On Setting the First Dose in Man: Quantitating Biotherapeutic Drug‐Target Binding through Pharmacokinetic and Pharmacodynamic Models

Abstract

Although the three (perhaps four) phases of clinical drug development are well known, it is relatively unappreciated that there are similar phases in pre-clinical development. These consist of 'Phase I' the initial, normally Research Discovery driven pharmacology; 'Phase II' non-good laboratory practice (GLP) dose range finding, followed by pivotal 'Phase III' GLP toxicology. Together with an array of in vitro experiments comparing species, these stages should enable an integrated safety assessment prior to entry into man, documenting to investigators and authorities evidence that the new pharmaceutic is unlikely to cause harm. Following the lessons learned from TeGenero TGN1412 and subsequent updates to regulatory guidelines, there are aspects peculiar to biotherapeutics, especially those that target key body systems, where calculations could be made for doses for human studies using pharmacokinetic and pharmacodynamic models. Two of these are exemplified in this paper. In the first, target-mediated drug disposition, where the binding of the drug to a cellular target quantitatively affects the pharmacokinetics, enables occupancy to be estimated without recourse to independent assays. In the second, assaying captured soluble target, as drug-target complexes, allows estimation of the concentration of the free ligand ensuring that in initial clinical studies, soluble targets are not overly suppressed. To support this methodology, it has been demonstrated using omalizumab, free and total IgE data that such analyses do predict the suppression of the free unbound ligand with reasonable accuracy. Overall, the objective of the process is to deliver a justification, through consideration of drug-target binding, of a safe starting and therapeutically relevant escalation doses for human studies.

Qualification of a free ligand assay in the presence of anti-ligand antibody Fab fragments

“…Although a number of reports have used assays to measure free ligand in the presence of anti-ligand antibody, [7][8][9][10][11][12][13][14][15][16] there are wellrecognized potential issues with these assays 4,6 that should be explored to provide confidence that the conditions selected will provide a reliable assessment of unbound ligand. To our knowledge, there is a lack of experimental data to address some of the fundamental problems that may arise with free ligand assays.…”

“…4,6 In recent years, a number of studies have examined the effect of dosed antibody on the in vivo levels of the target ligand. Of these, a subset has reported measurement of free ligand levels, including assays for IgE, [7][8][9][10][11][12] Dkk-1, 13 PCSK9 14,15 and VEGF. 16 The format for measurement of free ligand in these cases has been similar, and has included capture with an antibody that binds to the same epitope on the ligand as does the therapeutic agent, thus theoretically not allowing the ligand in the sample to bind to the capture antibody on the plate if it is already bound by therapeutic antibody.…”

Clinical Pharmacology Tools and Evaluations to Facilitate Comprehensive Dose Finding in Oncology: A Continuous Risk‐Benefit Approach

“…19 In their assessment Lowe et al presented evidence that binding model-based extrapolations may aid future development, suggesting a potential decrease in overall development cost due to the ability to predict the in vivo ligand when PK and at least 1 of the PD assays is available. 17 Discussion Dose justification on the basis of PK-PD relationships is common for antibacterial drugs and is clearly encouraged by regulatory authorities. 20,21 However, this acceptance stems from over 15 years of experience from numerous PK-PD studies in both animals and infected patients and being able to derive PK-PD measures closely associated with efficacy by in vivo or dynamic in vitro PK-PD systems.…”

“…16 PK-PD models for therapeutic proteins have been used to describe and predict PK, target binding, receptor occupancy thresholds, and free ligand presence and have been utilized as part of the exposureresponse assessment and analysis to aid scientifically driven dose finding and justification in the last 2 decades. 17 Both cell surface receptor and soluble ligand receptor binding targets can be analyzed using PK-PD models with different binding options accounted for in the model. Only a few examples of therapeutic proteins have been well described with quantitative PK-PD approaches, and one of the hallmark molecules utilizing quantitative approaches is efalizumab.…”

Applications of Human Pharmacokinetic Prediction in First-in-Human Dose Estimation

“…Humans and animals are assumed to share equal K u, p. Usually, commercial software such as GastroPlus™ (Simulations Plus Inc., Lancaster, CA), PKSim™ (Bayer Technologies, Leverkusen, Germany), or SimCyp™ (Sheffield, UK) are used to predict the rate and extent of oral drug absorption. The mechanism of GastroPlus™ is known as the ACAT model (30,94), which is a physiologically based model consisting of nine compartments corresponding to different segments of the gastrointestinal tract. The ACAT model can describe the release, dissolution, degradation, metabolism, uptake, and absorption of a compound as it transits through the different segments of the digestive tract.…”