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BACKGROUND A Phase 2, dose-ranging study of bococizumab, a monoclonal anti-proprotein convertase subtilisin/kexin type 9 antibody, was conducted in Japanese subjects to assess its efficacy, safety, and tolerability in this population.Methods and Results:Two different hypercholesterolemic study populations were enrolled concurrently: Japanese subjects with uncontrolled low-density lipoprotein cholesterol (LDL-C) despite atorvastatin treatment (LDL-C ≥100 mg/dL; n=121), and Japanese subjects naive to lipid-lowering agents and with LDL-C ≥130 mg/dL (n=97). Subjects within each study population were randomized to bococizumab 50, 100, or 150 mg, or placebo, q14D for 16 weeks; an open-label ezetimibe 10 mg daily arm was also included for the atorvastatin-treated population. Significant, dose-dependent reductions in fasting LDL-C levels were observed in all bococizumab arms of both study populations at Weeks 12 and 16 (adjusted mean percent changes from baseline: 54.1-76.7% for atorvastatin-treated subjects and 47.7-66.8% for treatment-naive subjects; P

Summary Background Dacomitinib (PF-00299804) is an oral, irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases. Methods This phase I, open-label, dose-escalation study (clinicaltrials.gov: NCT00783328) primarily evaluated the safety and tolerability of dacomitinib by dose-limiting toxicity (DLT), and determined the clinically recommended phase II dose (RP2D) in Japanese patients with advanced solid tumors. Dacomitinib was administered orally at three dose levels (15, 30, or 45 mg once daily [QD]). Patients initially received a single dose, and after 9 days of follow-up, continuously QD in 21-day cycles. Endpoints included pharmacokinetics (PK) and antitumor activity. Results Thirteen patients were assigned to the three dose levels (15 mg cohort: n = 3; 30 mg cohort: n = 3; 45 mg cohort: n = 7) according to a traditional ‘3 + 3’ design. None of the treated patients experienced a DLT. Toxicities were manageable and similar in type to those observed in other studies. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Of 13 evaluable patients, one with NSCLC (adenocarcinoma) had a partial response and nine patients had stable disease. Conclusions Dacomitinib 45 mg QD was defined as the RP2D and demonstrated preliminary activity in Japanese patients with advanced solid tumors.

Axitinib (AG-013736) is an oral, selective and potent inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, 2 and 3. This phase II study investigated axitinib efficacy, safety and biomarkers in Japanese patients with cytokine-refractory metastatic renal cell carcinoma (mRCC).In an open-label, multicentre study, 64 patients received an axitinib starting dose of 5mg twice daily.Objective response rate (ORR) was 50.0% and median progression-free survival (PFS) was 11.0 months per independent review committee. Common treatment-related adverse events were hypertension (84%; 70% grade ≥3), hand-foot syndrome (75%; 22% grade ≥3) and diarrhoea (64%; 5% grade ≥3). Eighteen patients (28%) developed proteinuria ≥2g/24h and required dose reduction or treatment interruption/discontinuation. Proteinuria was a major cause for treatment discontinuation. Baseline urine protein levels were associated with development of proteinuria ≥2g/24h (hazard ratio [HR]=5.457, P=0.0035 in patients with baseline proteinuria ≥1+ versus1+). Baseline urine protein levels correlated more strongly with axitinib-related proteinuria than other baseline renal function test values or blood pressure. Patients with greater decreases in soluble VEGFR-2 concentrations had significantly higher ORR and longer PFS than those with smaller decreases (ORR: 64.5% versus 37.5%, P=0.045; median PFS: 12.9 months versus 9.2 months, HR=0.42, P=0.01).Axitinib showed significant antitumour activity and was well tolerated in Japanese mRCC patients. Baseline proteinuria and soluble VEGFR-2 levels may be key indicators of axitinib-induced proteinuria and efficacy, respectively.

In new drug development, demonstrating a clinically important effect of the new drug is a key element of efficacy evaluations instead of simply showing a statistical significance. However, approaches to demonstrate clinically important effects are unclear and not well recognized among many investigators and sponsors. The minimal clinically important change from baseline (MCIC) and minimal clinically important difference between groups (MCID) are used to assess the clinically important effect. We state the roles of MCIC and MCID in each phase of new drug development and common approaches to establishing MCIC and MCID. Furthermore, we provide some common approaches on how to practically compare the clinical trial results with the MCIC and MCID and interpret the clinical importance from applications in new drug development. We also suggest incorporating the clinical importance at the planning phase of trials.

