• Carla Bastida, Virginia Ruiz-Esquide, Mariona Pascal, Aurelia H M de Vries Schultink, Jordi Yagüe, Raimon Sanmartí, HuitemaAlwin D RADRDepartment of Pharmacy & Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., and Dolors Soy.
• Pharmacy Department, Division of Medicines, Hospital Clinic Barcelona, Universitat de Barcelona, Spain.
• Br J Clin Pharmacol. 2018 Apr 1; 84 (4): 716-725.

AimsIntravenous 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.MethodsSerum 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 .ResultsA 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.ConclusionsOur 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.© 2018 The British Pharmacological Society.

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