Prediction of human clearance of therapeutic proteins: simple allometric scaling method revisited

Wang, Weirong; Prueksaritanont, Thomayant

doi:10.1002/bdd.708

Cited by 94 publications

(85 citation statements)

References 43 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Human CL predictions based on rat and monkey single-species scaling using a fixed allometric exponent of 0.80 were within 2-fold of clinically observed values for intact NT and CT of FGF21. A fixed exponent of 0.80 was previously shown to be an appropriate singlespecies scaling factor for predicting human CL for a wide variety of therapeutic proteins and mAbs (Wang and Prueksaritanont, 2010). Other studies based on an overlapping data set of therapeutic mAbs supported use of a fixed exponent ranging from 0.75 to 0.90 to predict human CL from monkey (Ling et al, 2009;Deng et al, 2011;Dong et al, 2011;Oitate et al, 2011Oitate et al, , 2012.…”

Section: Discussionmentioning

confidence: 97%

Mechanistic Investigation of the Preclinical Pharmacokinetics and Interspecies Scaling of PF-05231023, a Fibroblast Growth Factor 21–Antibody Protein Conjugate

Giragossian

Vage

et al. 2015

Drug Metabolism and Disposition

View full text Add to dashboard Cite

PF-05231023, a long-acting fibroblast growth factor 21 (FGF21) analog, was generated by covalently conjugating two engineered [des-His1, Ala129Cys]FGF21 molecules to a nontargeting human IgG 1k scaffold. The pharmacokinetics (PK) of PF-05231023 after i.v. and s.c. administration was evaluated in rats and monkeys using two enzyme-linked immunosorbent assays with high specificity for biologically relevant intact N termini (NT) and C termini (CT) of FGF21. Intact CT of FGF21 displayed approximately 5-fold faster systemic plasma clearance (CL), an approximately 2-fold lower steady-state volume of distribution, and at least 5-fold lower bioavailability compared with NT. In vitro serum stability studies in monkeys and humans suggested that the principal CL mechanism for PF-05231023 was degradation by serum proteases. Direct scaling of in vitro serum degradation rates for intact CT of FGF21 underestimated in vivo CL 5-fold, 1.4-fold, and 2-fold in rats, monkeys, and humans, respectively. The reduced steady-state volume of distribution and the bioavailability for intact CT relative to NT in rats and monkeys were compatible with proteolytic degradation occurring outside the plasma compartment via an unidentified mechanism. Human CL and PK profiles for intact NT and CT of FGF21 were well predicted using monkey single-species allometric and Dedrick scaling. Physiologically based pharmacokinetic models incorporating serum stability data and an extravascular extraction term based on differential bioavailability of intact NT and CT of FGF21 in monkeys improved accuracy of human PK predictions relative to Dedrick scaling. Mechanistic physiologically based pharmacokinetic models of this nature may be highly valuable for predicting human PK of fusion proteins, synthetically conjugated proteins, and other complex biologics.

show abstract

Section: Discussionmentioning

confidence: 97%

Mechanistic Investigation of the Preclinical Pharmacokinetics and Interspecies Scaling of PF-05231023, a Fibroblast Growth Factor 21–Antibody Protein Conjugate

Giragossian

Vage

et al. 2015

Drug Metabolism and Disposition

View full text Add to dashboard Cite

show abstract

“…Human PK of biologic drugs after intravenous administration can usually be predicted with reasonable confidence using allometric scaling (Mordenti et al, 1991;Mahmood, 2004;Wang and Prueksaritanont, 2010), but it is much more challenging to predict their subcutaneous absorption process in humans. There are fundamental differences in subcutaneous tissue structure between preclinical species and humans (Magnusson et al, 2001).…”

Section: Lymphatic Transport After Subcutaneous Administrationmentioning

confidence: 99%

Lymphatic Transport and Catabolism of Therapeutic Proteins after Subcutaneous Administration to Rats and Dogs

