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Tacrolimus pharmacokinetics is associated with gut microbiota diversity in kidney transplant patients: results from a pilot cross‐sectional study

他克莫司 药代动力学 肠道菌群 生物 基于生理学的药代动力学模型 维管菌 医学 药理学 内科学 移植 免疫学 链球菌 细菌 遗传学
作者
Alexandra L Degraeve,Laure B. Bindels,Vincent Haufroid,Serge Moudio,Lidvine Boland,Kévin-Alexandre Delongie,Joseph P. Dewulf,Djamila Chaïb Eddour,Michel Mourad,Laure Elens
出处
期刊:Clinical Pharmacology & Therapeutics [Wiley]
标识
DOI:10.1002/cpt.3077
摘要

Clinical use of tacrolimus, an essential immunosuppressant following transplantation, is complexified by its high pharmacokinetic variability. The gut microbiota gains growing interest but limited investigations have evaluated its contribution to tacrolimus pharmacokinetics. Here, we explore the associations between the gut microbiota composition and tacrolimus pharmacokinetics. In this pilot cross-sectional study (Clinicaltrial.gov NCT04360031), we recruited 93 CYP3A5 non-expressers stabilized kidney transplant patients. Gut microbiota composition was characterized by 16S rRNA gene sequencing, tacrolimus pharmacokinetic parameters were computed, and additional demographical and medical covariates were collected. Associations between pharmacokinetic parameters or diabetic status and the gut microbiota composition, as reflected by α- and β-diversity metrics, were evaluated. Patients with higher tacrolimus AUC/(dose/kg) had higher bacterial richness, and tacrolimus pharmacokinetic parameters were associated with specific bacterial taxa (e.g., Bilophila) and amplicon sequence variant (ASV) (e.g., ASV 1508 and ASV 1982 [Veillonella/unclassified Sporomusaceae]; ASV 664 [unclassified Oscillospiraceae]). Building a multiple linear regression model showed that ASV 1508 (co-abundant with ASV 1982) and ASV 664 explained respectively 16.0% and 4.6% of the inter-individual variability in tacrolimus AUC/(dose/kg) in CYP3A5 non-expressers patients, when adjusting for haematocrit and age. Anaerostipes relative abundance was decreased in diabetic patients. Altogether, this pilot study revealed unprecedented links between the gut microbiota composition and diversity and tacrolimus pharmacokinetics in stable kidney transplant patients. It supports the relevance of studying the gut microbiota as an important contributor to tacrolimus pharmacokinetic variability. Elucidating the causal relationship will offer new perspectives to predict tacrolimus inter- and intra-pharmacokinetic variability.
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