Background: Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is widely used in the prophylaxis for graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation (HSCT). MPA undergoes enterohepatic recycling (EHR). Oral antibiotics can affect MPA concentration by reducing intestinal flora-mediated EHR. However, the effect of intravenous antibiotics on MPA concentration is not clear, especially in patients whose EHR is already interrupted. This study was conducted to determine whether intravenous carbapenem antibiotics (CBP) influence the pre-dose plasma concentration (C0) of MPA in HSCT patients when the EHR of MPA is interrupted by cyclosporine and gut decontamination.
Methods: The HSCT patients who received immunosuppressive therapy with MMF and cyclosporine, as well as treatment with CBP were screened as potential candidates. Patients who lacked MPA C0 measurements before or during CBP use, had combination therapy of rifampin with MMF, or switched from IV to oral MMF were excluded. The liver/renal function, demographic information, albumin/cyclosporine concentration, MPA C0 and medication information were collected. The changes in the MPA C0 before and during CBP use were evaluated, and the influence of related clinical factors was also estimated.
Results: CBP resulted in a significant reduction in the MPA C0 from 0.65±0.33 to 0.43±0.30 µg/mL. Linear regression analysis indicated a weak correlation between the dose-normalized C0 of MPA and the dosage of CBP during CBP use (r2=0.129, P=0.009). Univariate and multivariate analysis confirmed that the MPA C0 had no relevance to rifaximin administration (P=0.249-0.700), demographics (P=0.118-0.599), fluctuation of plasma albumin (ALB, P=0.943 and 0.609) and cyclosporine concentrations (P=0.647 and 0.112), or liver and renal functions (P=0.078-0.887) no matter whether the CBP were used. However, compared with the non-gut decontamination group, larger interindividual variabilities and smaller decreases in MPA C0 (6.60% vs. 41.73%) during CBP therapy were seen in the gut decontamination group, although it was a nonsignificant trend.
Conclusions: CBP decreased the MPA C0 in Chinese HSCT patients even when MMF is used in combination with cyclosporine and rifaximin. If antibiotics must be used, and CBP in particular, therapeutic drug monitoring should be performed to ensure adequate exposure.
Keywords: Antibiotics; hematopoietic stem cell transplantation (HSCT); mycophenolate mofetil (MMF); mycophenolic acid (MPA).
2023 Annals of Translational Medicine. All rights reserved.