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Cited by 156Monoclonal and Polyclonal Antibodies ResearchPharmaceutical studies and practicesBiosimilars and Bioanalytical Methods

Quantitative Prediction of Human Pharmacokinetics for Monoclonal Antibodies: Retrospective Analysis of Monkey as a Single Species for First-in-Human Prediction

Dong, Jennifer Q., Salinger, David H., Endres, Christopher J., Gibbs, John P., Hsu, Cheng-Pang, Stouch, Brian J., Hurh, Eunju, Gibbs, Megan A.·2011·Clinical Pharmacokinetics
DOI 10.2165/11537430-000000000-00000
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Abstract

Background and objectives Prediction of human pharmacokinetics for monoclonal antibodies (mAbs) plays an important role for first-in-human (FIH) dose selection. This retrospective analysis compares observed FIH pharmacokinetic data for 16 mAbs to those predicted in humans based on allometric scaling of Cynomolgus monkey pharmacokinetic data.Methods Ten mAbs exhibited linear pharmacokinetics in monkeys based on non-compartmental analysis. For these, simple allometric scaling based on bodyweight was applied to predict human clearance (CL) and volume of distribution (V(d)) from those obtained in monkeys. Six mAbs exhibited nonlinear pharmacokinetics in monkeys based on population modelling. For these, a population modelling approach using nonlinear mixed-effects modelling software, NONMEM, was applied to describe monkey data by a two-compartment pharmacokinetic model with parallel linear and nonlinear elimination from the central compartment. The pharmacokinetic parameters in monkeys were then scaled to humans based on simple allometry. Human concentration-time profiles of these mAbs were then simulated and compared with those observed in the FIH studies.Results Antibodies with linear elimination in monkeys also exhibited linear elimination in humans. For these, observed CL and V(d) were predicted within 2.3-fold by allometry. The predictability of human peak serum concentration (C(max)) and area under the serum concentration-time curve (AUC) for mAbs with nonlinear pharmacokinetics in monkeys was, however, concentration dependent. C(max) was consistently overestimated (up to 5.3-fold higher) when below the predicted Michaelis-Menten constant (Km; range 0.3-4 μg/mL). The prediction of human C(max) was within 2.3-fold when concentrations greatly exceeded Km. Similarly, differences between predicted human AUCs and those observed in the FIH studies were much greater at low doses/concentrations. Consequently, predicted drug exposure in humans at low starting doses (range 0.01-0.3 mg/kg) in FIH studies was poorly estimated for three of six mAbs with nonlinear pharmacokinetics.Conclusions Allometric prediction of human pharmacokinetics may be sufficient for mAbs that exhibit linear pharmacokinetics. For mAbs that exhibited nonlinear pharmacokinetics, the best predictive performance was obtained after doses that achieved target-saturating concentrations.

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Authors
Dong, J. Q., Salinger, D. H., Endres, C. J., Gibbs, J. P., Hsu, C.-P., Stouch, B. J., Hurh, E., & Gibbs, M. A.
Affiliations
Amgen (United States) (US)
Corresponding author
Gibbs, Megan A.
ORCID
Venue
Clinical Pharmacokinetics
Publisher
Springer Science and Business Media LLC
Published
2011-02
Volume
50
Issue
2
Pages
131-142
ISSN
0312-5963 (ISSN-L)
DOI
10.2165/11537430-000000000-00000
OpenAlex
W2196423560
Cited by
156
References
48
Citations by year
2026: 3 · 2025: 3 · 2024: 13 · 2023: 7 · 2022: 11 · 2021: 16 · 2020: 6 · 2019: 9 · 2018: 10 · 2017: 11 · 2016: 16 · 2015: 15 · 2014: 10 · 2013: 14 · 2012: 8
FWCI
8.54
Type
journal article
Language
en
Open access
closed
Locations
  • Clinical Pharmacokinetics (publishedVersion)
  • PubMed (publishedVersion)
Funders
Amgen
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
  • Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
Keywords
monoclonal antibodies, human pharmacokinetic prediction, allometric scaling, Macaca fascicularis, first-in-human dose selection, nonlinear pharmacokinetics, Michaelis-Menten elimination, clearance, volume of distribution, concentration-time profiles, drug exposure prediction
MeSH terms
Animals, Antibodies, Monoclonal, Dose-Response Relationship, Drug, Humans, Macaca fascicularis, Metabolic Clearance Rate, Models, Biological, Research Design, Retrospective Studies, Linear Models, Clinical Trials, Phase I as Topic, Nonlinear Dynamics, Area Under Curve

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