 dosage formula was derived as follows:[Formula: see text]where AUC is the area under the concentration-time curve, CLcr is creatinine clearance, and BSA is body surface area. The recommended daily doses of S-1 in Asia and Europe were also proposed as nomograms according to exposure matching to the previously reported area under the concentration-time curve of 5-FU, which confirmed the efficacy and toxicity in pivotal registration studies. CONCLUSIONS: We have developed a novel formula for determining the S-1 dosage on the basis of renal function. Further validation is needed to confirm the formula for practical application.

Pharmacokinetics, dynamics and toxicity of docetaxel: Why the Japanese dose differs from the Western dose.

Docetaxel (Taxotere(®)) has been one of the most important chemotherapeutic drugs for cancer treatment since 1996. Although a large number of clinical studies have been conducted in various cancer fields, there is a discrepancy in the standard dose between Japan and Western countries. This article reviews the pharmacokinetic, pharmacodynamic and toxicological profiles of docetaxel, and explains why there exists an ethnic difference in dose, and further discusses which direction we should go forward to solve this problem. The original recommended dose was 100 mg/m(2) every 3 weeks in US and European populations, while a Japanese phase I study suggested the recommended dose as 60 mg/m(2) every 3 weeks. A prospective population pharmacokinetic analysis of docetaxel conducted in both the USA/Europe and Japan, indicated an absence of ethnic difference in the pharmacokinetics. Both analyses demonstrated that docetaxel clearance is related to α1-acid glycoprotein level, hepatic function, age and body surface area. The relationship was observed between increasing docetaxel dose and increased tumor response rates across the dose range of 60 to 100 mg/m(2). The area under the serum concentration time curve (AUC) of docetaxel at the first cycle was significantly related to time to progression. Hematological toxicities were well correlated with the AUC of docetaxel, and severe hematological toxicities were more frequently observed in Japanese patients treated with 60 mg/m(2), compared to the US/European patients treated with 75-100 mg/m(2) dose. The Japanese population seems more susceptible to the toxicity of docetaxel. A docetaxel dose of 75 mg/m(2) is now standard not only in global trials but also in recent Japanese trials. Although the optimal dose of docetaxel is still unclear, we need to continue to seek the appropriate dose of docetaxel depending on patient status and the goals of chemotherapy.

[The survey for anti-emetic guideline by using questioner].

BACKGROUND: Japan Society of Clinical Oncology published a guideline for anti-emetic therapy two years ago. This guideline was a first evidence based guideline of anti-emetic treatment for the patients who received chemotherapy in Japan. To investigate a current situation of anti-emetic treatment in Japan, we analyzed the data from nationwide questionnaire. MATERIAL: Questionnaire analysis; From June 2012 to August 2012, we gave 24 questionnaires on the Japan Society of Clinical Oncology Website and collected the response from the member of 5 major academic oncology societies. The questionnaires included degree of recognition, penetration, usefulness, problems and user type of medial stuff for the anti-emetic guideline published by (JSCO). RESULTS: Questionnaire; 1,529 medical stuff responded to our questionnaire. 1,308 (85.5%) stuffs recognized JSCO guidelines, 586 (51%) had regard for guideline and 489 (42.6%) referred to the guideline. 899 (78.3%) changed their practice in clinic to recommended practice by the guideline. But 385 (33.5%) complained high medical cost of recommended anti-emetic therapy. CONCLUSIONS: Degree of recognition and penetration of our guideline for anti-emetic therapy were very high in Japan.

[Pharmacokinetic issues on cancer pharmacotherapy].

Efficacy of cancer pharmacotherapy depends upon drug exposure to the body and responsiveness of the tumor to the drug treatment. Drug exposure is determined by pharmacokinetics and dose, whereas responsiveness is intrinsically variable by tumor heterogeneity. Molecular targeting drugs are used as promising therapy for cancers, and most of them are coupled with particular diagnostics which can predict responders and non-responders before treatment. On the other hand, lower drug exposure to the body can lead to insufficient efficacy. A number of important evidences have been published recently on exposure-response relationships for molecular targeting drugs including monoclonal antibodies and small molecules. In this chapter, two examples are presented; anti-HER2 antibody and tyrosine kinase inhibitor. Patients with the lowest trough concentrations of trastuzumab in cycle 1 showed shorter overall survival in metastatic gastric cancer study. Efficacy of imatinib in chronic myelogenous leukemia depended on plasma concentration of imatinib, and therapeutic drug monitoring (TDM) of imatinib is expected to improve the therapeutic outcome in CML.

A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese.

