22-09-2012, 10:51 AM
The projection of human pharmacokinetic (PK)
Abstract
The pharmacokinetics (PK) of therapeutic antibodies is determined by target and non-target mediated mechanisms. These antibody-specific factors need to be considered during prediction of human PK based upon preclinical information. Principles of allometric scaling established for small molecules using data from multiple animal species cannot be directly applied to antibodies. Here, different methods for projecting human clearance (CL) from animal PK data for 13 therapeutic monoclonal antibodies (mAbs) exhibiting linear PK over the tested dose ranges were examined: simple allometric scaling (CL versus body weight), allometric scaling with correction factors, allometric scaling based on rule of exponent and scaling from only cynomolgus monkey PK data. A better correlation was obtained between the observed human CL and the estimated human CL based on cynomolgus monkey PK data and an allometric scaling exponent of 0.85 for CL than other scaling approaches. Human concentration-time profiles were also reasonably predicted from the cynomolgus monkey data using species-invariant time method with a fixed exponent of 0.85 for CL and 1.0 for volume of distribution.
Introduction
The projection of human pharmacokinetic (PK) profiles to help estimate dose and dosing regimens is important during clinical development, especially prior to first-in-man studies, as drug efficacy and toxicity are usually linked to drug exposure. Often, it also supports an early assessment of efficacious doses and commercial viability. Our data suggest that, for monoclonal antibodies (mAbs), simple allometric scaling might not be the optimum method for projecting multi-exponential PK profiles. Equations to describe allometric scaling are based on the premise that physical or physiological parameters in species vary as a function of body weight. Interspecies PK parameters have been frequently scaled using a simple allometric equation, Y = aXb, where Y is the PK parameter such as clearance (CL), X is the body weight, a is the scaling coefficient and b is the scaling exponent.1 The constant a may be specific for a particular system, e.g., the drug or species used
Results
The mAbs analyzed in this study are summarized in Table 1. For mAbs that are cleared significantly via antigen-mediated mechanisms (omalizumab, GNE mAb S, GNE mAb T and GNE mAb Y), CL at doses that saturated the antigen-mediated clearance pathway was used for the analysis. The CL of 13 mAbs ranged from ∼3–16 mL/day/kg in mouse, ∼4–15 mL/day/kg in rats, ∼5–12 mL/day/kg in cynomolgus monkeys and ∼3–6 mL/day/kg in humans within their linear range.
Discussion
This is a detailed analysis of projected versus actual CLh using current available methods. Allometric scaling using three species for eight mAbs and two species for three mAbs (Table 1) showed that projected CL values of most mAbs were generally inconsistent with observed values. The use of correction factors such as BrW and MLP, as well as the application of ROE, helped to improve the estimations, but the overall %|PE| was still relatively high (Fig. 2). Notably, allometric scaling from a single species (cynomolgus monkey) for 13 mAbs, a fixed scaling exponent of 0.85 and the Dedrick plot,8clearly demonstrated that this method can be reliably used to project CLh and concentration-time profiles prior to initiating first-in-human trials. In fact, as outlined in Figure 2, this method resulted in the lowest %PE compared to other commonly used scaling methods.