A Novel Approach Using Pharmacometrics/Pharmacoeconomic (PMPE) Model for Cost-effectiveness Analysis of Tacrolimus-Diltiazem Combination in Liver Transplant Patients: Evidence from Real-world Clinical Data
Aole Zheng1#, Mak Wenyao1#, Xiaoping Shi2, Xiaoqiang Xiang1, Qingfeng He1
1: Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, China 2: Department of Clinical Pharmacy, Zhongshan Hospital, Fudan University, Shanghai #: joined first author
Introduction:
Tacrolimus (TAC) is a typical immunosuppressant that is metabolized by the CYP3A4/CYP3A5 enzyme[1], commonly used in liver transplants to prevent graft failure. Clinical guidelines recommend TAC trough concentration (Ctrough) should be between 6-12 ng/mL after 1 year [2]. The high cost of tacrolimus is a concern[3], and diltiazem (DTZ, a CYP3A4 inhibitor) is often co-administered to increase concentration and reduce cost [4]. Despite the widespread use of this combination, the cost-effectiveness of such a regime remains insufficiently explored. Traditional PE analyses which are conducted on real-world data ignore the information about the exposure-response relationship and it also fall short in forecasting the cost-effectiveness of various clinical scenarios.
By integrating the physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model with pharmacoeconomic (PE) model, the approach offers a promising method to deeply utilize the precise real-world data and predict the cost-effectiveness relationship under different TAC-DTZ dosing combinations [5].
Objectives:
- To quantify the relationship between PK and PD of TAC in Chinese liver transplant patients.
- To evaluate the cost-effectiveness of various TAC-DTZ dosing regimens.
Methods:
A PBPK-PD model was developed based on clinical data extracted from a tertiary hospital specializing in liver transplant surgeries. Patient information such as baseline demographic, TAC-DTZ dosing and whole blood concentration was retrieved. The incidence of graft failures and the timelines towards such events were documented.
The PBPK model was developed based on published model [6-8] and verified using the extracted clinical data, alongside a reliable PBPK model for DTZ (PBPK-DDI model). TAC concentrations were simulated and used to develop the corresponding PD model. PK-PD correlations were analyzed through multivariate logistic regression. The final PBPK-PD model was validated using the graft failure data from the hospital.
A Markov model was developed for cost-effectiveness analysis, of which was defined as: post-transplant, graft failure, and death. The transition rates between these stages and with the treatment costs were derived from the extracted data. The utility was sourced from a relevant Japanese PE study[9]. Population simulations for various TAC-DTZ dosages were performed to predict average Ctrough and graft failure rates for cost-effectiveness evaluation over 30 years.
Results:
A total of 215 liver transplant cases from Zhongshan Hospital (Shanghai, China) was included in the analysis. The average follow-up period was one year, with a total of 19 incidents of graft failure and 40 deaths recorded. PBPK-DDI model was validated with the extracted Ctrough concentrations. 87.5% of predicted Ctrough was within the 2-fold error compared to the observed Ctrough. The DDI simulations showed that the AUC0-t and Cmax increased by 149% and 116% respectively. The final model had an average accuracy 81.9% for predicting graft failure.
Four regimes were included for PE simulations (TAC alone: 2mg, 5mg; TAC-DTZ, 1/30mg, 2/30mg), which corresponded to the recommended target Ctrough. TAC alone resulted in Ctrough of 4.77ng/mL and 12.58 ng/mL, with graft failure ratios of 14% and 6%, costing $5250 and $13125 for a year, respectively. TAC-DTZ regimens resulted in Ctrough with 5.8ng/mL and 12.34ng/mL, with graft failure ratios of 11% and 6%, costing $2678 and $5303, respectively.
The PE analysis showed that 2mg TAC combined with DTZ is cost-effective, with incremental cost-effectiveness ratio (ICER) being 2152.54 compared with a 1mg combination regimen. Additionally, the incremental life years (LYs) of combination therapy is 6.17 compared with TAC alone. A cost-effectiveness acceptability curve showed the optimized treatment has a 93% probability at a threshold of $38201.
Conclusion:
This study demonstrated the cost-effectiveness of combination treatment in graft failure prevention, particularly the 2/30mg TAC-DTZ regime which was more cost-effective than the monotherapies. We also demonstrated the feasibility of a PBPK-PD-PE model for such analysis, underpinning the value of PMPE model to guide clinical and policy decision-making.
References:
- Sattler, M., et al., Cytochrome P-450 3A enzymes are responsible for biotransformation of FK506 and rapamycin in man and rat. Drug Metab Dispos, 1992. 20(5): p. 753-61.
- Association, B.o.O.T.o.C.M., - Diagnosis and treatment specification for immunosuppressive therapy and rejection of liver transplantation in China (2019 edition). ORGAN TRANSPLANTATION, 2021. 12(1): p. 8.
- McEwan, P., et al., Evaluation of the cost effectiveness of sirolimus versus tacrolimus for immunosuppression following renal transplantation in the UK. PharmacoEconomics, 2006. 24(1): p. 67-79.
- Li, J.L., et al., Effects of diltiazem on pharmacokinetics of tacrolimus in relation to CYP3A5 genotype status in renal recipients: from retrospective to prospective. Pharmacogenomics J, 2011. 11(4): p. 300-6.
- Hill-McManus, D., et al., Linked Pharmacometric-Pharmacoeconomic Modeling and Simulation in Clinical Drug Development. Clinical Pharmacology & Therapeutics, 2021. 110(1): p. 49-63.
- Cai, L., et al., Physiologically based pharmacokinetic model combined with reverse dose method to study the nephrotoxic tolerance dose of tacrolimus. Archives of Toxicology, 2023. 97(10): p. 2659-2673.
- Loer, H.L.H., et al., Physiologically based pharmacokinetic modeling of tacrolimus for food–drug and CYP3A drug–drug–gene interaction predictions. CPT: Pharmacometrics & Systems Pharmacology, 2023. 12(5): p. 724-738.
- Zhang, H., et al., Prediction of Drug–Drug Interaction between Tacrolimus and Principal Ingredients of Wuzhi Capsule in Chinese Healthy Volunteers Using Physiologically-Based Pharmacokinetic Modelling. Basic & Clinical Pharmacology & Toxicology, 2018. 122(3): p. 331-340.
- Tajima, T., et al., Cost-effectiveness analysis of adult living-donor liver transplantation in Japan. Hepatology Research, 2023. n/a(n/a).
