The HLS-14 demonstrated adequate reliability and validity as a generic HL measure for Japanese adults. This scale can be utilized for measuring functional, communicative, and critical HL in the clinical and public health contexts.

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The gap between Japan and both the United States (US) and the European Union (EU) with regard to access to new drugs is becoming a major issue in Japan. We analyzed the time lags involved in new drug application (NDA) and biological license application submissions in Japan, the US, and the EU in order to identify the causes of delayed access. The time lag related to submission of applications ("submission lag") was longer for in-licensed products and for non-Japanese companies. Factors related to costs of clinical studies and potential volumes of sales were not associated with the submission lag. A bridging strategy (extrapolative use of foreign clinical data in the clinical data package based on International Conference on Harmonisation guideline E5) seemed to reduce submission lag, but the association between the two diminished when the cause-and-effect relationship was specifically investigated. These results suggest that multinational companies are likely to place more emphasis on the choice of development strategies that successfully lead to their goal rather than on direct costs and expected sales when deciding to introduce their pharmaceutical products in Japan. Our findings indicate that the clinical development guidances that helps pharmaceutical companies decide on investment and strategies are also the key to narrowing the gap in access to new drugs.

Japan is unique among Asian countries in that it requires inclusion of substantial domestic clinical trial data in new drug application data packages. Some question the need for this and call for globalization of approved doses. The current study examines international differences in maximum daily dose of drugs approved in Japan between 2001 and 2007, and for all cardiovascular system (CVS) and central nervous system (CNS) drugs marketed in Japan. For 32% of the drugs approved in Japan between 2001 and 2007, the maximum recommended dose in the United States was > or =2 times higher than the maximum dose approved in Japan. Dose differences were rare for antitumor and antiviral drugs and also for priority-review and orphan drugs. Of all the price-listed CVS drugs currently available in Japan, 65% had maximum doses that were > or =2 times higher in the Netherlands than in Japan; similarly, 57% of the drugs had maximum doses that were > or =2 times higher in the United States than in Japan. For CNS drugs, these figures were 32% (the Netherlands) and 29% (United States). These results underscore the necessity to carry out quantitative analyses to determine the causes of these differences.

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ABSTRACT:Predicting major clearance pathways of drugs is important in understanding their pharmacokinetic properties in clinical use, such as drug-drug interactions and genetic polymorphisms, and their subsequent pharmacological/toxicological effects. In this study, we established an in silico classification method to predict the major clearance pathways of drugs by identifying the boundaries of physicochemical parameters in empirical decisions for each clearance pathway. It requires only four physicochemical parameters [charge, molecular weight (MW), lipophilicity (log D), and protein unbound fraction in plasma (f up )] that were predicted from their molecular structures without performing any benchwork experiments. The training dataset consisted of 141 approved drugs whose major clearance pathways were determined to be metabolism by CYP3A4, CYP2C9, and CYP2D6, hepatic uptake by OATPs, or renal excretion in an unchanged form. After grouping by charge, each drug was plotted in a three-dimensional space according to three axes of MW, log D, and f up . Then, rectangular boxes for each clearance pathway were drawn mathematically under the criterion of "maximizing F value (harmonic mean of precision and recall) with minimum volume," yielding to a precision of 88%, which was confirmed through two types of validation: leave-one-out method and validation using a new dataset. With further modification toward multiple pathways and/or other pathways, not only would this in silico classification system be useful for industrial scientists at the early stage of drug development, which can lead to the selection of candidate compounds with optimal pharmacokinetic properties, but also for regulators in evaluating new drugs and giving regulatory requirements that are pharmacokinetically reasonable.Once a drug enters the human body, it undergoes detoxification by the complementary functions of a wide variety of metabolic enzymes and transporters, resulting in numerous clearance pathways such as urinary elimination through glomerular filtration and renal tubular excretion, passive diffusion into the liver followed by hepatic metabolism by cytochrome P450 (P450) enzymes to an inactive metabolite, or hepatic uptake by transporters followed by excretion into the bile and then into the feces. The major clearance pathway of drugs is one of the most important pharmacokinetic features relevant for its clinical use. Understanding the major clearance pathways would enable prediction of the changes in the systemic exposure of a drug caused by drug-drug interactions or genetic polymorphisms of enzymes and transporters. Some drugs have been withdrawn from the market owing to fatal side effects that often occurred by drug-drug interactions of their major clearance pathways, such as cerivastatin and its interaction with gemfibrozil (Shitara et al., 2004). The withdrawals might have been avoided by clarifying their major clearance pathways in the human body and by recognizing the severity of drug interactions, leading to better decision-making b...

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This theoretical method well estimated the quantitative changes in pharmacokinetics of CYP2C9 substrates in subjects with mutated alleles of CYP2C9. This can be applied to drug development even from the early clinical phases.