Stefan P. H. van den Berg (1), Alyssa A. Toorop (3), Femke Hooijberg (4), Gertjan Wolbink (4), Nivea M.F. Voelkner (1), Liza M.Y. Gelissen (3), Joep Killestein (3), Zoé L. E. van Kempen (3), Thomas P.C. Dorlo (2), Theo Rispens (1)
(1) Department of Immunopathology, Sanquin Research Amsterdam, Amsterdam, The Netherlands, (2) Department of Pharmacy, Uppsala University, Uppsala, Sweden, (3) MS Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands, (4) Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, location Reade Amsterdam, Amsterdam, The Netherlands
Introduction: Natalizumab is highly effective in treating relapsing-remitting multiple sclerosis. However, the standard intravenous treatment interval of 4 weeks may be excessive for many patients [1,2]. Monoclonal antibodies exhibit high inter-individual variability, which underscores the importance of a personalized approach rather than a one-size-fits-all treatment [3]. Therefore, personalized interval extension guided by therapeutic drug monitoring (TDM) was executed to reach trough concentrations of either 10 or 5 µg/mL [4]. More recently, a trough concentration of 2 µg/mL has been proposed as a therapeutic target for efficacy [5]. By tailoring the dosing schedule, patients can achieve optimal drug exposure while minimizing side effects, hospital visits and healthcare expenses.
Objectives
- Would model-informed precision dosing (MIPD) improve selection of individual treatment intervals compared to a deployed TDM-based protocol, resulting in better precision of target attainment by less variability in trough levels and closer proximity to the target?
- Would MIPD be feasible to pursue a therapeutic trough concentration of 2 µg/mL?
Methods: Currently a personalized interval dosing protocol is deployed, further referred to as the TDM-based protocol. Intervals were determined on two 4-week interval trough samples and the target concentration, being either 10 or 5 µg/mL, while maintaining a dose of 300 mg. E.g. if two samples were above 45 µg/mL at trough, the new interval was 7 weeks. While one sample below 15 µg/mL resulted in a standard 4-week interval. The specific details are outlined in the corresponding publication [4].
Here, a population PK model was developed using NONMEM® on data collected in these studies deploying the TDM-based protocol including 322 patients in clinics across the Netherlands. Individual posterior PK estimates, referred to as empirical Bayesian estimates (EBEs) were derived using patient height, weight and two trough concentrations at the standard dose interval using MAXEVAL=0.
Individual PK were simulated using EBEs using dose intervals ranging from 3 to 10 complete weeks. Then, the model-informed interval was defined as the interval with the shortest distance between simulated trough and target concentration.
Model performance was assessed using EBEs to predict trough levels at extended intervals. The error between the prediction and the observation were quantified and expressed as the mean absolute prediction error (MAPE) and mean percentage prediction error (MPPE).
The following performance metrics were calculated for both the TDM-guided interval and the model-informed interval. Precision was assessed by the variability in simulated trough concentrations and root mean squared error (RMSE) between the simulated trough and target concentration. Bias was assessed by the mean percentage error (MPE) between the simulated trough and target concentration.
Simulations incorporating EBEs were conducted to assess the feasibility of attaining a therapeutic trough concentration of 2 µg/mL, with the interval chosen to achieve a simulated trough level closest to, and above, this target.
Results: Overall model performance revealed a MAPE of 22% and MPPE of 4.7%. Predicted trough levels associated with the model-informed interval compared to the TDM-guided interval exhibited 50% less variability for both 10 and 5 µg/mL as a trough target, resp. 4.8 vs 9.5 CV% and 2.5 vs 6.8%. The precision, in terms of the RMSE, when comparing the model-informed interval versus the TDM-guided interval for both 10 and 5 µg/mL, resulted in resp. 2.2 vs 3.9 µg/mL and 1.57 versus 5 µg/mL. The bias as demonstrated by the MPE of the model-informed interval versus the TDM-guided interval for both 10 and 5 µg/mL, exhibited resp. 3.5 vs 24.2% and 4.9 vs 87.2%.
Simulation with EBEs to reach 2 µg/mL resulted in a median (IQR) trough level of 3.5 (2.65-5) µg/mL. MIPD demonstrated an average dose interval of 7 weeks compared to 4 weeks, reducing infusions on average per patient per year by 40%.
Conclusions: MIPD outperformed the TDM-based protocol by providing improved precision in selecting individual treatment intervals, and resulting in more precise trough target attainment. Simulations further indicate a preferential clinical deployment of MIPD for natalizumab in terms of healthcare and patient burden.
References:
[1] Bomprezzi, R. and Pawate, S. (2014) ‘Extended interval dosing of natalizumab: a two-center, 7-year experience’, Therapeutic Advances in Neurological Disorders, 7(5), pp. 227–231. Available at: https://doi.org/10.1177/1756285614540224.
[2] Zhovtis Ryerson, L. et al. (2016) ‘Extended interval dosing of natalizumab in multiple sclerosis’, Journal of Neurology, Neurosurgery & Psychiatry, 87(8), pp. 885–889. Available at: https://doi.org/10.1136/jnnp-2015-312940.
[3] Bensalem, A. and Ternant, D. (2020) ‘Pharmacokinetic Variability of Therapeutic Antibodies in Humans: A Comprehensive Review of Population Pharmacokinetic Modeling Publications’, Clinical Pharmacokinetics, 59(7), pp. 857–874. Available at: https://doi.org/10.1007/s40262-020-00874-2.
[4] Toorop, A.A., Van Lierop, Z.Y., et al. (2023) ‘Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS)’, Journal of Neurology, Neurosurgery & Psychiatry, p. jnnp-2023-332119. Available at: https://doi.org/10.1136/jnnp-2023-332119.
[5] Van Kempen, Z.L. et al. (2022) ‘Extended dosing of monoclonal antibodies in multiple sclerosis’, Multiple Sclerosis Journal, 28(13), pp. 2001–2009. Available at: https://doi.org/10.1177/13524585211065711.
Reference: PAGE 32 (2024) Abstr 10891 [www.page-meeting.org/?abstract=10891]
Poster: Clinical Applications