Population pharmacokinetic model for intravenous tocilizumab in rheumatoid arthritis
Carla Bastida (1), Virginia Ruíz (2,5), Aurelia H.M. de Vries Schultink (1), Raimon Sanmartí (2,5), Mariona Pascal (3,5), Jordi Yagüe (3,5) Alwin D.R. Huitema (1,6) and Dolors Soy (4,5)
(1) Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek, Amsterdam, The Netherlands. (2) Rheumatology Department, Hospital Clinic Barcelona, Spain. (3) Immunology Department, Hospital Clinic Barcelona, Spain. (4) Pharmacy Department, Hospital Clinic Barcelona, Spain. (5) IDIBAPS, Barcelona, Spain. (6) Department of Clinical Pharmacy, University Medical Center Utrecht, The Netherlands.
Objectives: To develop a population pharmacokinetic (PK) model to describe the PK characteristics of intravenous (iv) tocilizumab (TCZ), estimate interindividual variability (IIV) and assess the influence of different covariates.
Methods: PK and clinical data were obtained from a prospective, observational, single-center study involving 35 subjects with rheumatoid arthritis (RA) treated with iv TCZ at a dose range from 8 to 4 mg/kg every 28 days. Samples were collected before TCZ administration and, when possible, once a week until the next administration. A PK model was developed using non-linear mixed-effects modeling implemented in NONMEM v7.3. Internal evaluation was assessed by visual predictive checks (VPC) and bootstrap resampling technique (with replacement).
Results: A total of 109 TCZ serum concentrations were adequately described by a one-compartment disposition model with parallel first-order (linear) and Michaelis-Menten (nonlinear) elimination kinetics. IIV was incorporated on clearance (CL) and volume of distribution (V) parameters. Residual variability was characterized by a combined error model with an additive part of 0.165 µg/mL (SD) and a proportional part of 24.2% (CV). Weight and C-reactive protein (CRP) levels (inflammatory biomarker) significantly affected CL. An increase in weight from 40 to 110 kg led to a 34% increase in CL and an increase of CRP levels from 0.01 to 20 mg/dL led to a 122% increase in CL. The VPC indicated adequate goodness-of-fit and the bootstrap 95% CIs demonstrated satisfactory precision.
Conclusions: A population PK model was developed to describe the PK of iv TCZ in RA patients. Drug disposition was significantly affected by weight and an inflammatory biomarker.
References:
[1] Shetty A et al. Drug Des Devel Ther 2014;8:349–64.
[2] Beal SL et al. NONMEM users guides (1989–2011), v. 7.3. Icon Development Solutions, Ellicott City, USA.