Multivariate statistical analysis has and will continue to play an important role in the development of pharmaceutical products. Although many examples have been reported, few have applied multivariate statistical analysis to the overall manufacturing process. In this study, the model drug core tablets were manufactured under different conditions, and the challenge to understand the cause-and-effect relationship between process parameters and response variables was addressed by applying three different multivariate statistical methods. It was confirmed that conventional multivariate statistical methods were able to extract the process parameters (granulation time, drying temperature, blending time, and compression force) that affected both the average and the variance of the response variables (hardness, content uniformity, and dissolution) with a science-based rationale. In order to overcome the multiobjective optimization problem among the response variables, an advanced multivariate statistical method was also applied. It was confirmed that the mathematical models of response variables were determined with sufficiently high accuracy and the optimal levels of both process parameters and response variables were determined with high reliability, which provided a more profound understanding of the process. These methods enable us to develop pharmaceutical products more efficiently and accurately.

Here, we describe a combination approach using Two Calibration-Free Methods with reflectance near-infrared (TCFM-NIR), which involves detecting end-points for active pharmaceutical ingredients (APIs) blending by simultaneously monitoring specific NIR peak intensity of APIs and calculating moving block standard deviation (MBSD). After determining the specific NIR peak range of nicaldipine hydrochloride, conditions for TCFM-NIR were established by monitoring the differential intensity of the second peak (1136 nm) while MBSD was calculated from the NIR peak intensity between 1100 and 1150 nm. In comparison with the validated reference method of UV–VIS spectroscopy, which is particularly destructive, TCFM-NIR was found to be useful in detecting end-points for blending of nicaldipine hydrochloride. TCFM-NIR monitors two important factors for estimation of blend uniformity: API concentration, using specific NIR peak intensity for APIs, and blend homogeneity, using MBSD. Also, the conditions of TCFM-NIR were confirmed to be adequate by using Partial Least Square (PLS). Further, simultaneously monitoring these two blend uniformity factors is more useful in preventing estimation errors for nondestructive monitoring of blend homogeneity than monitoring only one factor, as with NIR spectroscopy.

The goal of this study is to develop a novel sustained-release (SR) system for poorly water-soluble drugs by applying solid dispersion (SD) technique for improving the solubility. The developed SR system, disintegration-controlled matrix tablet (DCMT), consists of hydrogenated soybean oil (HSO) as wax and SD granules containing low-substituted hydroxypropylcellulose (L-HPC) as a disintegrant. In this study, nilvadipine (NiD) was chosen as a model compound. Sustained-release profiles of NiD from DCMT were identically controlled in several dissolution mediums in spite of varying pH and agitation speed. The release of NiD from DCMT was sustained more effectively by increasing the amount of wax or by decreasing the amount of disintegrant, and supersaturation of NiD was achieved without any re-crystallization in dissolution medium. The release rate of NiD from DCMT was controlled by the disintegration rate of tablet. The release profile of NiD was described by the Hixson-Crowell's model better than zero-order kinetics, first-order kinetics and Higuchi's model, which supports that the release of NiD from DCMT is regulated by the disintegration of the tablet. From this study, it was clarified that DCMT was one of the promising SR systems applying SD for the poorly water-soluble drugs.

Buserelin acetate, a gonadotropin-releasing hormone agonist (GnRH agonist), is widely used as a therapeutic agent for myoma uteri (MU). We investigated the standardtreatments for MU before and after the introduction of buserelin therapy by questionnaire given to gynecologists and according to official statistics. Based on our study, an economic analysis (cost analysis) was made using a tree model. The results indicated that: 1) the standard treatment for MU underwent a change after buserelin therapy became available, and 2) the therapeutic cost per patient with MU increased by a factor of 1.1-1.2. Finally, we discuss the justifiability of this cost increment based on the opinions of gynecologists who returned the questionnaire.

