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. 2024 Dec 28:18:6379-6388.
doi: 10.2147/DDDT.S503463. eCollection 2024.

Dosing Regimen Recommendations for Sirolimus in Adult Liver Transplant Recipients: Insights from a Population Pharmacokinetic Model

Juehui Mao  1   2   3 , Yunshan Cheng  4 , Dong Liu  1 , Bo Zhang  5 , Xiping Li  1
Affiliations

Dosing Regimen Recommendations for Sirolimus in Adult Liver Transplant Recipients: Insights from a Population Pharmacokinetic Model

Juehui Mao et al. Drug Des Devel Ther. .

Abstract

Background: Sirolimus is a commonly used immunosuppressant administered after solid organ transplantation. It is characterized by a narrow therapeutic window and highly variable exposure, necessitating the identification of the sources of variability and design of individualized drug therapies.

Aim: This study aimed to perform a population pharmacokinetic (PK) analysis of sirolimus in adult liver transplant recipients and develop dosing regimen recommendations according to patient characteristics.

Methodology: A total of 216 measurements of whole blood sirolimus concentrations in 103 adult patients were obtained for analysis. Covariates influencing the PKs of sirolimus were investigated using a stepwise procedure. Monte Carlo simulations were conducted to recommend dosing regimens for patients with different levels of covariates.

Results: A one-compartment model with first-order elimination provided the best fit of the data. Hematocrit (HCT) significantly influenced the apparent clearance of sirolimus. Monte Carlo simulations showed that for patients with a low HCT level of 28%, dosing regimens of 1.5 mg qd or 1 mg qd alternating with 1.5 mg qd should be recommended. For patients with a normal HCT level, the recommended dosing regimens were 1 mg qd, 2 mg qod, or 0.5 mg qd alternating with 1 mg qd.

Conclusion: Based on our population PK model of sirolimus in adult liver transplant recipients, which has the largest sample size to date, we recommend to tailor dosing regimens to various HCT levels in such patients.

Keywords: dosing regimen; hematocrit; liver transplant; population pharmacokinetic analysis; sirolimus.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1
Figure 1
Goodness-of-fit plots of the final model. (A) Observed versus individual predicted concentration; (B) observed versus population predicted concentration (PRED); (C) conditional weighted residuals (CWRES) versus PRED; (D) CWRES versus time after dose. The black solid lines are the identity lines, and the red solid lines are the loess smooth lines.
Figure 2
Figure 2
Prediction-corrected visual predictive check of the final model. The dots represent observed concentrations; solid lines represent the median (red), 5th, and 95th percentiles (blue) of the observations. The shaded areas represent the 90% confidence intervals for the median (red) and the 5th and 95th percentiles (blue) of the simulated values.
Figure 3
Figure 3
Normalized prediction distribution (NPD) plots of the final model. (A) Quantile-quantile plot of the distribution of the NPD versus theoretical normal distribution; (B) histogram of the distribution of the NPD with the density of the standard normal distribution overlaid; (C) NPD versus time after first dose; (D) NPD versus population prediction.
Figure 4
Figure 4
Boxplot of the distributions of simulated steady-state sirolimus whole-blood trough concentrations for patients with different hematocrit levels of 28%, 38%, and 46%. The dashed horizontal lines represent the therapeutic range of sirolimus (4–8 ng/mL).
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