Importance of study design for estimation of Vmax and Km characterising nonlinear monoclonal antibody clearance
Niebecker, R. (1, 2), Drescher, A. (1), Kloft, C. (1)
(1) Department of Clinical Pharmacy, Martin-Luther-Universitaet Halle-Wittenberg/Freie Universitaet Berlin, (2) and Graduate Research Training program PharMetrX, Germany
Objectives: For numerous monoclonal antibodies (mAbs), nonlinear pharmacokinetics (PK) has been reported, and Michaelis-Menten elimination pathways are commonly employed in population PK models [1, 2]. However, characterisation of this nonlinearity – in particular Vmax and Km – did not always succeed, thus linear models were often regarded as sufficient. As PK analyses depend on the data situation, the number and range of dose groups in the clinical studies together with other aspects of study design influence the reliability – i.e. accuracy and precision – of parameter estimation. The objectives of this analysis were to explore the importance of several dose groups concerning the estimation of Vmax and Km at the example of a humanised mAb directed at a tissue-bound antigen, and to establish a workflow for more systematic investigations on critical parameters of study design.
Methods: The PK of the mAb has been previously described by a 2-compartment model with parallel linear and Michaelis-Menten elimination from the central disposition compartment. Model development was based on data from three multicentre multiple-dose studies. Dosing ranged from 5 mg/m² body surface area to a fixed dose of 100 mg. For the current investi-gations, the total dataset was split in two: A low dose subset (median dose=11 mg) and a high dose subset (median dose=100 mg) were analysed separately. In order to establish a basis for more systematic investigations, analyses with stochastically simulated data were to be performed. The development of an appropriate workflow was based on that reported in a recent simulation study . All analyses were performed with NONMEMTM VI FOCEI.
Results: For the total dataset, the estimates for Vmax and Km were 141 µg/h [95% CI: 74.4; 226] and 1.43 µg/mL [95% CI: 0.646; 2.92], respectively. If estimation was based on the two subsets, considerable differences became apparent: The point estimates for Vmax and Km were up to 12-fold and 40-fold higher for the high dose subset, compared to the low dose subset. The workflow for systematic simulation studies from  could successfully be adapted to the local IT environment and is currently exploited.
Conclusions: The investigations confirmed the influence of study design and in particular the administered dosing regimen on parameter estimates. Using the established workflow, further research might contribute to study design enabling better determination of critical model parameters.
 N.L. Dirks, B. Meibohm. Clin Pharmacokinet 49: 633–59 (2010).
 K. Kuester, C. Kloft. In: B. Meibohm (ed): Pharmacokinetics and pharmacodynamics of biotech drugs. Wiley-VCH, Weinheim: 45–91 (2006).
 N.L. Dirks, PhD thesis, The University of Tennessee (2010).