PurposeThiotepa is used in high-dose chemotherapy (HDT) before autologous hematopoietic stem cell transplantation (HSCT) to treat solid tumors and hematological malignancies. This Phase 1 study was conducted to establish the pharmacokinetics (PK) of thiotepa in a Japanese population.MethodsHDT/HSCT was performed in pediatric patients (≥ 2 years) with solid tumors or brain tumors (thiotepa 200 mg/m2/day IV-infused over 24 h on HSCT Days − 12, − 11, − 5, and − 4 and melphalan 70 mg/m2/day IV-infused over 1 h on Days − 11, − 5, and − 4) and adult patients (≥ 16 years) with malignant lymphoma (thiotepa 200 mg/m2/day 2-h IV-infusion on HSCT Days − 4 and − 3 plus busulfan 0.8 mg/kg 2-h IV-infusion every 6 h from HSCT Days − 8 to − 5). Pharmacokinetics of thiotepa were assessed following initial dose. Safety and efficacy were also evaluated.ResultsNine pediatric and 10 adult patients were enrolled. Mean volume of distribution (Vz) of thiotepa normalized with body surface area (BSA) was lower for pediatric patients (16.4 L/m2) compared with adult patients (26.4 L/m2) as expected due to the higher specific surface area of children. Clearance and biological half-life were similar between pediatric and adult patients. Two serious adverse events (cardiac arrest and pulmonary edema) were observed. Survival rate (Day 100 post-HSCT) was 77.8% (95% CI 36.5–93.9%) for pediatric patients and 100% for adult patients.ConclusionThiotepa elimination was comparable in pediatric and adult patients with cancer. Lower Vz in pediatric compared with adult patients was expected. HDT with thiotepa prior to autologous HSCT was well tolerated.Study registrationJapic CTI-163433.Electronic supplementary materialThe online version of this article (10.1007/s00280-019-03914-2) contains supplementary material, which is available to authorized users.

Hydrogen peroxide was cytotoxic to the small intestine epithelial cell line, IEC-6, as judged from an MTT assay and the release of lactate dehydrogenase. The glutathione S-transferase and thioredoxin reductase activities and SH content decreased dose-dependently with H2O2, but thioredoxin activity increased at low H2O2 concentrations. In addition, the increase in thioredoxin activity was time-dependent during the initial stages of oxidative stress. A reverse transcription-polymerase chain reaction (RT-PCR) amplification also showed that the mRNA content in IEC-6 cells increased time-dependently at 0.25 mM H2O2. These results indicate that cellular oxidative shock causes an increase in the activity of thioredoxin, which is involved in the defense mechanism against oxidative stress.

EPI-589 attenuates oxidative stress due to the radical scavenging activity of the reduced form and affects mitochondrial energy metabolism as a substrate of quinone-oxidoreductases. Given the effects of EPI-589 on oxidative stress and mitochondrial dysfunction, EPI-589 shows promise as a potential therapy for patients with amyotrophic lateral sclerosis. This phase 1 study evaluated the safety, tolerability, and pharmacokinetic profiles of EPI-589. Sixty-eight healthy participants were randomly assigned to EPI-589 or placebo. All adverse events were mild or moderate in severity, and no severe adverse events were reported. After single-dose administration under fasting conditions, time to maximum plasma concentration (t max ) occurred 0.25 to 1.00 hour after administration. Both peak plasma concentration (C max ) and area under the plasma concentration-time curve (AUC) were approximately linear with increases in single doses over a dose range of 250-1000 mg. Under fed conditions, the C max decreased to 62.6% of the C max under fasting conditions, the AUC was slightly increased, and the t max was delayed by 1 hour. When EPI-589 was administered daily on days 1 and 7 with twice-daily dosing on days 2 through 6, the plasma trough concentration appeared to reach steady state by day 3. At both doses studied (500 mg twice daily and 750 mg twice daily), C max, t max , and AUC were generally comparable between day 1 and day 7 and between the Japanese and White participants. EPI-589 was well tolerated as a single daily dose up to 1000 mg and as twice-daily doses up to 750 mg, with a linear pharmacokinetic profile.

