Carla Bastida (1,2), Merel J l’Ami (3), Gerrit Jan Wolbink (3,4), Raimon Sanmartà (5), Alwin D.R. Huitema(1,6) , Dolors Soy (2,7).
(1) Department of Pharmacy & Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands. (2) Pharmacy Service, Division of Medicines, Hospital Clinic Barcelona, Universitat de Barcelona, Spain. (3) Rheumatology, Amsterdam Rheumatology and immunology Center, Location Reade, Amsterdam, The Netherlands. (4) Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, Amsterdam, The Netherlands. (5) Arthritis Unit, Rheumatology Department, Hospital Clinic Barcelona, Universitat de Barcelona, Spain. (6) Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. (7) IDIBAPS, Barcelona, Spain.
Introduction: Tocilizumab is a humanized monoclonal antibody approved for the treatment of rheumatoid arthritis (RA) that competitively inhibits interleukin 6 receptors [1]. In Europe, it is current practice to implement empirical dose tapering strategies in those patients showing sustained remission or low disease activity (LDA) [2] to avoid overtreatment, minimize side-effects and foster a reduction in costs. Another approach is the Therapeutic Drug Monitoring (TDM)-guided dose tapering, which has already been proven to be superior to empirical dose tapering in inflammatory bowel disease [3] and comparable in RA [4,5].
Objectives: Using modeling and simulation, the aim was to compare different dose tapering strategies for iv tocilizumab and assess the performance of these strategies by quantifying the percentage of patients who maintain in disease remission/LDA according to the Disease Activity in 28 joints (DAS28) score, as well as the reduction in direct drug-related costs.
Methods: A previously developed PKPD model for iv tocilizumab [6] was used for simulations. A total of four scenarios were evaluated on a simulated population of 5000 individuals. In all scenarios, the same initial dose was administered every 28 days for six consecutive months. After six months of treatment, different dose tapering strategies were considered:
- Scenario 1: Label dosing; Label-dosing was continued at 8 mg/kg every 28 days [1].
- Scenario 2: Mild Empirical dose tapering; In those individuals in disease remission/LDA a 25% dose reduction of the initial label dose was applied, resulting in 6 mg/kg every 28 days.
- Scenario 3: Intense Empirical dose tapering; In those individuals in disease remission/LDA a 50% dose reduction of the initial label dose was applied, leading to a final dosing of 4 mg/kg every 28 days.
- Scenario 4: TDM-guided dose tapering; If Ctrough at six months was ≥5 µg/mL, a dose reduction was applied. This dose reduction was conducted using a model-based algorithm [7] in which subsequent doses were chosen to approach the steady-state target Ctrough of 5(±1) µg/mL. This PK target was chosen based on literature [6,8]. Subsequent simulated doses for patients with a Ctrough
The different strategies were primarily evaluated on the proportion of patients who maintain remission/LDA one year after the intervention. In addition, cost savings of direct drug costs were estimated.
All PKPD simulations and dose optimizations were performed with R [9], using the differential equation-solving R-packaged deSolve.
Results: After six months of treatment at the initial dose, 77.5% of the simulated population was in DAS28 remission/LDA and 79.7% showed serum drug concentrations ≥5 µg/mL.
The overall proportion of simulated patients in DAS28 remission/LDA after one year of the intervention was comparable between the mild empirical dose-tapering strategy and the TDM-guided dose tapering strategy (80.3% and 78.2%, respectively). The intense empirical dose-tapering strategy showed a lower overall percentage of patients in DAS28 remission/LDA (69.0%). Likewise, one-year flare rates were lower for the mild empirical dose tapering and TDM-guided tapering strategies (6.5% and 10.6%, respectively) compared to a 24.8% flare rate for the intense empirical dose-tapering strategy. There was also a difference between the cost-savings among the three tapering strategies (relative dose intensity was of 80.4%, 61.2% and 71.0% for the mild and intense empirical dose-tapering and the TDM-guided dose tapering strategies, respectively).
A lower variability in serum drug concentrations was observed for the TDM-guided strategy compared to the other tested scenarios. Within the empirical tapering strategies, higher simulated median serum drug concentrations were found in patients who kept in remission/LDA compared to those who lost response after tapering.
Conclusions: From the in silico study, we demonstrated that the TDM-guided strategy using model-based algorithms approach performed similarly to mild empirical dose tapering strategies in overall remission/LDA rates but proved to be superior in target achievement and cost-savings. Further studies are needed to test new dose tapering strategies for iv tocilizumab based on TDM using the developed algorithms as a tool to optimize patients’ treatment in clinical practice.
References:
[1] RoActemra® SPC (Roche registration Limited), 2009.
[2] Inciarte-Mundo J, et al. Reumatol Clin. 10:10–6.
[3] Spencer EA, Dubinsky MC. Pediatr Clin North Am. 2017;64:1309–26.
[4] l’Ami MJ, et al. Ann Rheum Dis. 2018;77:484–7.
[5] Mulleman D, Balsa A. Ann Rheum Dis. 2018;77:473–5.
[6] Bastida C, et al. [under review]
[7] Bastida C, et al. Br J Clin Pharmacol. 2018;84:716–25.
[8] Levi M, et al. J Clin Pharmacol. 2013;53:151–9.
[9] Schett G, et al. Ann Rheum Dis. 2016;75:1428–37.
Reference: PAGE 28 (2019) Abstr 8812 [www.page-meeting.org/?abstract=8812]
Poster: Clinical Applications