Microbiome-Informed Dosing: Exploring Gut Microbial Communities Impact on Mycophenolate Enterohepatic Circulation and...

Area of Science:

• Pharmacology
• Microbiology
• Immunology

Background:

• Pharmacomicrobiomics is crucial for understanding drug metabolism and patient outcomes.
• Mycophenolic acid (MPA), the active form of mycophenolate mofetil (MMF), undergoes enterohepatic circulation (EHC) influenced by gut bacteria.
• Bacterial β-glucuronidases play a key role in regenerating MPA from its glucuronidated metabolite (MPAG).

Purpose of the Study:

• To investigate the impact of the stool microbiome on MPA pharmacokinetics, metabolism, and EHC in hematopoietic cell transplant (HCT) recipients.
• To correlate specific microbiome community structures with MPA exposure and therapeutic target attainment.
• To evaluate MMF dosing regimens based on microbiome composition through simulations.

Main Methods:

• Utilized a semi-mechanistic population pharmacokinetic model for MPA and its metabolites in HCT recipients.
• Employed correlation network analysis to identify key microbiome communities.
• Assessed pharmacokinetic impacts using full fixed-effects modeling and conducted simulations for dosing optimization.

Main Results:

• High abundance of *Bacteroides uniformis* and *Bacteroides vulgatus* communities correlated with increased EHC and MPA exposure.
• Low abundance of these communities led to significantly lower EHC (52-80%) and MPA exposure (4-83%).
• Simulations indicated that higher MMF doses (1,250 mg Q8h or 1,750 mg Q12h) improve therapeutic target achievement in patients with low-abundance communities.

Conclusions:

• The gut microbiome composition significantly modulates MPA pharmacokinetics and EHC in HCT recipients.
• Microbiome-informed dosing strategies, particularly adjusting MMF dosage, can optimize therapeutic efficacy.
• This study highlights the potential for personalized immunosuppressant therapy based on individual microbiome profiles.