Vitamin B consists of a group of water-soluble micronutrients that are mainly derived from the daily diet. They serve as cofactors, mediating multiple metabolic pathways in humans. As an integrated part of human health, gut microbiota could produce, consume, and even compete for vitamin B with the host. The interplay between gut microbiota and the host might be a crucial factor affecting the absorbing processes of vitamin B. On the other hand, vitamin B supplementation or deficiency might impact the growth of specific bacteria, resulting in changes in the composition and function of gut microbiota. Together, the interplay between vitamin B and gut microbiota might systemically contribute to human health. In this review, we summarized the interactions between vitamin B and gut microbiota and tried to reveal the underlying mechanism so that we can have a better understanding of its role in human health.

Human-derived in vitro models can provide high-throughput efficacy and toxicity data without a species gap in drug development. Challenges are still encountered regarding the full utilisation of massive data in clinical settings. The lack of translated methods hinders the reliable prediction of clinical outcomes. Therefore, in this study, in silico models were proposed to tackle these obstacles from in vitro to in vivo translation, and the current major cell culture methods were introduced, such as human-induced pluripotent stem cells (hiPSCs), 3D cells, organoids, and microphysiological systems (MPS). Furthermore, the role and applications of several in silico models were summarised, including the physiologically based pharmacokinetic model (PBPK), pharmacokinetic/pharmacodynamic model (PK/PD), quantitative systems pharmacology model (QSP), and virtual clinical trials. These credible translation cases will provide templates for subsequent in vitro to in vivo translation. We believe that synergising high-quality in vitro data with existing models can better guide drug development and clinical use.

This study aimed to develop a physiologically‐based pharmacokinetic pharmacodynamic (PBPK/PD) parent‐metabolite model of edoxaban, an oral anticoagulant with a narrow therapeutic index, and to predict pharmacokinetic (PK)/PD profiles and potential drug–drug‐disease interactions (DDDIs) in patients with renal impairment. A whole‐body PBPK model with a linear additive PD model of edoxaban and its active metabolite M4 was developed and validated in SimCYP for healthy adults with or without interacting drugs. The model was extrapolated to situations including renal impairment and drug‐drug interactions (DDIs). Observed PK and PD data in adults were compared with predicted data. The effect of several model parameters on the PK/PD response of edoxaban and M4 was investigated in sensitivity analysis. The PBPK/PD model successfully predicted PK profiles of edoxaban and M4 as well as anticoagulation PD responses with or without the influence of interacting drugs. For patients with renal impairment, the PBPK model successfully predicted the fold change in each impairment group. Inhibitory DDI and renal impairment had a synergistic effect on the increased exposure of edoxaban and M4, and their downstream anticoagulation PD effect. Sensitivity analysis and DDDI simulation show that renal clearance, intestinal P‐glycoprotein activity, and hepatic OATP1B1 activity are the major factors affecting edoxaban‐M4 PK profiles and PD responses. Anticoagulation effect induced by M4 cannot be ignored when OATP1B1 is inhibited or downregulated. Our study provides a reasonable approach to adjust the dose of edoxaban in several complicated scenarios especially when M4 cannot be ignored due to decreased OATP1B1 activity.

Objective: Antineoplastic agent-induced systolic dysfunction is a major reason for interruption of anticancer treatment. Although targeted anticancer agents infrequently cause systolic dysfunction, their combinations with chemotherapies remarkably increase the incidence. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a potent in vitro model to assess cardiovascular safety. However, quantitatively predicting the reduction of ejection fraction based on hiPSC-CMs is challenging due to the absence of the body's regulatory response to cardiomyocyte injury. Methods: Here, we developed and validated an in vitro-in vivo translational platform to assess the reduction of ejection fraction induced by antineoplastic drugs based on hiPSC-CMs. The translational platform integrates drug exposure, drug-cardiomyocyte interaction, and systemic response. The drug-cardiomyocyte interaction was implemented as a mechanism-based toxicodynamic (TD) model, which was then integrated into a quantitative system pharmacology-physiological-based pharmacokinetics (QSP-PBPK) model to form a complete translational platform. The platform was validated by comparing the model-predicted and clinically observed incidence of doxorubicin and trastuzumab-induced systolic dysfunction. Results: A total of 33,418 virtual patients were incorporated to receive doxorubicin and trastuzumab alone or in combination. For doxorubicin, the QSP-PBPK-TD model successfully captured the overall trend of systolic dysfunction incidences against the cumulative doses. For trastuzumab, the predicted incidence interval was 0.31–2.7% for single-agent treatment and 0.15–10% for trastuzumab-doxorubicin sequential treatment, covering the observations in clinical reports (0.50–1.0% and 1.5–8.3%, respectively). Conclusions: In conclusion, the in vitro-in vivo translational platform is capable of predicting systolic dysfunction incidence almost merely depend on hiPSC-CMs, which could facilitate optimizing the treatment protocol of antineoplastic agents.

Despite the recent advances in this field, there are limited methods for translating organoid-based study results to clinical response. The goal of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model to facilitate the translation, using oxaliplatin and irinotecan treatments with colorectal cancer (CRC) as examples. The PK models were developed using qualified oxaliplatin and irinotecan PK data from the literature. The PD models were developed based on antitumor efficacy data of SN-38 and oxaliplatin evaluated in vitro using tumor organoids. To predict the clinical response, translational scaling of the models was established by incorporating predicted ultrafiltration platinum in plasma or SN-38 in tumors to PD models as the driver of efficacy. The final PK/PD model can predict PK profiles and responses following treatments with oxaliplatin or irinotecan. After generation of virtual patient cohorts, this model simulated their tumor shrinkages following treatments, which were used in analyzing the efficacies of the two treatments. Consistent with the published clinical trials, the model simulation suggested similar patient responses following the treatments of oxaliplatin and irinotecan with regards to the probabilities of progression-free survival (HR = 1.05, 95%CI [0.97;1.15]) and the objective response rate (OR = 1.15, 95%CI [1.00;1.32]). This proposed translational PK/PD modeling approach provides a significant tool for predicting clinical responses of different agents, which may help decision-making in drug development and guide clinical trial design.

B vitamins and probiotics are commonly used dietary supplements with well-documented health benefits. However, their potential interactions remain poorly understood. This study aims to explore the effects and underlying mechanisms of the combined use of B vitamins and probiotics by liquid chromatography-triple quadrupole mass spectrometry analysis, pharmacokinetic modeling, and 16S rRNA gene sequencing. By intragastric administration of seven B vitamins and three Lactobacillus strains to healthy rats (n = 8 per group), we found that probiotics significantly promoted the absorption (by approximately 14.5% to 71.2%) of vitamins B1, B3, B5, and B12. By conducting in vitro experiments (n = 3 per group) and a pseudo-germ-free rat model-based pharmacokinetic study (n = 6 per group), we confirmed that probiotics primarily enhanced the B vitamin absorption through gut microbiota-mediated mechanisms, rather than by directly producing B vitamins. Furthermore, we evaluated the effects of B vitamins and probiotics on the colon and gut microbiota by treating the pseudo-germ-free rats with blank solution, B vitamins, probiotics, and B vitamins + probiotics (n = 5 per group), respectively. Histopathological examination showed that the combination of B vitamins and probiotics synergistically alleviated the rat colon damage. High-throughput genetic sequencing also revealed the synergistic effect of B vitamins and probiotics in modulating the gut microbiota, particularly increasing the abundance of Verrucomicrobia and Akkermansia. In summary, the combined administration of B vitamins and probiotics may have a higher efficacy than using them alone.