Linked pharmacometrics-pharmacoeconomics model for cost-effectiveness analysis of tacrolimus in liver transplant patients from real-world data

Background: Tacrolimus (TAC) is a common immunosuppressant to prevent liver graft failure which is metabolized by CYP3A4/3A5. Costs of TAC are often a concern and diltiazem (DTZ, CYP3A4 inhibitor) which is co-administered for accompanying hypertension, may increase TAC concentration and therefore reduce cost. Despite the widespread use of this combination, the cost-effectiveness of such a regimen remains insufficiently explored. We aim to evaluate the cost-effectiveness of various TAC/DTZ dosing regimens in liver transplant patients complicated by hypertension with different CYP3A5 genotypes.Methods: Clinical data were extracted from a tertiary hospital specialized in liver transplant. A physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model was developed to quantify relationship between TAC trough concentrations and graft failure risks and to identify an optimal regimen. A cost-effectiveness analysis was then performed using a Markov model to evaluate annual costs and graft failures of these regimens.Findings: A total of 483 liver transplant cases from the hospital were included. Results showed that the 2/30 mg TAC/DTZ regimen was most cost-effective for CYP3A5 expressors, while the 1/30 mg TAC/DTZ regimen was optimal for nonexpressors. A cost-effectiveness acceptability curve showed that the optimized treatment for CYP3A5 expressors and nonexpressors had a 73.0% and 90.9% probability of being cost-effective at a threshold of $38,201, respectively.Interpretation: This study showcased that TAC/DTZ treatments could be cost-effective in hypertensive patients with different CYP3A5 polymorphisms. The feasibility of a linked pharmacometrics-pharmacoeconomics (PMPE) model for such analysis was also demonstrated, and underpinned a novel approach to generate PE evidence to guide clinical and policy decision-making.Funding: Shanghai Municipal Health Commission (20234Y0233)