Although many association studies of polymorphisms in candidate genes with the clinical outcomes of breast cancer patients receiving adjuvant tamoxifen therapy have been reported, genetic factors determining individual response to tamoxifen are not fully understood. To identify genetic polymorphisms associated with clinical outcomes of patients with tamoxifen treatment, we conducted a genome-wide association study (GWAS). We studied 462 Japanese patients with hormone receptor-positive, invasive breast cancer receiving adjuvant tamoxifen therapy. Of them, 240 patients were analyzed by genome-wide genotyping using the Illumina Human610-Quad BeadChips, and two independent sets of 105 and 117 cases were used for replication studies. In the GWAS, we detected significant associations with recurrence-free survival at 15 single-nucleotide polymorphisms (SNPs) on nine chromosomal loci (1p31, 1q41, 5q33, 7p11, 10q22, 12q13, 13q22, 18q12 and 19p13) that satisfied a genome-wide significant threshold (log-rank P= 2.87 × 10(-9)-9.41 × 10(-8)). Among them, rs10509373 in C10orf11 gene on 10q22 was significantly associated with recurrence-free survival in the replication study (log-rank P= 2.02 × 10(-4)) and a combined analysis indicated a strong association of this SNP with recurrence-free survival in breast cancer patients treated with tamoxifen (log-rank P= 1.26 × 10(-10)). Hazard ratio per C allele of rs10509373 was 4.51 [95% confidence interval (CI), 2.72-7.51; P= 6.29 × 10(-9)]. In a combined analysis of rs10509373 genotype with previously identified genetic makers, CYP2D6 and ABCC2, the number of risk alleles of these three genes had cumulative effects on recurrence-free survival among 345 patients receiving tamoxifen monotherapy (log-rank P= 2.28 × 10(-12)). In conclusion, we identified a novel locus associated with recurrence-free survival in Japanese breast cancer patients receiving adjuvant tamoxifen therapy.

Sunitinib-induced severe toxicities in a Japanese patient with the ABCG2 421 AA genotype.

BACKGROUND: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor that acts against receptors for vascular endothelial growth factor and platelet-derived growth factor. Common toxicities of sunitinib treatment include hypertension, hand-foot syndrome, vomiting, and diarrhea, and the proportion of grade 3 or 4 adverse events relating to sunitinib treatment range from 1 to 13% for all categories. It is reported that increased exposure to sunitinib is associated with improved clinical outcomes but also carries an increased risk of adverse effects. CASE PRESENTATION: A 73-year-old Japanese woman with metastatic renal cell carcinoma who received sunitinib at a dose of 50 mg once daily suffered a high-grade fever on day 11 of treatment. Sunitinib treatment was discontinued on day 12; however, severe thrombocytopenia and transaminase elevation occurred and persisted more than a week. Additionally, severe hypoxia due to pleural effusion and pulmonary edema developed despite immediate discontinuation of sunitinib. On day 14, three days after the discontinuation of sunitinib, the plasma concentrations of sunitinib and its major active metabolite N-desethyl sunitinib (SU12662) were extremely high (131.9 ng/mL and 28.4 ng/mL, respectively). By day 25, all toxicities had resolved, and a CT scan revealed marked tumor shrinkage. Genotyping of seven single-nucleotide polymorphisms that are potentially relevant to the pharmacokinetics of sunitinib was performed. The patient's genotype of ABCG2 (ATP-binding cassette, sub-family G (WHITE), member 2) 421C > A was homozygous for the variant allele (AA), which was reported to be associated with high exposure to sunitinib. Therefore, we speculated that the extremely high plasma concentrations of sunitinib and SU12662 caused by the ABCG2 421 AA genotype might have resulted in severe toxicities to the patient. CONCLUSION: The minor allele frequencies of ABCG2 421C > A are approximately three-fold higher in Asians than in Caucasians. Our report suggests that pharmacogenetic factors should be considered when severe and rapid-onset adverse drug reactions occur in Asian patients, including Japanese treated with sunitinib.

Forced expression of S100A10 reduces sensitivity to oxaliplatin in colorectal cancer cells.

BACKGROUND: Individual responses to oxaliplatin (L-OHP)-based chemotherapy remain unpredictable. Our recent proteomics studies have demonstrated that intracellular protein expression levels of S100A10 are significantly correlated with the sensitivity of colorectal cancer (CRC) cells to L-OHP, but not 5-FU, suggesting that S100A10 is a candidate predictive marker for the response to L-OHP. In this study, we investigated whether S100A10 is involved in L-OHP sensitivity or not. RESULTS: Forced expression of S100A10 in COLO-320 CRC cells significantly increased the 50% inhibitory concentration (IC50) for L-OHP (P = 0.003), but did not change that for 5-FU, indicating that S100A10 is more specific to L-OHP than 5-FU. Silencing of the S100A10 gene showed no apparent effect on sensitivity to L-OHP in HT29 cells. Silencing of the annexin A2 (a binding partner of S100A10) gene alone downregulated both annexin A2 and S100A10 protein levels, with no change in S100A10 gene expression. However, original levels of intact S100A10 protein in CRC cells positively correlated with S100A10 mRNA levels (P = 0.002, R = 0.91). CONCLUSIONS: The present results have shown that protein expression of S100A10 was associated with resistance to L-OHP, but not 5-FU, supporting the hypothesis that S100A10 expression may predict L-OHP sensitivity. Thus, our present study provides basic findings to support that S100A10 expression can be used as a predictive marker for tumor sensitivity to L-OHP.

Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk: a milk concentration-based prediction model.

AIMS: Population pharmacokinetic (pop PK) modelling can be used for PK assessment of drugs in breast milk. However, complex mechanistic modelling of a parent and an active metabolite using both blood and milk samples is challenging. We aimed to develop a simple predictive pop PK model for milk concentration-time profiles of a parent and a metabolite, using data on fluoxetine (FX) and its active metabolite, norfluoxetine (NFX), in milk. METHODS: Using a previously published data set of drug concentrations in milk from 25 women treated with FX, a pop PK model predictive of milk concentration-time profiles of FX and NFX was developed. Simulation was performed with the model to generate FX and NFX concentration-time profiles in milk of 1000 mothers. This milk concentration-based pop PK model was compared with the previously validated plasma/milk concentration-based pop PK model of FX. RESULTS: Milk FX and NFX concentration-time profiles were described reasonably well by a one compartment model with a FX-to-NFX conversion coefficient. Median values of the simulated relative infant dose on a weight basis (sRID: weight-adjusted daily doses of FX and NFX through breastmilk to the infant, expressed as a fraction of therapeutic FX daily dose per body weight) were 0.028 for FX and 0.029 for NFX. The FX sRID estimates were consistent with those of the plasma/milk-based pop PK model. CONCLUSIONS: A predictive pop PK model based on only milk concentrations can be developed for simultaneous estimation of milk concentration-time profiles of a parent (FX) and an active metabolite (NFX).

Clinical practice guidelines for therapeutic drug monitoring of arbekacin: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring.

Arbekacin (ABK) was approved and widely used in Japan for treatment of patients infected with MRSA, and TDM was introduced in clinical practice. The Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring decided to develop a clinical practice guidelines for TDM of ABK for the following reasons. First, although the daily dose of 150-200 mg was approved in Japan, recent PK-PD studies revealed that higher serum concentration is required to achieve better clinical efficacy and several findings concerning the usefulness of higher dosage regimen have obtained recently. Second, although maximal concentrations that obtained immediately after the end of administration (Cmax) was generally adopted, the serum concentration at 1 h after initiation of administration [peak serum concentration (Cpeak)] proved to be more suitable as an efficacy indicator of aminoglycosides. Lastly, as ABK is approved only in Japan, no international practice guideline for TDM has not been available in ABK to date. This guideline evaluated the scientific data associated with serum ABK monitoring and provided recommendations based on the available evidence. Potential limitations of this guideline, however, include the findings that few prospective clinical trials of TDM of ABK are available in the treatment of MRSA infections and that most of the published literature describes observational studies.

Polymorphisms in the UGT1A1 gene predict adverse effects of irinotecan in the treatment of gynecologic cancer in Japanese patients.

Irinotecan is a key chemotherapeutic drug used to treat many tumors, including cervical and ovarian cancers; however, irinotecan can cause toxicity, particularly in the presence of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphisms, which are associated with reduced enzyme activity. Here, we investigated the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28) and their relationships with irinotecan-induced adverse events in patients with gynecologic cancer, who are treated with lower doses of irinotecan than patients with other types of solid tumors. Fifty-three female patients treated with irinotecan and 362 female patients not treated with irinotecan were screened for UGT1A1*6, UGT1A1*27 and UGT1A1*28. Homozygosity for UGT1A1*6 or heterozygosity for UGT1A1*6/*28 was associated with a high risk of severe absolute neutrophil count decrease or diarrhea (odds ratios: 16.03 and 31.33, respectively). In contrast, serum bilirubin levels were not associated with irinotecan toxicity. Homozygosity for UGT1A1*6/*6 and heterozygosity for UGT1A1*6/*28 were associated with an increased risk of absolute neutrophil count and/or diarrhea in Japanese gynecologic cancer patients, despite the lower doses of irinotecan used in these patients. UGT1A1*6 and UGT1A1*28 are potential predictors of severe absolute neutrophil decrease and diarrhea caused by low-dose irinotecan in gynecologic cancer patients.

Population pharmacokinetics and pharmacodynamics of sitafloxacin in patients with community-acquired respiratory tract infections.