Wang¹,

Chen²,

Shen³

et al. 2012

Drug Metabolism and Disposition

Self Cite

View full text Add to dashboard Cite

ABSTRACT:The mechanism underlying subcutaneous absorption of macromolecules and factors that can influence this process were studied in rats using PEGylated erythropoietins (EPOs) as model compounds. Using a thoracic lymph duct cannulation (LDC) model, we showed that PEGylated EPO was absorbed from the subcutaneous injection site mainly via the lymphatic system in rats, which is similar to previous reports in sheep. After subcutaneous administration, the serum exposure was reduced by ϳ70% in LDC animals compared with that in the control animals, and most of the systemically available dose was recovered in the lymph. In both LDC and intact rats, the total radioactivity recoveries in excreta after subcutaneous administration were high (70-80%), indicating that catabolism, not poor absorption, was the main cause for the observed low bioavailability (30-40%). Moreover, catabolism of PEGylated EPO was found with both rat subcutaneous tissue homogenate and lymph node cell suspensions, and a significant amount of dose-related breakdown fragments was found in the lymph of LDC rats. In addition, the bioavailability of PEGylated EPOs was shown to be 2-to 4-fold lower in "fat rats," indicating that physiologic features pertinent to lymphatic transport can have a profound impact on subcutaneous absorption. Limited studies in dogs also suggested similar subcutaneous absorption mechanisms. Collectively, our results suggest that the lymphatic absorption mechanism for macromolecules is probably conserved among commonly used preclinical species, e.g., rats and dogs, and that mechanistic understanding of the subcutaneous absorption mechanism and associated determinants should be helpful in biologic drug discovery and development.

show abstract

“…Subsequently, Mahmood et al (10) expanded the allometric scaling to 15 protein drugs. Wang et al (11) performed a meta-analysis on 34 therapeutic proteins and scaled the clearance values using three different Electronic supplementary material The online version of this article (doi:10.1208/s12248-014-9690-8) contains supplementary material, which is available to authorized users. approaches; i.e., simple allometry, allometry with brain weight correction, and fixed exponent method.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Prediction of Human Pharmacokinetics for mAbs Exhibiting Target-Mediated Disposition

Singh

Krzyzanski

Martin

et al. 2014

AAPS J

View full text Add to dashboard Cite

Abstract. Prediction of human pharmacokinetics (PK) can be challenging for monoclonal antibodies (mAbs) exhibiting target-mediated drug disposition (TMDD). In this study, we performed a quantitative analysis of a diverse set of six mAbs exhibiting TMDD to explore translational rules that can be utilized to predict human PK. A TMDD model with rapid-binding approximation was utilized to fit PK and PD (i.e., free and/or total target levels) data, and average absolute fold error (AAFE) was calculated for each model parameter. Based on the comparative analysis, translational rules were developed and applied to a test antibody not included in the original analysis. AAFE of less than two-fold was observed between monkey and human for baseline target levels (R 0 ), body-weight (BW) normalized central elimination rate (K el /BW −0.25 ) and central volume (V c /BW 1.0 ). AAFE of less than three-fold was estimated for the binding affinity constant (K D ). The other four parameters, i.e., complex turnover rate (K int ), target turnover rate (K deg ), central to peripheral distribution rate constant (K pt ) and peripheral to central rate constant (K tp ) were poorly correlated between monkey and human. The projected human PK of test antibody based on the translation rules was in good agreement with the observed nonlinear PK. In conclusion, we recommend a TMDD model-based prediction approach that integrates in vitro human biomeasures and in vivo preclinical data using translation rules developed in this study.

show abstract

Prediction of human clearance of therapeutic proteins: simple allometric scaling method revisited

Cited by 94 publications

References 43 publications

Mechanistic Investigation of the Preclinical Pharmacokinetics and Interspecies Scaling of PF-05231023, a Fibroblast Growth Factor 21–Antibody Protein Conjugate

Mechanistic Investigation of the Preclinical Pharmacokinetics and Interspecies Scaling of PF-05231023, a Fibroblast Growth Factor 21–Antibody Protein Conjugate

Lymphatic Transport and Catabolism of Therapeutic Proteins after Subcutaneous Administration to Rats and Dogs

Quantitative Prediction of Human Pharmacokinetics for mAbs Exhibiting Target-Mediated Disposition

Contact Info

Product

Resources

About