PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
PAGE 21 (2012) Abstr 2383 [www.page-meeting.org/?abstract=2383]
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Poster: Other Drug/Disease Modelling
Nicholas Frey (1), Olivier Harari (2) and Leonid Gibiansky (3)
(1) F. Hoffmann-La Roche Ltd, Basel, Switzerland; (2) Roche Products Ltd, Welwyn, United Kingdom; (3) QuantPharm LLC, North Potomac, MD, USA
Objectives: Tocilizumab (TCZ) is a recombinant humanized IL-6 receptor monoclonal antibody that inhibits binding of IL-6 to its receptors. The aim of the analysis was to describe the time course of peripheral neutrophil counts (NTC) after TCZ administration in a pediatric population.
Methods: Serum TCZ concentrations and NTC were available from 75 patients with active systemic juvenile idiopathic arthritis (sJIA) who received 12 mg/kg (for patients < 30 kg) or 8 mg/kg (for patients ≥ 30 kg) infusions of TCZ every 2 weeks (total of 6 doses). Neutrophil counts were assessed at screening, baseline (week 0), and at 1, 2, 3, 6, 8, 10 and 12 weeks. A previously developed two-compartment model with parallel linear and Michaelis-Menten elimination described TCZ concentrations [1, 2]. Different PKPD models with direct and indirect response were tested to characterize the TCZ-NTC relationship.
Results: The TCZ-NTC relationship was described by a model that included an immediate TCZ effect on NTC decline (possibly, neutrophil margination ) and a longer term TCZ effect on NTC decline (toward normal levels) due to the improvement of patients' condition (e.g. decrease of inflammation). The immediate effect was described by a direct sigmoid Emax model (Emax = 0.724 (%RSE 14.8%) and EC50 = 6.38 µg/mL (%RSE 15.8%)). The PKPD parameters were very similar to the respective values obtained earlier for adult patients  (Emax = 0.788 and EC50 = 7.49 mcg/mL). The maximum rate of decline of the long term effect was 0.166 day-1 and the TCZ concentration corresponding to half of this rate was 151 µg/mL. The corresponding NTC decline for a typical patient was estimated to go from 8.12×109/L to 5.72×109/L. Diagnostic plots and predictive check simulations indicated a good agreement of model predictions with the observed data.
Conclusions: The NTC time course following TCZ administration in pediatric patients with sJIA was characterized by a combination of an immediate response corresponding to the direct blockade of the IL-6 signaling pathway and a slow decline possibly related to the improvement of the patients' condition (e.g. decrease of inflammation)