Factor XII (FXII) is a serine protease involved in multiple cascades, including the kallikrein-kinin system. It may play a role in diseases in which the downstream cascades are dysregulated, such as hereditary angioedema. Garadacimab (CSL312) is a first-in-class, fully human, monoclonal antibody targeting activated FXII (FXIIa). We describe how translational pharmacokinetic (PK) and pharmacodynamic (PD) modeling enabled dose selection for the phase I, first-in-human trial of garadacimab. The PK/PD data used for modeling were derived from preclinical PK/PD and safety studies. Garadacimab plasma concentrations rose with increasing dose, and clear dose-related PD effects were observed (e.g., a mechanism-based prolongation of activated partial thromboplastin time). The PK/PD profile from cynomolgus monkeys was used to generate minimal physiologically-based pharmacokinetic (mPBPK) models with target-mediated drug disposition (TMDD) for data prediction in cynomolgus monkeys. These models were later adapted for prediction of human data to establish dose selection. Based on the final mPBPK model with TMDD and assuming a weight of 70 kg for an adult human, a minimal inhibition (<10%) of FXIIa with a starting dose of 0.1 mg/kg garadacimab and a near maximal inhibition (>95%) at 10 mg/kg garadacimab were predicted. The phase I study is complete, and data on exposure profiles and inhibition of FXIIa-mediated kallikrein activity observed in the trial support and validate these simulations. This emphasizes the utility and relevance of translational modeling and simulation in drug development.

T cell-redirecting bispecific antibodies (bsAbs) are highly potent tumor-killing molecules. Following bsAb mediated engagement with target cells, T cells get activated and kill target cells while inducing cytokine release, which at higher levels may lead to life-threatening cytokine release syndrome (CRS). Clinical evidence suggests that CRS can be mitigated by implementing a stepwise dosing strategy. Here, we developed a mechanism-based minimal physiologically-based pharmacokinetic/pharmacodynamic (mPBPK/PD) model using reported preclinical and clinical data from blinatumomab. The mPBPK/PD model reasonably captured blinatumomab PK and B cell depletion profiles in blood and in various tissue sites of action (i.e., red marrow perivascular niche, spleen, and lymph nodes) in patients with non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukemia (ALL). Using interleukin 6 (IL-6) as an example, our model quantitatively characterized the mitigation of cytokine release by a blinatumomab 5-15-60 mu g/m(2)/day stepwise dosing regimen comparing to a 60 mu g/m(2)/day flat dose in NHL patients. Furthermore, by only modifying the system parameters specific for ALL patients, the mPBPK/PD model successfully predicted the mitigation of IL-6 release by a blinatumomab 5-15 mu g/m(2)/day stepwise dosing regimen comparing to a 15 mu g/m(2)/day flat dose. Our work provided a case example to show how mPBPK/PD model can be used to support the discovery and clinical development of T cell-redirecting bsAbs.

Understanding the Exposure-Response (ER) relationship is critical for translation of biologics from preclinical to clinical stage and for projection of safe and efficacious doses in humans. Mechanism and physiologically based pharmacokinetics (PBPK)/pharmacodynamics (PD) modeling approaches are valuable tools to quantitatively characterize and account for the differences in biologics tissue distribution, target dynamics, and target binding, etc., and thus facilitate more reliable translation of biologics from preclinical to clinical stages. This chapter reviews current progress and potential challenges in this area. Emphasis is placed on providing a few case examples showing how mechanistic PBPK/PD models can be utilized to decipher the underpinnings of biologics ER relationship and to showcase value of such modeling in the transitions of biologics at the preclinical-clinical interface. The chapter focuses on monoclonal antibodies and Fc-fusion proteins, the major class of biologics in preclinical and clinical development.

