Dataset Information

A Physiologically-Based Pharmacokinetic Model for the Prediction of 'Half-Life Extension' and 'Catch and Release' Monoclonal Antibody Pharmacokinetics.

ABSTRACT: Monoclonal antibodies (mAbs) can be engineered to have 'extended half-life' and 'catch and release' properties to improve target coverage. We have developed a mAb physiologically based pharmacokinetic (PBPK) model that describes intracellular trafficking, neonatal Fc receptor (FcRn) recycling and non-specific clearance of mAbs. We extended this model to capture target binding as a function of target affinity, expression and turnover. For mAbs engineered to have an 'extended half-life', the model was able to accurately predict the terminal half-life (82% within 2-fold error of the observed value) in the human FcRn transgenic (Tg32) homozygous mouse and human. The model also accurately captures the trend in PK and target coverage data for a set of mAbs with differing 'catch and release' properties in Tg32 mouse. The mechanistic nature of this model allows us to explore different engineering techniques early in drug discovery, potentially expanding the number of 'druggable' targets.

SUBMITTER: Jones HM

PROVIDER: S-EPMC7499188 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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A Physiologically-Based Pharmacokinetic Model for the Prediction of "Half-Life Extension" and "Catch and Release" Monoclonal Antibody Pharmacokinetics.

Jones Hannah M HM Tolsma John J Zhang Zhiwei Z Jasper Paul P Luo Haobin H Weber Gregory L GL Wright Katherine K Bard Joel J Bell Robert R Messing Dean D Kelleher Kerry K Piche-Nicholas Nicole N Webster Robert R

CPT: pharmacometrics & systems pharmacology 20200817 9

Monoclonal antibodies (mAbs) can be engineered to have "extended half-life" and "catch and release" properties to improve target coverage. We have developed a mAb physiologically-based pharmacokinetic model that describes intracellular trafficking, neonatal Fc receptor (FcRn) recycling, and nonspecific clearance of mAbs. We extended this model to capture target binding as a function of target affinity, expression, and turnover. For mAbs engineered to have an extended half-life, the model was abl ...[more]

PMID: 32697437

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Project description:In this investigation, we tested the hypothesis that a physiologically based pharmacokinetic (PBPK) model incorporating measured in vitro metrics of off-target binding can largely explain the inter-antibody variability in monoclonal antibody (mAb) pharmacokinetics (PK). A diverse panel of 83 mAbs was evaluated for PK in wild-type mice and subjected to 10 in vitro assays to measure major physiochemical attributes. After excluding for target-mediated elimination and immunogenicity, 56 of the remaining mAbs with an eight-fold variability in the area under the curve (AUC0-672h: 1.74 × 106 -1.38 × 107 ng∙h/mL) and 10-fold difference in clearance (2.55-26.4 mL/day/kg) formed the training set for this investigation. Using a PBPK framework, mAb-dependent coefficients F1 and F2 modulating pinocytosis rate and convective transport, respectively, were estimated for each mAb with mostly good precision (coefficient of variation (CV%) <30%). F1 was estimated to be the mean and standard deviation of 0.961 ± 0.593, and F2 was estimated to be 2.13 ± 2.62. Using principal component analysis to correlate the regressed values of F1/F2 versus the multidimensional dataset composed of our panel of in vitro assays, we found that heparin chromatography retention time emerged as the predictive covariate to the mAb-specific F1, whereas F2 variability cannot be well explained by these assays. A sigmoidal relationship between F1 and the identified covariate was incorporated within the PBPK framework. A sensitivity analysis suggested plasma concentrations to be most sensitive to F1 when F1 > 1. The predictive utility of the developed PBPK model was evaluated against a separate panel of 14 mAbs biased toward high clearance, among which area under the curve of PK data of 12 mAbs was predicted within 2.5-fold error, and the positive and negative predictive values for clearance prediction were 85% and 100%, respectively. MAb heparin chromatography assay output allowed a priori identification of mAb candidates with unfavorable PK.

Project description:Minimal physiologically based pharmacokinetic (mPBPK) models provide a simple and sensible approach that incorporates physiological elements into pharmacokinetic (PK) analysis when only plasma data are available. With this modeling concept, a second-generation mPBPK model was further developed with specific accommodations for the unique PK properties of monoclonal antibodies (mAb). This study applied this model to extensively survey mAb PK in man in order to seek general perspectives on mAb distributional and elimination features. Profiles for 72 antibodies were successfully analyzed with this model. The model results provide assessment regarding: (1) predominant clearance site, in plasma or interstitial fluid (ISF); (2) mAb ISF concentrations in two groups of lumped tissues with continuous (V(tight)) or fenestrated (V(leaky)) vascular endothelium; (3) Transcapillary escape rate (TER), an indicator of systemic vascular permeability. For 93% of surveyed mAbs, the model assuming clearance from plasma (CL) produced better or at least equivalent model performance than the model with clearance from ISF and yielded most consistent values of vascular reflection coefficients (σ1 and σ2) among all antibodies. The average mAb ISF concentration in V(tight) and V(leaky) at equilibrium was predicted to be about 6.8 and 37.9% of that in plasma. A positive correlation was detected between plasma clearance and TER among most mAbs, which could be interpreted as both parameters having common determinants related to ISF tissue distribution in this model context. The mAbs with relative higher plasma clearance (>0.035 L/h/70 kg) did not reveal such positive correlation between clearance and TER, implying that the factors contributing to high clearance may not necessarily increase tissue distribution and penetration. In conclusion, this mPBPK model offers a more mechanistic approach for analyzing plasma mAb PK than compartment models and generates parameters providing useful intrinsic distributional and elimination insights for a large number of mAbs that were examined in man.

Dataset Information

A Physiologically-Based Pharmacokinetic Model for the Prediction of 'Half-Life Extension' and 'Catch and Release' Monoclonal Antibody Pharmacokinetics.

Publications

A Physiologically-Based Pharmacokinetic Model for the Prediction of "Half-Life Extension" and "Catch and Release" Monoclonal Antibody Pharmacokinetics.

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