P. Chanu (1), F. Mercier (1)
(1) Pharsight Consulting Services, Pharsight, a CertaraTM Company
Objectives: The “One dose fits all” concept still dominates in clinical development. Pharmacometrics could definitely contribute to implement Personalized Healthcare (PH). S1P (Sphingosine 1-phosphate) receptor modulators prevent the egress of lymphocytes from lymph nodes, reducing the amount of circulating lymphocytes and their potential to transit to the brain and damage neurons in relapsing forms of multiple sclerosis (RRMS). As a consequence of their therapeutic effect, S1P receptor modulators induce lymphopenia. Siponimod, is a S1P receptor modulator currently in Phase 3. Model-based simulations were performed to investigate how dose individualization could improve its efficacy and safety.
Methods: A simulation framework using public-domain information was developed to describe the clinical effect of siponimod. A PK model and a drug-specific model linking siponimod concentration to lymphocyte count [1] were implemented in Pharsight® Trial SimulatorTM. Model-based simulations were performed targeting lymphocyte count between 0.2 to 0.5 109/L. Four different daily siponimod dose regimens were tested: 1 mg; 2 mg; 1 mg starting dose with one dose adjustment (-50% or +100% when above or below the target) 2 weeks after treatment initiation; and 1 mg starting dose with two dose adjustments 2 and 4 weeks after treatment initiation. Drug-independent models linking lymphocyte count to lesion count [2], and lesion count to relapse rate [3] were used to simulate clinical efficacy.
Results: Simulations results showed a clear benefit of both dose-adjustment scenarios over both fixed-dose scenarios with approximately 25% of subjects within target after 7 weeks versus 12% respectively. Simulations results showed a reduction of the risk of grade 4 lymphopenia (9/L) by 50% with dose-adjustment scenarios. Simulated clinical efficacy (lesion count and relapse rate) was similar for the four dosing regimens though with less variability with those using dose adjustments.
Conclusions: Simulations showed the benefit of dose adjustments during the first weeks of treatment with siponimod using a simple dose adjustment algorithm. This is particular interesting for drug classes where efficacy and safety can be monitored by the same biomarker and model-based simulations can help delineate best dosing strategies to maximize therapeutic index.
References:
[1] Pigeolet E. et al. Population PKPD modeling of dose-response and time course of peripheral lymphocytes after single and repeated administration of the S1P1/5 modulator, BAF312, in healthy volunteers. PAGE 20 (2011) Abstr 2089 [www.page-meeting.org/?abstract=2089].
[2] Hartung et al. The selective sphingosine 1-phosphate receptor modulator siponimod (BAF312): magnetic resonance imaging lesion and lymphocyte relationship in a phase 2 study in relapsing–remitting multiple sclerosis. European Committee for Treatment and Research in Multiple Sclerosis (2012).
[3] Sormani et al. Magnetic resonance imaging as a potential surrogate for relapses in multiple sclerosis: a meta-analytic approach. Ann Neurol (2009) 65: 268–275.
Reference: PAGE 24 () Abstr 3414 [www.page-meeting.org/?abstract=3414]
Poster: Methodology - Study Design