Ethnic evaluation of the pharmacokinetics and safety of new drugs is required in Japan before implementing bridging or joining global studies. As therapeutic monoclonal antibodies (mAbs) show limited ethnic differences, their pharmacokinetics and safety in Japanese individuals could be estimated from prior non-Japanese studies. Therefore, there is potential to re-evaluate the development program for mAbs in Japan. We reviewed the pharmacokinetics of mAbs approved in Japan. Although some differences had been observed in pharmacokinetics of mAbs between Japanese and non-Japanese populations (mainly Caucasians), these differences were attributed to differences of body weight and/or antigen levels. Moreover, the influential factors can be estimated without conducting regional pharmacokinetic/safety studies. The pharmacokinetics of some mAbs is presumably non-linear and show differences between healthy volunteers and patients because of differences in antigen levels. However, for 10/24 mAbs approved in Japan, Japanese healthy volunteer studies were conducted before the patient studies. Additionally, for the mAbs that showed ethnic differences in pharmacokinetics, the doses selected in subsequent patient studies were the same as the doses approved in the United States. In this review, we discuss new drug development strategies in various regions, and assess the need for regional pharmacokinetics/safety studies before joining global studies.

Apixaban was safe and well-tolerated in healthy Japanese subjects. The pharmacokinetic profile of apixaban following multiple twice-daily doses was linear, and exposure parameters such as C(max), observed at ~ 3 hours post-dose, and area under the plasma concentration-time curve increased in a dose-proportional manner. Pharmacodynamic profiles closely followed the apixaban plasma concentration-time profiles.

Cephalosporinases of Enterobacter cloacae and Citrobacter freundii were responsible for resistance to newercephalosporins such as cefotaximeand ceftazidime but not BMY-28142.Interaction of these cephalosporins including hydrolysis, binding, inhibition, and inactivation with cephalosporinases from E. cloacae GN7471and C. freundii GN7391were studied. BMY-28142was much more stable against the both enzymes than cephalothin, but more hydrolyzable than cefotaxime and ceftazidime at higher concentration such as 100^m. Because of low affinity for the enzymes, i.e. large Kmand Ki, the calculated hydrolysis rate of BMY-28142at 0.1^m was smaller than those of cefotaxime and ceftazidime, that explained the difference in activity against cephalosporinase-producing strains between BMY-28142and cefotaxime or ceftazidime. The effects of cephalosporinase production on susceptibility of Escherichia coli ompmutants were examined using a plasmid having cephalosporinase gene of C. freundii GN346. Decrease in susceptibility of E. coli by cephalosporinase production was larger in the strain lacking outer membrane proteins (Omp) F and C, and smaller in the strain producing OmpFconstitutively.BMY-28142, a new oxyiminocephalosporin, has excellent activity against both Gram-positive and Gram-negative bacteria1>2). Among these organisms, Enterobacter cloacae and Citrobacter freundii, which produce chromosomal cephalosporinases, are more susceptible to BMY-28142than to other cephalosporins3~5). Recently, the emergence of cephalosporinase hyperproducing strains in these species which show resistance to newer cephalosporins, such as cefotaxime and ceftazidime, was reported6). On the resistance mechanismof cephalosporinase-high-producing strains against the newer cephalosporins, the theory of a "non-hydrolytic barrier" has been proposed7>8). BMY-28142 showshigher activity against these strains than other cephalosporins10. The relation of its low affinity, i.e. large Ki values, for cephalosporinases and its high activity was reported in comparison with ceftazidime^. However, how the low affinity leads less influence of cephalosporinase production on activity is still unclear. On the other hand, the importance of very slow hydrolysis by cephalosporinases was also reported10). In this paper, we attempted to clarify whyBMY-28142 is so effective and examined kinetically the interaction of drugs with cephalosporinases using cephalothin, ceftazidime and T Present address:

Results suggest no clinically significant short-term safety signals with DCV and ASV at single or multiple doses in this population.

omp mutants, MH1160 (MC4100 ompRI) and MH760 (MC4100 ompR2), by transformation. Effects of the combination of the omp mutations and these P-lactamases on the susceptibility of E. coli strains were studied with 15 ,B-lactam antibiotics including cephalosporins, cephamycins, penicillins, imipenem, and aztreonam. The ompRI mutant, MH1160, lacks OmpF and OmpC, and it showed reduced susceptibility to 11 of the 15 P-lactam agents. The reduction in susceptibility to cefoxitin, moxalactam, and flomoxef was much greater than reduction in susceptibility to the other agents. When the ompRI mutant produced the cephalosporinase of C. freundii, the susceptibility of the mutant to 12 of the 15 P-lactam antibiotics decreased. The reduction in susceptibility of MH1160 to 10 of the 12 agents affected by the enzyme was two-to fourfold greater than that observed in MC4100. Such a synergistic effect was also observed with the cephalosporinase of P. vulgaris and ompRI mutation against six cephalosporins, moxalactam, and aztreonam.P-Lactamases of gram-negative bacteria play an important part in bacterial resistance to P-lactam antibiotics. They are mediated by chromosomes or by plasmids. Both expression of P-lactamases, i.e., amount of the enzymes, and substrate profiles of the enzymes are major factors that determine resistance levels. Also, permeability of r-lactam antibiotics through the bacterial outer membrane affects susceptibility to r-lactam agents (21). Since OmpF and OmpC porins of Escherichia coli were found to act as pores for diffusion through the outer membrane, the role of the porin channels in permeation of r-lactams has been studied actively (24, 29). Some P-lactam antibiotics, e.g., cefoxitin, are known to penetrate much more rapidly through the OmpF porin than through the OmpC porin (11). Decreased permeability of the outer membrane and alterations in the outer membrane proteins also have been studied as factors in resistance to P-lactam antibiotics (1,6, 12). Recently, the contributions of 1-lactamases and outer membrane permeability to resistance have been studied simultaneously (15,20,27). Such an approach is more appropriate when both hydrolytic rate and permeation rate are slow (5). In our studies on bacterial resistance to newer cephalosporins by cephalosporinases, a decrease in permeability intensified the reduction in antimicrobial activity by cephalosporinase against cefotaxime and ceftazidime in E. coli (7,8