A Semi-mechanistic Model of Lymphocyte Dynamics in Patients with Multiple Sclerosis Treated with Cladribine Tablets

Transcription

1 A Semi-mechanistic Model of Lymphocyte Dynamics in Patients with Multiple Sclerosis Treated with Cladribine Tablets A.L. Quartino (), P. Girard (), M.O. Karlsson (), A. Munafo () () Dept of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; () Modeling and Simulation, Merck Serono S.A. Geneva, Switzerland* *An affiliate of Merck KGaA, Darmstadt, Germany Cladribine tablets: effective in multiple sclerosis (MS) Cladribine selectively reduces peripheral lymphocyte counts Evaluated in the 96-week, parallel group, double-blind phase III CLARITY trial (,6 patients) Placebo Cumulative dose. mg/kg courses (,, 8 and ) Cumulative dose. mg/kg 6 courses (,, 9,, 8 and ) Patients with no relapse (%) Cladribine tablets. mg/kg P<. Cladribine tablets. mg/kg P<. 7 Treatment course ( days) Placebo Cumulative no. of relapses Placebo Cladribine tablets. mg/kg p<. Cladribine tablets. mg/kg p< Giovannoni G, et al. N Engl J Med ;6():6 6

2 Most common adverse event: lymphocytopenia Lymphocytopenia was mostly graded as mild or moderate Infection rates may increase with severe lymphocytopenia (below CTCAE Grade ) Mean and observed ALC values in each patient over time The dotted blue line represents the lower limit of CTCAE Grade lymphopenia Placebo. mg/kg group. mg/kg group Lymphocyte count (* 9 /L) Time after dose (weeks) Treatment course ( days) ALC, absolute lymphocyte count; CTCAE, Common Terminology Criteria for Adverse Events Rationale and objectives of ALC model and simulator Treatment delay may be necessary in a few cases to allow recovery of ALC to above CTCAE Grade and prevent the development of severe lymphopenia Need for a tool to evaluate the potential impact of treatment delay Identify a predictive model for ALC Build a simulator for evaluation of Lymphocyte dynamics in the rare cases of patients requiring treatment delay Proportion of patients showing Grade and over, and their recovery time Percentage of patient completing treatments

3 Initial model for ALC Based on myelosuppression model Cladribine myelosuppression reversible effect + Cumulative cladribine non-reversible effect + Gender, body weight and creatinine clearance (CRCL) covariate influence A max* Dose E cum /CRCL Clad, cum = A Dose cum /CRCL + Feedback = ALC ALC t γ Proliferating cell pool Non-mitotic compartments Blood circulation ALC k circ = LN() / T½ E Clad = SLOPE * C p MMT=(n+)/. Friberg LE, et al. J Clin Oncol ;:7 Typical prediction ALC versus time (typical 67 kg female). mg/kg group. mg/kg group Cumulative drug effect Combined drug effect Transient drug effect Cumulative drug effect Combined drug effect Transient drug effect Lymphocyte count (* 9 /L) Time (weeks) 6

4 VPC looks OK... The model seems to adequately describe the data and its variability:., and 97. percentiles of observed data and their model-derived 9% CI Placebo. mg/kg group. mg/kg group Lymphocyte count (* 9 /L) Time after dose (weeks) CI, confidence interval; VPC, Visual Predictive Check 7 But NPC revealed over-estimation of lymphopenia after year NPC, Numerical Predictive Check 8 lymphopenia grade=; initial model lymphopenia grade=; initial model 8 6 lymphopenia grade=; initial model lymphopenia grade=; initial model,,, Observed % of patients with CTCAE grade Cladribine courses Simulated % of patients ALC check for rd course

5 Model update for ALC Cladribine myelosuppression reversible effect + Cumulative cladribine (formerly non-reversible) effect + Gender, body weight and CRCL covariate influence + Recovery on cumulative effect A max* Σ[Dose E cum /CRCL*e -K(t-Tdose) ] Clad, cum = A + Σ[Dose ALC γ cum /CRCL*e -K(t-Tdose) ] Feedback = ALC t Proliferating cell pool Non-mitotic compartments Blood circulation ALC k circ = LN() / T½ E Clad = SLOPE * C p MMT=(n+)/ 9 Model validation: with cumulative AUC recovery lymphopenia grade=; updated model lymphopenia grade=; updated model 8 6 lymphopenia grade=; updated model lymphopenia grade=; updated model,,, Observed % of patients with CTCAE grade Cladribine courses Simulated % of patients ALC check for rd course

6 Simulation of ALC model* Patients may in rare cases need to delay additional courses while their ALC recovers Mean and observed ALC values in each patient over time Lymphocyte count (* 9 /L).. mg/kg group Lower limit of CTCAE Grade Time after dose (weeks), patients resampled from CLARITY study database for gender, body weight, creatinine clearance and baseline ALC One course of treatment = days of body-weight, dose-adjusted cladribine tablets No more than courses of treatment per 8 weeks *TS (Pharsight, under Windows XP) Model + patient resampling in TS simulated patients and nominal dose timings Lymphocyte count (,/mmˆ).. 6. Time (weeks) 6

7 Simulation to estimate percentage of patients in CTCAE Grade at start of courses to, and their time to recovery Patients with Grade lymphopenia, % Week Week 9 Week Week after Grade observation NB This simulation assumes that if ALC <8 / mm at starting of nd, rd or th course, corresponding to weeks, 9 and, respectively, no more treatment is given Proportion of patients achieving to courses (simulated data) No postponing Postpone course when ALC <8/mm +% Patients % -8% -% Number of courses 7

8 Conclusions A model has been developed of lymphocyte dynamics with transient and slowly-recovering effect in patients with multiple sclerosis receiving cladribine tablets treatment The proposed model can be used to predict ALC dynamics in patients receiving cladribine tablets in a clinical trial or real-life setting Simulations allow exploration of % of patients recovering to CTCAE Grade and their recovery time % of patients completing the full treatment ( courses over 96 weeks) The ALC model is being coupled with an efficacy model It will be further refined with longer observation data Acknowledgements and disclosures Uppsala University Merck Serono Pharmacometrics Marianne Ekblom, PharmD, PhD Dan Mikol, MD This study was funded by Merck Serono S.A. Geneva, Switzerland* M Karlsson is a paid consultant for Merck Serono S.A.* A Munafo and P Girard are employees of Merck Serono S.A.* Cladribine tablets treatment is not approved in the USA. Marketing authorization for the use of cladribine tablets in patients with RRMS has been granted in Russia and Australia (). Please refer to full prescribing information for further details on use 6 *An affiliate of Merck KGaA, Darmstadt, Germany 8