Minesapride (drug code: DSP-6952) is a potential gastrointestinal prokinetic agent with high selectivity for 5-hydroxytryptamine 4 (5-HT 4) receptor that acts as a partial agonist. Although 5-HT 4 receptor agonists are expected to show efficacy in patients with irritable bowel syndrome with constipation, only tegaserod is available for female patients, with limitations, in the United States. Previously, another 5-HT 4 receptor agonist, cisapride, was widely used for the treatment of upper gastrointestinal diseases, but was withdrawn from the market because of arrhythmia with QT prolongation. Chemically, benzamide is one of the most common structures among 5-HT 4 receptor agonists. Some benzamide derivatives, such as cisapride, are responsible for QT prolongation, while some, such as mosapride, are not. Thus, we planned a thorough QT/QTc study to investigate the effects of minesapride, a newly designed benzamide derivative, on the QT/QTc. This was a randomized, placebo-controlled, 4-arm, 4-period, crossover study conducted in healthy adults, with administration of single oral doses of minesapride (40 mg and 120 mg), placebo, and moxifloxacin in the fasted state. Minesapride and placebo were administered in a double-blind fashion, while the positive control moxifloxacin was administered in an open-label fashion. Japanese subjects (48 total: 24 males and 24 females) were randomized, and 47 subjects completed all treatment periods. A review of other electrocardiographic data revealed that neither therapeutic (40 mg) nor supratherapeutic (120 mg) doses of minesapride were associated with increased risk of prolonged QT interval.

Abstract.In vitro anticancer drug sensitivity assessments have been performed for various types of cancer, and an association with clinical response has been observed. The collagen gel droplet-embedded culture drug sensitivity test (CD-DST) is an in vitro anticancer drug sensitivity test that has recently reported to be useful in oral squamous cell carcinoma (OSCC). CD-DST allows for the analysis of a smaller number of cells compared with other anticancer drug sensitivity tests. The present study reported a successful analysis of anticancer drug sensitivity using CD-DST on cervical lymph node tissue dissected following neoadjuvant chemotherapy from a 55-year-old man with advanced hard palate cancer. Tumor resection and bilateral neck dissection were performed following neoadjuvant chemotherapy (docetaxel + cisplatin + 5-fluorouracil; TPF) for hard palate cancer T2N2cM0. Local recurrence and cervical multiple skin metastasis occurred ~8 months after surgery, and the patient received six doses of cetuximab (C-mab) + cisplatin + 5-fluorouracil (C-mab + PF) administration, which is a type of molecular-targeted therapy. Following the use of the CD-DST method, the clinical response was noted as stable disease following execution of TPF and partial response following execution of C-mab + PF. In addition, low sensitivity by TPF and high sensitivity by C-mab + PF were reported. The CD-DST method reflected the clinical response for the patient, and the results of the current study indicate that CD-DST is a useful tool for selecting chemotherapeutic drugs for patients with OSCC. IntroductionThe recent introduction of the anticancer drug cetuximab [an epidermal growth factor receptor (EGFr) inhibitor: C-mab] as a molecular-targeted therapy for treating head and neck cancers has expanded the scope of anticancer drugs for treating these cancers. However, no biomarkers are currently available that can predict C-mab efficacy against oral squamous cell carcinoma (OSCC); therefore, it is typically administered irrespective of patient sensitivity (1). Hence, we investigated C-mab use with the collagen gel droplet-embedded culture drug sensitivity test (CD-DST). Kobayashi et al (2,3) developed CD-DST which combines the collagen gel droplet culture method, a simple method of three-dimensional (3D) culture that allows a very small number of clinical samples to be tested with a serum-free medium step and quantitative evaluation by image analysis. CD-DST has little effect on non-cancerous cells, allowing accurate measurements of cancerous cells only. This method has been primarily used on tumors of the digestive system (4-6). Compared to such cancers of the primary organs, OSCC and other oral cancers generally have a smaller tumor volume. CD-DST is, therefore, likely to be a suitable method for testing the sensitivity of anticancer drugs on OSCC. However, there is little application of the CD-DST method to OSCC, with no evaluation of molecularly targeted drugs. In the present study, the CD-DST method was performed using a patient biops...