Impact of Target‐Mediated Elimination on the Dose and Regimen of Evolocumab, a Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)
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Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) relationship of a therapeutic monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) exhibiting target‐mediated drug disposition (TMDD) is critical for selecting optimal dosing regimens. We describe the PK/PD relationship of evolocumab using a mathematical model that captures evolocumab binding and removal of unbound PCSK9 as well as reduction in circulating low‐density lipoprotein cholesterol (LDL‐C). Data were pooled from 2 clinical studies: a single‐dose escalation study in healthy subjects (7‐420 mg SC; n = 44) and a multiple‐dose escalation study in statin‐treated hypercholesterolemic patients (14 mg weekly to 420 mg monthly [QM] SC; n = 57). A TMDD model described the time course of unbound evolocumab concentrations and removal of unbound PCSK9. The estimated linear clearance and volume of evolocumab were 0.256 L/day and 2.66 L, respectively, consistent with other monoclonal antibodies. The time course of LDL‐C reduction was described by an indirect response model with the elimination rate of LDL‐C being modulated by unbound PCSK9. The concentration of unbound PCSK9 associated with half‐maximal inhibition (IC 50) of LDL‐C elimination was 1.46 nM. Based on simulations, 140 mg every 2 weeks (Q2W) and 420 mg QM were predicted to achieve a similar time‐averaged effect of 69% reduction in LDL‐C in patients on statin therapy, suggesting that an approximate 3‐fold dose increase is required for a 2‐fold extension in the dosing interval. Evolocumab dosing regimens of 140 mg Q2W or 420 mg QM were predicted to result in comparable reductions in LDL‐C over a monthly period, consistent with results from recently completed phase 3 studies.
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Gibbs et al. demonstrated the critical importance of characterizing target-mediated clearance in selecting an optimal dosing regimen for the PCSK9 antibody evolocumab; their TMDD PK/PD modeling suggested that doubling the dose and extending the dosing interval from biweekly to monthly did not adequately maintain the reduction in LDL-C, and a higher dose was required to maintain stable LDL-C levels
“For example, Gibbs et al. demonstrated the critical importance of characterizing target‐mediated clearance in selecting an optimal dosing regimen for protein convertase substilisin kexin type 9 (PCSK9) antibody evolucumab.37 Their target‐mediated drug disposition PK/PD modeling suggested that doubling the dose and extending the dosing interval from biweekly to monthly did not adequately maintain”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [37]
PK/PD analysis using unbound evolocumab, unbound PCSK9, and LDL-C data has enabled dose and regimen selection in clinical trials.
“PK/PD analysis using unbound evolocumab, unbound PCSK9, and LDL‐C data has enabled dose and regimen selection in clinical trials37”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [37]
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Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development
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Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor
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“The absence of overt toxicity and the lack of additional benefit at higher doses suggest a therapeutically actionable window, consistent with target-mediated dynamics reported for PCSK9-directed therapies 42 .”
- Authors
- Gibbs, J. P., Doshi, S., Kuchimanchi, M., Grover, A., Emery, M. G., Dodds, M. G., Gibbs, M. A., Somaratne, R., Wasserman, S. M., & Blom, D.
- Affiliations
- Amgen (United States) (US)
- University of Cape Town (ZA)
- Corresponding author
- Gibbs, John P.
- ORCID
- Venue
- The Journal of Clinical Pharmacology
- Publisher
- Wiley
- Published
- 2016-11-15
- Volume
- 57
- Issue
- 5
- Pages
- 616-626
- ISSN
- 0021-9754 (ISSN-L)
- 0091-2700
- 1552-4604
- PMC
- PMC5412926
- OpenAlex
- W2550315736
- Cited by
- 42
- References
- 45
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 1 · 2020: 3 · 2019: 6 · 2018: 13 · 2017: 1
- FWCI
- 7.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Clinical Pharmacology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Amgen
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
- Keywords
- evolocumab, PCSK9, target-mediated drug disposition, pharmacokinetic-pharmacodynamic modeling, LDL cholesterol lowering, monoclonal antibodies, dosing regimen optimization, indirect response model, mathematical pharmacokinetic model
- MeSH terms
- PCSK9 Inhibitors, Antibodies, Monoclonal, Biological Availability, Female, Humans, Hypercholesterolemia, Cholesterol, LDL, Male, Middle Aged, Models, Biological, Antibodies, Monoclonal, Humanized
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