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Review
. 2022 Oct 22;23(21):12754.
doi: 10.3390/ijms232112754.

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

Blaise Pasquiers  1   2 , Salih Benamara  1 , Mathieu Felices  1 , Laurent Nguyen  3 , Xavier Declèves  2
Affiliations
Review

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

Blaise Pasquiers et al. Int J Mol Sci. .

Abstract

The interest in therapeutic monoclonal antibodies (mAbs) has continuously growing in several diseases. However, their pharmacokinetics (PK) is complex due to their target-mediated drug disposition (TMDD) profiles which can induce a non-linear PK. This point is particularly challenging during the pre-clinical and translational development of a new mAb. This article reviews and describes the existing PK modeling approaches used to translate the mAbs PK from animal to human for intravenous (IV) and subcutaneous (SC) administration routes. Several approaches are presented, from the most empirical models to full physiologically based pharmacokinetic (PBPK) models, with a focus on the population PK methods (compartmental and minimal PBPK models). They include the translational approaches for the linear part of the PK and the TMDD mechanism of mAbs. The objective of this article is to provide an up-to-date overview and future perspectives of the translational PK approaches for mAbs during a model-informed drug development (MIDD), since the field of PK modeling has gained recently significant interest for guiding mAbs drug development.

Keywords: ADA; PBPK; PopPK; first-in-human; mPBPK; modeling; monoclonal antibody; pharmacokinetics; translational.

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Conflict of interest statement

Blaise Pasquiers & Mathieu Felices are employed by PhinC Development (CRO). Laurent Nguyen is employed by Sanofi.

Figures

Figure 1
Figure 1
Simplified 2-compartments model for mAbs PK. V1: central volume; V2: peripheral volume; Ke: first-order rate constant of elimination; K12: first-order rate constant of distribution from V1 to V2; K21: first-order rate of distribution from V2 to V1; IV: mAbs intravenous administration.
Figure 2
Figure 2
Representation of 2nd generation of mPBPK adapted from Cao et al. [19]. Vplasma: plasma volume; Vtight: tight tissues volume; Vleaky: leaky tissues volume; Clp: clearance from plasma volume; L: total lymph flow; L1: lymph flow for Vtight; L2: lymph flow for Vleaky; σ1: vascular reflection coefficient for Vtight; σ2: vascular reflection coefficient for Vleaky; σL: lymphatic capillary reflection coefficient; Vlymph: lymph volume; IV: mAbs administration by IV. Vtight = 0.65 × ISF × Kp. Vleaky = 0.35 × ISF × Kp. L1 = 0.33 × L. L2 = 0.67 × L. ISF: total system interstitial fluid; Kp: available fraction of ISF for mAb distribution.
Figure 3
Figure 3
Extended mPBPK model with endosomal compartment adapted from Maas et al. [20]. Vplasma: plasma volume; Vtight: tight tissues volume; Vleaky: leaky tissues volume; L: total lymph flow; L1: lymph flow for Vtight; L2: lymph flow for Vleaky; σ1: vascular reflection coefficient for Vtight; σ2: vascular reflection coefficient for Vleaky; σL: lymphatic capillary reflection coefficient; Vlymph: lymph volume, Clup: rate from Vplasma to endosomal space; ClIgG: clearance from endosomal space; Clrec: recycled from endosomal space to Vplasma; IV: mAbs administration by IV. Clrec = Clup − ClIgG.
Figure 4
Figure 4
Pharmacokinetics model of a TMDD adapted from Mager and Jusko [25]. V1: central volume; V2: peripheral volume; Ke: first-order rate constant of elimination; K12: first-order rate of distribution from V1 to V2; K21: first-order rate of distribution from V2 to V1; R: receptor-target concentration; Ksyn: zero-order synthesis rate of the target; Kdeg: first-order degradation rate of the target; Kint: first-order internalization rate of the DR complex; Kon: first-order association rate of the mAb with the target; Koff: first-order dissociation rate of the mAb with the target; DR: drug-receptor complex concentration; IV: mAbs administration by IV.
Figure 5
Figure 5
TMDD modeling hierarchy reprinted with permission from Lixoft® [26]. Different models’ approximation to describe a TMDD profile. QE/QSS: quasi-equilibrium or quasi-steady state approximation; V: central volume; Kel: clearance rate; Kint: first-order internalization rate of the complex mAb-target; Kon: first-order association rate of the mAb with the target; Kd: first-order dissociation constant of the mAb with the target; Ksyn: zero-order synthesis rate of the target; R0: initial target concentration; K12: first-order rate of distribution from V1 to V2; K21: first-order rate of distribution from V2 to V1; Km: Michaelis–Menten constant.
Figure 6
Figure 6
mPBPK of a mAbs including TMDD adapted from Pawaska et al. [29]. Vplasma: plasma volume; Vtight: tight tissues volume; Vleaky: leaky tissues volume; Ke: first-order rate constant of endogenous elimination of drug from plasma volume; L: total lymph flow; L1: lymph flow for Vtight; L2: lymph flow for Vleaky; σ1: vascular reflection coefficient for Vtight; σ2: vascular reflection coefficient for Vleaky; σL: lymphatic capillary reflection coefficient; Vlymph: lymph volume; D: Drug concentration, R: Receptor-target concentration; DR: drug-receptor complex concentration; Ksyn: zero-order synthesis rate of the target; Kdeg: first-order degradation rate of the target; Kon: first-order association rate of the mAb with the target; Koff: first-order dissociation rate of the mAb with the target; Kint: first-order internalization rate of the DR complex; IV: mAbs administration by IV.
Figure 7
Figure 7
(a) PBPK model of IgG disposition where the major organs are included in the model, and the various compartments are connected by plasma (solid arrows) and lymphatic flow (dashed arrows). Each tissue within this model is divided into sub-compartments [34] (b) Intra-tissue compartmental model of IgG (mAb) disposition.
Figure 8
Figure 8
Representation of the half-life scaling method adapted from Nakamura et al [23]. The terminal monkey half-life (t1/2β) of a mAb is sufficient to predict the IV PK profile in human with the half-life method.
Figure 9
Figure 9
Representation of the four types of monoclonal antibodies adapted from Santos et al. [78]. Blue: murine part of the mAb; grey: humanized part of the mAb. The more the mAb is humanized, the less it is immunogenic.
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