Pietro Laddomada (1), Alessandro Di Deo (1), Bianca Maria Goffredo (2), Sara Cairoli (2), Raffaele Simeoli (2), Oscar Della Pasqua (1)
(1) Clinical Pharmacology & Therapeutics Group, University College London, United Kingdom, (2) Bambino Gesù Children's Hospital IRCCS, Rome, Italy
Introduction: Tacrolimus (TAC) is an immunosuppressant prescribed often in combination with mycophenolic acid to patients who undergo organ transplantation. TAC exerts its effects by inhibiting calcineurin, thereby reducing the risk of organ rejection [1]. Despite its efficacy, TAC has a narrow therapeutic range (Ctrough 5-15 ng/mL) [2], which leads to the requirement for individual dose adjustment and therapeutic drug monitoring (TDM). Its pharmacokinetics is significantly influenced by age, weight, genetics, type of transplantation, time after transplantation and interaction with co-medications. Even though the probability of rejection in patients who are closely monitored is low, the use of immunosuppressant combinations makes it challenging to establish what the adequate exposure range should be. This issue is of particular interest when considering the concomitant use of tacrolimus with mycophenolate or mycophenolic acid (MPA) (Ctrough 1-3.5 mg/L) [3,4]. However, dose adjustment recommendations based on TDM do not take into account the effect of combination therapy. In fact, adjustments are based primarily on the evidence of variability and fluctuation of TAC trough concentrations over time. This practice in TDM has persisted despite data suggesting that AUC may be a more reliable metric of exposure [5], showing a better correlation with the overall treatment response.
Objectives: The present study aimed to assess the role of demographic and clinical factors on the pharmacokinetic disposition of TAC in paediatric patients undergoing solid organ transplantation. The final goal was to identify a dosing algorithm considering dose adjustment considering the concurrent levels of MPA and intraindividual variability in the predicted exposure profile over time.
Methods: This was a retrospective, single-centre, observational study in paediatric and adult solid organ transplant patients (N = 96). Sparse therapeutic drug monitoring data (TDM) for both TAC and MPA were used in conjunction with clinical and demographic data collected at different follow-up visits. A nonlinear mixed effects modelling approach was implemented in NONMEM using prior parameter distributions derived from previously published models for TAC and MPA [6,7]. Here we focus on the development of a strategy for integrating TDM and treatment response data from both immunosuppressant agents. Goodness-of-fit and predictive performance of the final model for TAC were tested with standard graphical and statistical procedures. Finally, simulation scenarios including regimens for both drugs were implemented to explore alternative, more efficient dose adjustment algorithms. Optimisation of the dosing scheme aimed to maximise the proportion of subjects reaching the desired therapeutic exposures for both drugs, reducing or limiting the proportion of subjects under/overexposed.
Results:
The pharmacokinetics of TAC and MPA was described by one- or two-compartment models, respectively. Inclusion of body weight, organ function, post-operative days and CYP3A5 gene expression were found to be significant covariate factors on clearance for both drugs, despite considerable inter-occasion and inter-individual variability in drug disposition. Genetic polymorphism (i.e., phenotype) was found to play an important role regarding the time to target steady-state concentration after transplantation. A model-based daily dose (mg) for TAC was derived according to the formula [CL/F (L/h) x Ctarget (ng/mL)x24 h] / 1000.
In addition, an exploratory analysis revealed an inverse relationship between the Ctrough levels of the two drugs. Target concentrations for both immunosuppressant drugs are achieved and maintained when individual TAC and MPA levels remain within the interquartile range of 3.2-6.1 ng/mL and 0.6-2.1 mg/L, respectively.
Conclusion: In contrast to empirical dose adjustment, based on a predetermined mg/kg dosing regimen, the utilization of a model-based dosing algorithm for TAC and MPA ensures the integration of baseline covariates that are currently disregarded. Moreover, the proposed approach allows the prediction of individual concentration vs time profiles for both drugs, thereby ensuring tailored interventions in a rigorous manner. Whilst a prospective evaluation of the performance of the proposed dosing algorithm has been planned, it can be anticipated that personalised dosing will minimise the proportion of patients experiencing unnecessary under/overexposure.
References:
[1] J. R. Scalea, S. T. Levi, W. Ally, and K. L. Brayman, “Tacrolimus for the prevention and treatment of rejection of solid organ transplants,” 2015, doi: 10.1586/1744666X.2016.1123093.
[2] P. Lancia, E. Jacqz-Aigrain, and W. Zhao, “Choosing the right dose of tacrolimus”, doi: 10.1136/archdischild-2013-305888.
[3] M. Brunet et al., “Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report,” 2019. [Online]. Available: www.drug-monitoring.com
[4] P. E. Wallemacq and R. K. Verbeeck, “Comparative Clinical Pharmacokinetics of Tacrolimus in Paediatric and Adult Patients”.
[5] A. Prytula and T. Van Gelder, “Clinical aspects of tacrolimus use in paediatric renal transplant recipients”, doi: 10.1007/s00467-018-3892-8.
[6] W. Zhao et al., “Population pharmacokinetics and pharmacogenetics of once daily prolonged-release formulation of tacrolimus in pediatric and adolescent kidney transplant recipients,” Eur J Clin Pharmacol, vol. 69, no. 2, pp. 189–195, Feb. 2013, doi: 10.1007/s00228-012-1330-6.
[7] A. Di Deo et al. “A model-based algorithm for mycophenolate dose adjustment in paediatric transplantation patients”, Clinical Pharmacology Report, Clinical Pharmacology & Therapeutics, UCL,[Unpublished].
Reference: PAGE 32 (2024) Abstr 11261 [www.page-meeting.org/?abstract=11261]
Poster: Drug/Disease Modelling - Other Topics