The interleukin (IL)-23/T(h)17/IL-17 immune pathway has been identified to play an important role in the pathogenesis of psoriasis. Many therapeutic proteins targeting IL-23 or IL-17 are currently under development for the treatment of psoriasis. In the present study, a mechanistic pharmacokinetics (PK)/pharmacodynamics (PD) study was conducted to assess the target-binding and disposition kinetics of a monoclonal antibody (mAb), CNTO 3723, and its soluble target, mouse IL-23, in an IL-23-induced psoriasis-like mouse model. A minimal physiologically based pharmacokinetic model with target-mediated drug disposition features was developed to quantitatively assess the kinetics and interrelationship between CNTO 3723 and exogenously administered, recombinant mouse IL-23 in both serum and lesional skin site. Furthermore, translational applications of the developed model were evaluated with incorporation of human PK for ustekinumab, an anti-human IL-23/IL-12 mAb developed for treatment of psoriasis, and human disease pathophysiology information in psoriatic patients. The results agreed well with the observed clinical data for ustekinumab. Our work provides an example on how mechanism-based PK/PD modeling can be applied during early drug discovery and how preclinical data can be used for human efficacious dose projection and guide decision making during early clinical development of therapeutic proteins.

T-cell redirecting bispecific antibodies (bsAbs) or antibody-derived agents that combine tumor antigen recognition with CD3-mediated T cell recruitment are highly potent tumor-killing molecules. Despite the tremendous progress achieved in the last decade, development of such bsAbs still faces many challenges. This work aimed to develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that can be used to assist the development of T-cell redirecting bsAbs. A Target cell-Biologics-Effector cell (TBE) complex-based cell killing model was developed using in vitro and in vivo data, which incorporates information on binding affinities of bsAbs to CD3 and target receptors, expression levels of CD3 and target receptors, concentrations of effector and target cells, as well as respective physiological parameters. This TBE model can simultaneously evaluate the effect of multiple system-specific and drug-specific factors on the T-cell redirecting bsAb exposure-response relationship on a physiological basis; it reasonably captured multiple reported in vitro cytotoxicity data, and successfully predicted the effect of some key factors on in vitro cytotoxicity assays and the efficacious dose of blinatumomab in humans. The mechanistic nature of this model uniquely positions it as a knowledge-based platform that can be readily expanded to guide target selection, drug design, candidate selection and clinical dosing regimen projection, and thus support the overall discovery and development of T-cell redirecting bsAbs.

The soluble cytokine tumor necrosis factor-α (TNF-α) is an important target for many therapeutic proteins used in the treatment of rheumatoid arthritis. Biologics targeting TNF-α exert their pharmacologic effects through binding and neutralizing this cytokine and preventing it from binding to its cell surface receptors. The magnitude of their pharmacologic effects directly corresponds to the extent and duration of free TNF-α suppression. However, endogenous TNF-α is of low abundance, so it is quite challenging to assess the free TNF-α suppression experimentally. Here we have applied an experimental approach to bypass this difficulty by giving recombinant human TNF-α (rhTNF-α) to rats by s.c. infusion. This boosted TNF-α concentration enabled quantification of TNF-α in plasma. Free rhTNF-α concentrations were measured after separation from the infliximab-rhTNF-α complex using Dynabeads Protein A. The interrelationship of infliximab and TNF-α was assessed with minimal physiologically based pharmacokinetic models for TNF-α and infliximab with a target-mediated drug disposition component. Knowledge of TNF-α pharmacokinetics allows reliable prediction of the free TNF-α suppression with either free or total TNF-α concentration profiles. The experimental and modeling approaches in our study may aid in the development of next-generation TNF-α inhibitors with improved therapeutic effects.