混練り過程により構造の安定化状態の異なるカーボンブラック複合NR加硫物について三次元応力疲労試験を行い, 疲労における構造, 物性の変化と層状異方性構造の形成, 及び疲労破壊形態に与える影響について検討した. その結果, 混練り過程の進行により, 安定構造を形成した系ほど疲労による構造, 物性変化は少なく, カーボンブラックの層状配向, 及びゴム分子鎖の配向による層状異方性構造の形成は減少する. また, 疲労破壊形態は, 混練りの進行により, 周方向に平行な層状はく離破壊から遂次, 周方向に垂直な方向の破壊に転移する.

A novel sustained-release (SR) system, disintegration-controlled matrix tablet (DCMT), was developed for poorly water-soluble drugs. DCMT, consisting of wax and solid dispersion (SD) granules containing a disintegrant, could control the release of nilvadipine (NiD), a model compound, by its disintegration. In the present study, two DCMTs (DCMT-1 and DCMT-2) with different release rates of NiD were orally administered to beagle dogs, and in vivo absorption of NiD from DCMTs was compared with that from immediate-release (IR) tablets. DCMTs successfully sustained the absorption of NiD longer than IR tablets, while they did not decrease the bioavailability of NiD. DCMT-2, providing the slower release of NiD than DCMT-1, prolonged the absorption longer than DCMT-1. In vivo absorption profiles of NiD from DCMTs were significantly correlated with in vitro release profiles, suggesting that the release property from DCMTs would maintain regardless of the change in physiological condition through the gastrointestinal tract. Furthermore, the food intake did not affect the absorption of NiD after oral administration of DCMT-2. The present results strongly indicate that the DCMT system would be a promising SR system, which could improve the solubility and sustain the absorption of poorly water-soluble drugs.

In order to establish a rapid and accurate in vitro drug assay method, we have applied the avidin D-biotin complex enzyme-linked immunosorbent assay using 5-bromodeoxyuridine (BrdU-ELISA) in the microplate cultures. To study the rat gastric cell proliferation, BrdU was treated with the cultured cells, and then, the rate of the uptake of BrdU into the cells was measured using an anti-BrdU antibody. Prostaglandin E2 (PGE2) (0.01, 0.1 and 1 microM), cimetidine (1, 3 and 10 microM) and omeprazole (3 and 10 microM) were shown to induce the significant proliferation of rat gastric cultured cells. Indomethacin (IND) (0.1, 0.25 and 0.5 mM) caused a dose-dependent inhibition of the proliferation of the cultured cells proliferation. The result obtained by the BrdU-ELISA method was more reproducible than that by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay method. PGE2 (0.01, 0.1 and 1 microM), cimetidine (1, 3 and 10 microM), omeprazole (1, 3 and 10 microM), cetraxate (3, 10 and 30 microM) and famotidine (30 microM), but not sofalcone and NC-1300-O-3, have been shown to protect significantly rat gastric cultured cells against IND-induced damage in vitro. From these results, it might be suggested that this BrdU-ELISA method is useful for investigating the effect of drugs on the proliferation of rat gastric cultured cells.

工業上最も広範に用いられている変圧変速沢過に関して, 本報ではスラリーの圧縮透過または定圧沢過データに基づき, 使用ポンブの吐出し特性から変圧変速沢過々程の沢液量対沢過時間の関係などを推定する解析的方法について述べた。さらに, 二種類の圧縮性スラリーについて渦巻ポンブを用いた変圧変速沢過実験を行なって, これら推定値と実測値とがかなり良い精度で一致することを報告した。

Here, we describe a nondestructive approach using terahertz wave to detect crack initiation in a film-coated layer on a drug tablet. During scale-up and scale-down of the film coating process, differences in film density and gaps between the film-coated layer and the uncoated tablet were generated due to differences in film coating process parameters, such as the tablet-filling rate in the coating machine, spray pressure, and gas–liquid ratio etc. Tablets using the PEO/PEG formulation were employed as uncoated tablets. We found that heat and humidity caused tablets to swell, thereby breaking the film-coated layer. Using our novel approach with terahertz wave nondestructively detect film surface density (FSD) and interface density differences (IDDs) between the film-coated layer and an uncoated tablet. We also found that a reduced FSD and IDD between the film-coated layer and uncoated tablet increased the risk of crack initiation in the film-coated layer, thereby enabling us to nondestructively predict initiation of cracks in the film-coated layer. Using this method, crack initiation can be nondestructively assessed in swelling tablets after the film coating process without conducting accelerated stability tests, and film coating process parameters during scale-up and scale-down studies can be appropriately established.