Fixed dosing of intravenous tocilizumab in rheumatoid arthritis. Results from a population pharmacokinetic analysis

Abstract

Aims: Intravenous tocilizumab is currently dosed on body weight, although a weak correlation between body weight and clearance has been described. The aim of the study was to assess the current dosing strategy and provide a scientific rational for dosing using a modelling and simulation approach.

Methods: Serum concentrations and covariates were obtained from intravenous tocilizumab treated subjects at a dose of 4, 6 or 8 mg every 28 days. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling. The final model was used to simulate tocilizumab exposure to assess a dosing strategy based on body weight or fixed dosing, using as target a cumulative area under the curve at 24 weeks of treatment above 100 × 103 μg h ml-1 .

Results: A one-compartment disposition model with parallel linear and nonlinear elimination best described the concentration-time data. The typical population mean values for clearance, apparent volume of distribution, maximum elimination rate and Michaelis-Menten constant were 0.0104 l h-1 , 4.83 l, 0.239 mg h-1 and 4.22 μg ml-1 , respectively. Interindividual variability was included for clearance (17.0%) and volume of distribution (30.8%). Significant covariates for clearance were patient body weight and C-reactive protein serum levels. An estimated exponent for body weight of 0.360 confirms the weak relationship with tocilizumab clearance. Simulations demonstrate that patients with lower weights are at risk of underdosing if the weight-based dosing approach is used. However, fixed-dosing provides a more consistent drug exposure regardless of weight category.

Conclusions: Our study provides evidence to support fixed dosing of intravenous tocilizumab in rheumatoid arthritis patients since it reduces variability in tocilizumab exposure among weight categories compared to the current weight-based dosing approach.

Keywords: body weight; fixed dosing; monoclonal antibodies; population pharmacokinetics; rheumatoid arthritis; tocilizumab.

© 2018 The British Pharmacological Society.

Figures

Figure 1

Visual predictive check of the final pharmacokinetic model. Comparisons were performed between the 10th, 90th (dashed lines) and 50th (solid line) percentiles of the observed tocilizumab plasma concentrations (open circles) vs. time after dose (h) and the 80% confidence interval (shaded area) obtained from 1000 simulations

Figure 2

Box plot of cumulative area under the curve (cAUC) values at 24 weeks of treatment with intravenous tocilizumab at different doses along weight (WT) categories, from our population final PK model, without considering the effect of C‐reactive protein. Target is set in a cAUC values above 100 × 103 μg h ml–1. Median (percentile 50: q50) of the data set is represented with a solid line inside the box. Box edges are the third (q75) and first quartile (q25) for the superior and inferior, respectively. Superior and inferior limits (q90 and q10) are depicted with a thin horizontal line. Dots represent outliers. (a) 8 mg kg–1; (b) 6 mg kg–1; (c) 4 mg kg–1; (d) 560 mg; (e) 420 mg; (f) 280 mg. (Results from 1000 simulations)

Figure 3

Percentage of patients reaching the efficacy target (cumulative area under the curve at 24 weeks of treatment with intravenous tocilizumab above 100 × 103 μg h ml–1) with intravenous tocilizumab at different doses: high dose, 560 mg and 8 mg kg–1; medium dose, 420 mg and 6 mg kg–1; low dose, 280 mg and 4 mg kg–1 along a weight (WT) range, using two different dosing approaches: fixed dosing (solid line) vs. body‐weight based dosing (dashed line). Results from 1000 simulations, without considering the effect of CRP (left column) and considering a CRP of 2.8 mg dl–1 (right column)