An optimal dosage regimen of sitafloxacin was considered based on a pharmacokinetics and pharmacodynamics (PK-PD) analysis in patients with community-acquired respiratory tract infections (RTI). A population pharmacokinetic analysis of sitafloxacin was conducted using clinical data of five clinical pharmacology studies and one clinical PK-PD study in patients with RTIs. The pharmacokinetic parameters in individual patients were estimated by the Bayesian method to examine any correlation between pharmacokinetics and bacteriological efficacy. Efficacy data were obtained from the clinical PK-PD study, in which 50 or 100 mg sitafloxacin was administered twice daily for 7 days. In addition, an efficacy was simulated for a hypothetical dose regimen of 100 mg once daily. The fAUC(0-24h)/MIC and the fC max/MIC of sitafloxacin at a dose of 50 mg twice daily were 117.5 ± 78.0 and 7.3 ± 4.7 (mean ± SD), respectively. As a result of the univariate logistic regression analysis, the larger the value of fAUC(0-24h)/MIC or fC max/MIC becomes, the higher the bacteriological efficacies. The eradication rates for fAUC(0-24h)/MIC ≥ 30 and for fC max/MIC ≥ 2 were 96.4% and 96.3%, respectively. The PK-PD target values of sitafloxacin for the treatment of mild to moderate RTIs were considered to be fAUC(0-24h)/MIC ≥ 30 and fC max/MIC ≥ 2. The PK-PD parameters at the regimen of 50 or 100 mg twice daily in patients with RTIs reached the target values. Furthermore, a 100 mg once-daily regimen was expected to show similar efficacy based on the PK-PD simulations.

Clinical dose findings of sitafloxacin treatment: pharmacokinetic-pharmacodynamic analysis of two clinical trial results for community-acquired respiratory tract infections.

The adequacy of sitafloxacin clinical dose regimens was assessed by comparing the efficacy of the administration of 100 mg sitafloxacin once daily (100 mg qd group) and 50 mg sitafloxacin twice daily (50 mg bid group). Patients with respiratory tract infections caused by pneumococci were orally treated with sitafloxacin (100 mg qd or 50 mg bid) for 7 days. The clinical efficacy, pneumococci eradication rate, safety, and pharmacokinetic and pharmacodynamic indices of the two groups were then assessed. The clinical efficacy was 93.5 % in both groups. The pneumococci eradication rate was 98.2 % in the 100 mg qd group and 92.7 % in the 50 mg bid group. The mean of the free AUC0-24h divided by the minimum inhibitory concentration (MIC) (fAUC0-24h/MIC) did not differ significantly between the 100 mg qd (103.24) and the 50 mg bid groups (105.25). The mean of the free C peak divided by the MIC (fC peak/MIC) was higher in the 100 mg qd group (10.19) than in the 50 mg bid group (6.53). The pathogen eradication rate was 98.9 % (89/90) when the fAUC0-24h/MIC was greater than 30, and the eradication rate was 98.9 % (89/90) when the fC peak/MIC was greater than 2. The incidences of adverse drug reactions were 33.7 % in the 100 mg qd group and 40.4 % in the 50 mg bid group. No obvious differences in the efficacy and safety were observed between the dosage groups. For cases in which a sufficiently high C peak is necessary to ensure the susceptibility of the pathogens to the drug, 100 mg sitafloxacin once daily should be administered.

Clinical and bacteriological efficacies of sitafloxacin against community-acquired pneumonia caused by Streptococcus pneumoniae: nested cohort within a multicenter clinical trial.

We evaluated the clinical and bacteriological efficacy of oral sitafloxacin (STFX) in clinically diagnosed community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae. Additionally, we cultured these patient samples to test the minimal inhibitory concentrations (MICs) of levofloxacin (LVFX), moxifloxacin (MFLX), STFX, and penicillin G (PCG), as well as identified mutations in the quinolone resistance determinant regions (QRDRs) in LVFX-resistant strains. This study is a nested cohort from a prospective, multicenter clinical trial consisting of 139 patients with community-acquired pneumonia (CAP), from which 72 were included in this study. After diagnosis of CAP caused by S. pneumoniae, STFX (50 mg twice daily, or 100 mg once daily) was orally administered for 7 days. Sixty-five patient sputum samples were then cultured for MIC analysis. In a LVFX-resistant strain that was identified, mutations in the QRDRs of the gyrA, gyrB, parC, and parE genes were examined. Of 72 patients eligible for this study, S. pneumoniae was successfully cultured from the sputum of 65 patients, and only 7 patients were diagnosed by urinary antigen only. Clinical improvement of CAP was obtained in 65 of the 69 clinically evaluable patients (65/69, 94.2 %). Eradication of S. pneumoniae was observed in 62 patients of the 65 bacteriologically evaluable patients (62/65, 95.4 %). Additionally, STFX showed the lowest MIC distribution compared with LVFX, MFLX, and PCG, and no major adverse reactions were observed. STFX treatment in patients with CAP caused by S. pneumoniae was found to be highly effective both clinically (94.2 %) and bacteriologically (95.4 %).