Carla Bastida (1,2), Dolors Soy (2,3), Virginia RuÃz (3,4), Raimon Sanmartà (3,4), Mariona Pascal (3,5), Jordi Yagüe (3,5), Alwin D.R. Huitema(1,6)
(1) Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek, Amsterdam, The Netherlands. (2) Pharmacy Department, Division of Medicines, Hospital Clinic Barcelona, Universitat de Barcelona, Spain. (3) IDIBAPS, Barcelona, Spain. (4) Arthritis Unit, Rheumatology Department, Hospital Clinic Barcelona, Universitat de Barcelona, Spain. (5) Immunology Department, CDB, Hospital Clinic Barcelona, Universitat de Barcelona, Spain. (6) Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Introduction: Tocilizumab (TCZ) is a humanized anti-IL-6 receptor monoclonal antibody that has shown efficacy in the management of moderate to severe rheumatoid arthritis (RA) [1]. Disease activity in RA patients is routinely assessed using composite indexes that include clinical and/or laboratory variables. We find the disease activity score using 28 joint counts (DAS28) in its two versions employing erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) and the simplified and clinical disease activity scores (SDAI and CDAI, respectively). Formulas are shown below:
– DAS28-ESR = 0.56*SQRT(TJC) + 0.28*SQRT(SJC) + 0.70*ln(ESR) + 0.014*PGA (mm)
– SDAI = SJC + TJC + PGA (cm) + EGA (cm) + CRP (mg/dL)
– CDAI = SJC + TJC + PGA (cm) + EGA (cm)
*EGA: global health assessment by the evaluator; PGA: global health assessment by the patient; SJC: swollen joint count; TJC: tender joint count.
These composite indexes assume all variables to have the same dynamics but on TCZ treatment, it has been reported that inflammatory markers (CRP and ESR) show faster response compared to clinical variables, which complicates interpretation of these composite indexes [2].
Objectives: The purpose of the study was to assess the dynamics of the different individual variables included in composite indexes in RA patients on treatment with intravenous (iv) TCZ using a modeling approach.
Methods: Pharmacokinetic and clinical data were obtained from a prospective, observational, single-center study involving 35 subjects with RA treated with iv TCZ at a dose range from 4 to 8 mg/kg every 28 days. Clinical data and levels of inflammation markers such as CRP and ESR were retrospectively collected from the beginning of TCZ treatment every 28 days until the moment of inclusion at the PK study. A PK/pharmacodynamics (PKPD) model was developed using a previously published PK model and non-linear mixed-effects modeling implemented in NONMEM v7.3 [3].
Results: The relationship between TCZ concentration and disease activity was described using an indirect response model with inhibition of the variable input (Kin). Dynamics of the PD data could be adequately described grouping them in slow-decreasing variables (for tender and swollen joint counts and patient and evaluator global health assessment) and fast-decreasing variables (for CRP and ESR). Slow decreasing variables show a higher EC50 (EC50: 6.98 µg/mL (RSE 6.7%, IIV: 155%)) and a lower maximum effect (Emax: 0.765 (RSE 2.8%)) and output constant (Kout: 0.00117 h-1 (RSE 12%, IIV: 73.6%)) than the fast decreasing variables, which have an EC50 of 1.06 µg/mL (RSE 22.5%, IIV: 103%), Emax: 1 (not estimated) and Kout: 0.00245 h-1 (RSE 15.6%, IIV: 68.8%).
*EC50: concentration at which 50% of the maximum effect is reached; IIV: inter-individual variability; RSE: relative standard error.
Conclusions: Higher serum TCZ concentrations are needed to normalize tender/swollen joint counts and health assessment values than to normalize inflammation markers such as CRP and ESR. Moreover, composite indexes that include fast-decreasing variables in their formula (DAS28-ESR and SDAI), would overestimate the number of patients in remission at the beginning of the treatment with TCZ.
References:
[1] Bastida et al. Br J Clin Pharmacol. (2018) Jan 4
[2] Nishimoto et al. Mod Rheumatol (2010) 20:539–547
[3] Beal SL et al. 1989-2011. NONMEM Users Guides. Icon Development Solutions, Ellicott City, Maryland, USA.
Reference: PAGE 27 (2018) Abstr 8482 [www.page-meeting.org/?abstract=8482]
Poster: Drug/Disease Modelling - Other Topics