Microbiome-Mediated Pharmacokinetics and Informed Dosing of Mycophenolate in Kidney Transplantation

The gut microbiome contributes to interindividual variability in drug pharmacokinetics; however, its role in guiding dose adjustments remains unclear. Mycophenolic acid (MPA), the active metabolite of the immunosuppressant mycophenolate mofetil (MMF), exhibits high pharmacokinetic variability, potentially linked to microbial activity. This study aimed to characterize the gut microbiome effect on MPA pharmacokinetics and determine if these effects necessitate dose modifications.

In 84 kidney transplant recipients, plasma and urine concentration-time profiles for MPA and its glucuronide metabolites were characterized using population pharmacokinetic modeling in NONMEM^®. Stool samples were collected within 2 days of pharmacokinetic sampling for microbiome shotgun metagenomic sequencing. Machine learning was used to identify microbial species associated with pharmacokinetic variability. The impact of these species and clinical covariates was evaluated using full fixed-effect modeling. Simulations were conducted to assess the effect of microbial relative abundance on MPA therapeutic target attainment across various MMF doses.

Five bacteria were associated with the magnitude or duration of enterohepatic circulation (EHC). High relative abundance of Eubacterium callanderi increased EHC and MPA exposure by 29-63%, requiring a 17% lower MMF dose. Conversely, high Faecalibacterium SGB15315 abundance reduced EHC and MPA exposure by 13-26%, requiring a 50-75% higher dose. While Gemmiger formicilis and Eisenbergiella tayi prolonged EHC by >100% and Anaerostipes caccae decreased it by 30%, these taxa did not clinically impact therapeutic target attainment.

We identified several stool microbial species affecting MPA pharmacokinetics. Specifically, Eubacterium callanderi and Faecalibacterium SGB15315 may identify patients who require additional therapeutic drug monitoring or possible dose modifications to reach target concentrations.

Clinicaltrials.gov, NCT04953715.