Paul Healy (1), Pauline P. Thémans (1), J-P. Casas (2), Oscar Della Pasqua (1)
(1) Clinical Pharmacology & Therapeutics, School of Pharmacy, University College London, (2) Institute of Health Informatics, Faculty of Population Health Sciences, University College London.
Objectives: Whereas moderate C-reactive protein (CRP) elevation in the general population is linked to long-term risk of coronary heart disease, an exponential, acute escalation of CRP following myocardial infarction (MI) has been found to be associated with increased risk of death and cardiac complications [1]. Tocilizumab (TCZ), a humanized monoclonal antibody that inhibits IL-6 receptor-binding, is currently indicated in rheumatoid arthritis and juvenile idiopathic arthritis (dosages of 4-12mg/kg). We assessed the dose rationale for preventing reperfusion injury in patients subjected to percutaneous coronary angioplasty (PCA) following an acute MI. To be efficacious in the proposed indication, tocilizumab effects on CRP levels must be clinically significant within 48h post-dose.
Methods: Pharmacokinetic (PK) and pharmacodynamic (PD) parameter data (such as clearance rate, volumes of distribution of TCZ and endogenous production rates of CRP production) from published literature were used with hierarchical modelling to assess the impact of different TCZ doses on CRP levels. An existing PK model [2] enabled the simulation of plasma TCZ concentrations, which were then used as input into a final pharmacokinetic-pharmacodynamic (PKPD) model to describe the inhibitory effects of TCZ on CRP levels. Clinical trial simulations were performed using a cohort of virtual ‘at-risk subjects’ assembled from the NHANES database to characterise the overall response to different TCZ doses ranging from 4-16mg/kg, proposed to treat patients post-MI in a hospital setting.
Results: Our results show that a single intravenous infusion (IV) at 4mg/kg per dose produces significant inhibition levels within 150h after administration of a single dose. Higher doses of 8mg/kg and 12mg/kg only demonstrated a prolonged, dose-dependent effect of TCZ on CRP, without a significantly faster onset of action.
Conclusion: In conclusion, modelling and simulation has allowed us to inspect the dose rationale for TCZ in a new indication. However, our analysis suggests that CRP inhibition reached within 48h may not translate into a protective anti-inflammatory response.
References:
[1] Casas JP, Shah T, Hingorani AD, Danesh J, Pepys MB. C-reactive protein and coronary heart disease: a critical review. J Intern Med. 2008 Oct;264(4):295-314.
[2] Frey N, Grange S, Woodworth T, Population pharmacokinetic analysis of tocilizumab in patients with rheumatoid arthritis, J Clin Pharmacol. 2010;50 754-766.
Reference: PAGE 25 (2016) Abstr 5719 [www.page-meeting.org/?abstract=5719]
Poster: Drug/Disease modeling - Other topics