Tumor necrosis factor-α (TNF-α) is a soluble cytokine and target of specific monoclonal antibodies (mAbs) and other biologic agents used in the treatment of inflammatory diseases. These biologics exert their pharmacological effects through binding and neutralizing TNF-α, and thus they prevent TNF-α from interacting with its cell surface receptors. The magnitude of the pharmacological effects is governed not only by the pharmacokinetics (PK) of mAbs, but also by the kinetic fate of TNF-α We have examined the pharmacokinetics of recombinant human TNF-α (rhTNF-α) in rats at low doses and quantitatively characterized its pharmacokinetic features with a minimal physiologically based pharmacokinetic model. Our experimental and literature-digitalized PK data of rhTNF-α in rats across a wide range of doses were applied to global model fitting. rhTNF-α exhibits permeability rate-limited tissue distribution and its elimination is comprised of a saturable clearance pathway mediated by tumor necrosis factor receptor binding and disposition and renal filtration. The resulting model integrated with classic allometry was further used for interspecies PK scaling and resulted in model predictions that agreed well with experimental measurements in monkeys. In addition, a semimechanistic model was proposed and applied to explore the absorption kinetics of rhTNF-α following s.c. and other routes of administration. The model suggests substantial presystemic degradation of rhTNF-α for s.c. and i.m. routes and considerable lymph uptake contributing to the overall systemic absorption through the stomach wall and gastrointestinal wall routes of dosing. This report provides comprehensive modeling and key insights into the complexities of absorption and disposition of a major cytokine.

Therapeutic monoclonal antibodies (mAb) targeting soluble inflammatory cytokines exert their pharmacological effects in rheumatoid arthritis through binding and neutralizing free cytokines in target tissue sites. Therefore suppression of free cytokines in such sites directly relates to the magnitude of therapeutic response. Although the interrelationships between mAb and cytokines have been examined in the systemic circulation, less is known about the interaction of mAb and cytokines in inflamed joints. In the present study, the interplay between the mAb, CNTO 345, and its target IL-6 in serum as well as ankle joint synovial fluid were characterized in collagen-induced arthritic mice. A minimal physiologically-based pharmacokinetic model with target-mediated drug disposition (TMDD) features in serum and ankle joint synovial fluid was developed for the assessment of the TMDD dynamics of CNTO 345 and IL-6. Our model indicates that TMDD kinetics in ankle joints differ greatly from that in serum. The differences can be attributed to the limited tissue distribution of CNTO 345 in ankle joint synovial fluid, the significant rise of the IL-6 baseline in ankle joint synovial fluid in comparison with serum, and the relative time-scales of elimination rates between CNTO 345, free IL-6 and CNTO 345-IL-6 complex in serum and ankle joint synovial fluid.

Many monoclonal antibodies (mAbs) and other protein drugs have targets usually residing within tissues, making tissue concentrations of mAbs relevant to their pharmacologic effects. Therefore, knowledge of tissue distribution kinetics is important to better understand their pharmacokinetics and pharmacodynamics. The tissue distribution of mAbs is affected by many physiologic factors that may be altered in disease status. In the present work, we studied the tissue distribution kinetics of the fusion protein etanercept in inflamed joint tissues and examined the impact of inflammation on the tissue distribution of etanercept. Etanercept concentration profiles in plasma, blister fluid, and different tissues were obtained from healthy and collagen-induced arthritic (CIA) rats by use of a fluorescence quantification method via IRDye800CW labeling. Stepwise minimal and full physiologically based pharmacokinetic (PBPK) approaches were applied to characterize the distribution kinetics of etanercept in tissues in healthy and diseased animals. Etanercept exhibited modest tissue access (tissue/plasma area under the concentration curve [AUC] ratios 0.03-0.15 and estimated tissue reflection coefficients [σ] of 0.6-1.0), but with good penetration into arthritic paws (tissue/plasma AUC ratio 0.23 and σ 0.36). Etanercept exposure in the inflamed paws of CIA rats was approximately 3-fold higher than in normal paws taken from either CIA or healthy rats (tissue/plasma AUC ratios 0.23 versus 0.07 and σ 0.36 versus 0.71). The tissue distribution kinetics of etanercept in arthritic paws were well characterized with PBPK modeling approaches. Etanercept shows good penetration to arthritic paws in CIA rats. Our study indicates that inflammation produced increased tissue distribution of etanercept in CIA rats.