ABSTRACT
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.
ABSTRACT
BACKGROUND: Tacrolimus has been widely accepted as the backbone of acute graft-versus-host disease (aGVHD) prophylaxis in allogeneic hematopoietic stem cell transplantation (alloHSCT). The present work evaluated whether tacrolimus concentrations early after transplant correlate with the incidence of aGVHD in Chinese alloHSCT recipients. METHODS: One hundred four Chinese alloHSCT recipients were included in this retrospective study. All patients received standard prophylaxis with tacrolimus and short-term methotrexate. Blood samples were taken at steady-state for those on i.v. tacrolimus (Cv) or predose (C0) and 2 hours after the last oral dose (C2). RESULTS: In the first 8 weeks after alloHSCT, significant variability in Cv, C0, and C2 of Chinese patients was observed. It was found that higher tacrolimus C0 and C2 values tended to be associated with a reduced risk of aGVHD, although this was a nonsignificant trend due to the small sample size involved. Receiver operating characteristic curve analysis indicated that Cv levels of ≥16.52 ng/mL, C0 levels of ≥5.56 ng/mL, and C2 levels of ≥7.83 ng/mL minimized the incidence of treatment failure during weeks 3-4 with intravenous administration and weeks 5-6 with oral administration. There was no statistically significant association of the patient liver and kidney function with the blood concentration of tacrolimus in the desired range of 5-20 ng/mL. CONCLUSIONS: Tacrolimus therapeutic drug monitoring improved treatment outcomes of Chinese alloHSCT recipients. Cv measurements during weeks 3-4 and C0 or C2 measurements during weeks 5-6 better predicted aGVHD (I-IV) than the concentrations measured at other time points during the first 6 weeks after alloHSCT.
