Background: Tacrolimus (TAC), an important immunosuppressant for liver transplantation, has a narrow therapeutic index and large individual differences in pharmacokinetics. Ascitic fluid is commonly drained after liver transplantation. However, the distribution of TAC in ascitic fluid and the influence of drained ascitic fluid on whole-blood TAC are unclear. Methods: The ascitic fluid samples from twenty liver transplant recipients who were received TAC treatment within 12h after the transplantation surgery were collected for consecutive 24h in different days after the surgery. The distribution of TAC in ascitic fluid were evaluated by using a sensitive UPLC-MS/MS method. Chromatographic separation was achieved on an Agilent ZORBAX Eclipse Plus Phenyl-Hexyl column (2.1×100mm, 3.5μm). Mass spectrometry was performed in multiple reaction monitoring (MRM) conditions of transitions m/z 821.4→768.5 for TAC. Results: The concentrations of TAC in ascitic fluid samples range from 0.2 to 3.0 ng/mL, accounting for 1.19-31.87% of whole-blood TAC concentrations. A linear mixed model showed a statistically significant positive correlation between the steady-state trough blood concentration of TAC (C0) and the corresponding amount of TAC excreted in the ascitic fluid for 24 consecutive hours, especially after normalization by the daily dose per unit body weight (D/W). Conclusions: These data suggested that the distribution of TAC in ascitic fluid has great individual differences. The whole-blood TAC concentration, D/W and other confounding factors may contribute to the excretion of TAC in ascitic fluid, but the influence of TAC excretion in drained ascitic fluid on the whole-blood TAC concentration is negligible.

Objectives: This study aimed to establish a population pharmacokinetic model for elderly individuals receiving intravenous voriconazole, and to assess and optimize the dosing regimens using a simulating approach. Methods: A population pharmacokinetic analysis was conducted using the NONMEN software based on 438 plasma concentrations from 150 elderly patients receiving multiple intravenous doses of voriconazole. The individualized optimal dosage regimen was proposed based on the obtained population pharmacokinetics parameters. The final model was assessed by the goodness of fit plots, non-parametric bootstrap method, and visual predictive check. Monte Carlo simulations were carried out to assess and optimize the dosing regimens with a therapeutic range of 2.0-5.0 mg/L as the target plasma trough concentration (Cmin). Results: A one-compartment model with first-order absorption and elimination fitted well to the concentration-time profile of voriconazole. The typical voriconazole clearance was 3.55 L/h, and the typical volume of distribution was 194 L. Covariate analysis indicated that the CL of voriconazole was substantially influenced by albumin (ALB), gamma glutamyl transpeptidase, and direct bilirubin, while the volume was associated with body weight. Conclusions: The first study on the population pharmacokinetics of voriconazole in Chinese elderly people was performed. Individualized dosing regimens were recommended for different ALB levels based on population PK model prediction. The proposed dosing regimens could provide a rationale for dosage individualization to improve clinical outcomes and minimize drug-related toxicities.