A Semi-mechanistic Model of Lymphocyte Dynamics in Patients with Multiple Sclerosis Treated with Cladribine Tablets
A.L. Quartino (1), P. Girard (2), M.O. Karlsson (1), A. Munafo (2)
(1) Dept of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (2) Modelling and Simulation, Merck Serono S.A. – Geneva, Switzerland.
Objectives: Cladribine tablets therapy has shown substantial effectiveness in multiple sclerosis (MS) [1–3]. Since the drug selectively reduces peripheral lymphocyte counts, monitoring of absolute lymphocyte count (ALC) is pivotal. According to the Australian Prescribing Information , treatment (3.5 mg/kg cumulative dose over 96 weeks) is initiated with 2 consecutive courses of 4–5 days of cladribine tablets at a 28-day interval. Re-treatment comprises 2 additional courses at Weeks 48 and 52. However, patients can not receive a subsequent treatment course when their ALC is grade >=2 (Common Terminology Criteria for Adverse Events), and therefore patients may in rare cases need to delay additional courses while their ALC recovers. We developed an ALC model for MS patients receiving cladribine tablets, to gain more insight into lymphocyte dynamics in such patients by means of clinical trial simulation.
Methods: Our analysis was based on data from the randomized, placebo-controlled CLARITY study, with more than 19,000 ALC measurements from 1319 MS patients receiving cladribine tablets (3.5 mg/kg or 5.25 mg/kg over 96 weeks) or placebo . The exposure–ALC model was developed using NONMEM VI, based on the well-known myelosuppression model , adapted to include long-lasting inhibition, and validated by visual predictive check. The exposure–ALC model was implemented in Trial Simulator (Pharsight) to evaluate re-treatment with respect to lymphopenia and proportion of patients taking the (full) treatment courses. Patients’ covariates and baseline ALC were resampled from the CLARITY database.
Results: ALC response was well described by a model which included both a transient linear and a long-lasting saturable drug effect, driven by cladribine concentrations and cumulative AUC, respectively. The lymphocyte mean transit time in bone marrow was set to 81h. The dual model correctly predicted the rapid drop and slow recovery of ALC over time. The recovery t1/2 was long (average 90 weeks) and highly variable between patients (138%). Gender was the only covariate identified, women being more sensitive to transient drug effect (+31% in slope).
Conclusion: The dynamics of ALC response to cladribine tablets was quantified and characterized based on a large database in MS. A dual model with transient and long-lasting drug effects described the time-course of ALC well. The proposed model allows prediction of ALC dynamics in patients receiving cladribine tablets in a clinical trial or market setting.
 Giovannoni G, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010;362(5):416–26.
 Savic R, Munafo A, Karlsson M. The effect of cladribine tablets on disease progression in multiple sclerosis: a non-linear mixed effect analysis. Poster P477 presented at: 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), 13–16 October 2010, Gothenburg, Sweden.
 Savic R, Munafo A, Karlsson M. Disease progression model for multiple sclerosis and effect of cladribine tablets therapy on clinical endpoints. Poster presented at: American Conference on Pharmacometrics (ACoP), 3–6 April 2011, San Diego, USA.
 Merck Serono Australia Pty Ltd. Movectro Tablets Product Information. 12 November 2010.
 Friberg L, et al. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol 2002;20:4713–21.
This study was funded by Merck Serono S.A. – Geneva, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany.
AL. Quartino and MO. Karlsson are paid consultants for Merck Serono S.A.; P. Girard and A. Munafo are employees of Merck Serono S.A.