This study shows that therapeutic drug monitoring is indicated in patients with a voriconazole-related SAE and that dose adjustment is required if the trough concentration of voriconazole exceeds 5.83 mg/l.

Simvastatin (SV), a HMG-CoA reductase inhibitor, is widely used for the treatment of hyperlipidaemia. The objectives of the present study were to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model for simvastatin and to evaluate its usefulness in predicting the dose-response relationship of simvastatin in patients with hyperlipidaemia. The data were obtained from a drug-drug interaction study to assess the effect of aspirin on the PK of simvastatin. Twenty-seven healthy volunteers were given simvastatin 40 mg daily for 14 days in whom aspirin 100 mg q.d. was co-administered after day 8. Full PK studies were performed on days 1, 7 and 14 in addition to trough sampling on days 5, 6, 12 and 13. Low-density lipoprotein-cholesterol (LDL-C) levels were also measured serially. Then, a population PK-PD model for simvastatin and its active metabolite, simvastatin acid (SVA), was developed using mixed effect methods (NONMEM Ver. 6.2). A simple linear PK model with parent and metabolite compartments provided the best fit for the 2647 concentrations of simvastatin and sim-vastatin acid, and a turnover model was used to describe the change in LDL-C levels. The dose-response curve simulated from the final model and those obtained from the literature overlapped very closely. No influence of aspirin was observed in PK or PD. A simple PK-PD model developed using only 2-week study data from fewer than 30 healthy volunteers successfully predicted the dose-response relationship of simvastatin in patients when compared with published data. Simvastatin (SV) is a HMG-CoA reductase inhibitor effective in the treatment of hypercholesterolaemia and hypertri-glyceridaemia [1]. It is widely used to reduce the risk of cardiovascular morbidity and mortality [2] and thromboem-bolic stroke in high-risk patients [3,4]. After oral administration , simvastatin is rapidly absorbed (t max of 1-2 hr) [5,6] and eliminated. Less than 10% of the peak HMG-CoA reductase inhibitory activity remains after 12 hr (t 1 ⁄ 2 = 2-5 hr) [5,7]. Once administered, simvastatin rapidly undergoes reversible non-enzymatic or carboxylesterase-mediated conversion to its active metabolite, simvastatin acid (SVA), in the liver, intestinal mucosa and plasma [1,8]. CYP450 is also known to metabolize a small fraction of simvastatin. Simvastatin acid prevents HMG-CoA reductase from converting HMG-CoA to mevalonate, which is a rate-limiting step in cholesterol biosynthesis [9]. Inhibition of the HMG-CoA reductase in the liver results in the reduction in cholesterol synthesis. Moreover, the up-regulation of low-density lipoprotein (LDL) receptors located on the cell membranes of the liver and extrahepatic tissues thereby also contributes to the reduction in plasma LDL-cholesterol (LDL-C) concentrations [10]. There are many reports on the safety, efficacy and metabolism of simvastatin. To date, there have been no published population pharmacokinetic-pharmacodynamic (PK-PD) models for simvastatin or simvastatin acid. Recently, we performed a drug-drug interaction s...

Data concerning the human microbiota composition during Clostridioides (Clostridium) difficile infection (CDI) using next-generation sequencing are still limited. We aimed to confirm key features indicating tcdB positive patients and compare the microbiota composition between subgroups based on toxin gene load ( tcdB gene) and presence of significant diarrhea. Ninety-nine fecal samples from 79 tcdB positive patients and 20 controls were analyzed using 16S rRNA gene sequencing. Chao1 index for alpha diversity were calculated and principal coordinate analysis was performed for beta diversity using Quantitative Insights into Microbial Ecology (QIIME) pipeline. The mean relative abundance in each group was compared at phylum, family, and genus levels. There were significant alterations in alpha and beta diversity in tcdB positive patients (both colonizer and CDI) compared with those in the control. The mean Chao1 index of tcdB positive patients was significantly lower than the control group ( P <0.001), whereas there was no significant difference between tcdB groups and between colonizer and CDI. There were significant differences in microbiota compositions between tcdB positive patients and the control at phylum, family, and genus levels. Several genera such as Phascolarctobacterium , Lachnospira , Butyricimonas , Catenibacterium , Paraprevotella , Odoribacter , and Anaerostipes were not detected in most CDI cases. We identified several changes in the microbiota of CDI that could be further evaluated as predictive markers. Microbiota differences between clinical subgroups of CDI need to be further studied in larger controlled studies.

While the CDAI does not accurately reflect inflammatory activity in CD, a one-off FC reliably detects the presence or absence of intestinal inflammation in adult patients with CD, compared to WCS.