Impact of Different Body Size Descriptors on the Population Pharmacokinetics of a Monoclonal Antibody
R. Niebecker (1,2), K. Kuester (1), U. Kunz (3), C. Kloft (1)
(1) Department of Clinical Pharmacy, Martin-Luther-Universitaet Halle-Wittenberg (2) Graduate Research Training program PharMetrX (3) Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, all Germany
Objectives: Pharmacokinetics (PK) of monoclonal antibodies and in particular their clearances have been reported to be related to body size [1]. Covariate relations in population PK models utilised different body size descriptors (BSD), including body weight (BW), body surface area (BSA) or ideal body weight (IBW) [2]. The objective of this analysis was to compare the suitability of different BSDs in a sibrotuzumab population PK model, to suggest the optimal BSD and to investigate the impact of extremes in body size on drug exposure.
Methods: Sibrotuzumab PK has best been described with a two-compartment model with both linear and nonlinear elimination (parameterised with Vmax and Km) from the central disposition compartment, interindividual (IIV) and interoccasion variability (IOV). BW was included as a covariate on 4 structural model parameters, in a linear covariate relation [3]. Nonlinear mixed-effect modelling with NONMEMTM was applied to estimate model parameters for the baseline model excluding covariates and for the models including the following BSDs: BW, patient height, body mass index (BMI), BSA, fat-free mass, IBW, lean-body mass.
Results: (i) Compared to the baseline model, incorporation of body size significantly improved model performance: the objective function value decreased, unexplained variability was reduced, particularly IIV on the volumes of distribution and Vmax. Despite the highest relative covariate effect, IIV of linear clearance (CLL) was only marginally reduced. IOV remained virtually unaffected. (ii) The different BSDs performed similar, with the exception of BMI, being inferior. (iii) Covariate relations in patients with median and “extreme“ (0.05 and 0.95 percentile) BSD values indicated considerable influence of body size on CLL and the central volume of distribution. (iv) These influences were confirmed by deterministic simulations of the concentration-time profiles for a 12 week treatment period with weekly dosing of 100 mg sibrotuzumab. Minimum Css in patients with “extremely low” body size even exceeded maximum Css of patients with “extremely high” body size.
Conclusions: The analysis confirmed that body size does have an impact on sibrotuzumab PK. No single BSD appears to be superior. In order to further evaluate this hypothesis, different covariate models including the allometric power model will be investigated, and stochastic simulation will be implemented.
References:
[1] D.R. Mould, B. Green. BioDrugs 24: 23 (2010).
[2] D.D. Wang. J Clin Pharmacol 49: 1012 (2009).
[3] C. Kloft et al. Invest New Drugs 22: 39 (2004).