Pharmacokinetic/pharmacodynamic modeling for dose selection for the first‐in‐human trial of the activated Factor XII inhibitor garadacimab (CSL312)

Abstract

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. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Models based on physiology and mechanisms of action can be highly useful in translating pharmacokinetic/pharmacodynamic (PK/PD) data from animal studies to expectations in humans.

HDX-MS study on garadacimab binding to activated FXII reveals potential binding interfaces through differential solvent exposure

“…Findings from our study lead to an improved understanding of the MOA for garadacimab, validating its observed preclinical and clinical efficacy in the reduction of HAE attacks. 8 , 10 , 12 The studies also demonstrate that the solvent-accessibility approach, accomplished using HDX-MS complemented by SPR and EM, is a valuable tool to study protein binding in antigen/antibody complexes, particularly when the crystal structures are not immediately available. 16 …”

Review of the Existing Translational Pharmacokinetics Modeling Approaches Specific to Monoclonal Antibodies (mAbs) to Support the First-In-Human (FIH) Dose Selection

“…Richter et al showed in 2020 that mAbs SC absorption was generally faster in animals than in humans due to their physiology [ 12 , 50 , 66 ]. One of the translational methods for K a could be to scale the parameters from the monkey as the other parameters with an allometric exponent of −0.25 [ 29 , 67 ], even if the C max can be regularly over-predicted with this exponent and the translation is considered as unreliable by some papers [ 63 , 66 ]. In other papers, K a was assumed to be the same in humans and in monkeys [ 51 ].…”

“…To translate the linear parameters part, he used an allometric scaling [ 67 ]. This method is largely used and found in each paper with a mAbs TMDD [ 29 , 51 , 63 , 73 ].…”

“…This method has been better described since; however, some limitations remain. The semi-physiological approach is split in two types of models, TMDD integrated into a simple popPK model as described by Mager et al in 2001 [ 25 ], or, more recently, into a minimal PBPK model as represented by Pawaskar et al in Figure 6 [ 29 ]. Scaling of the TMDD parameters was equivalent for both methods.…”

“… mPBPK of a mAbs including TMDD adapted from Pawaska et al [ 29 ]. V plasma : plasma volume; V tight : tight tissues volume; V leaky : leaky tissues volume; K e : first-order rate constant of endogenous elimination of drug from plasma volume; L: total lymph flow; L 1 : lymph flow for V tight ; L 2 : lymph flow for V leaky ; σ 1 : vascular reflection coefficient for V tight ; σ 2 : vascular reflection coefficient for V leaky ; σ L : lymphatic capillary reflection coefficient; V lymph : lymph volume; D: Drug concentration, R: Receptor-target concentration; DR: drug-receptor complex concentration; K syn : zero-order synthesis rate of the target; K deg : first-order degradation rate of the target; K on : first-order association rate of the mAb with the target; K off : first-order dissociation rate of the mAb with the target; K int : first-order internalization rate of the DR complex; IV: mAbs administration by IV.…”