Impact of Target-Mediated Elimination on the Dose and Regimen of Evolocumab, a Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)
© 2016, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology..
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 (IC50 ) 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:57 |
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| Enthalten in: |
Journal of clinical pharmacology - 57(2017), 5 vom: 04. Mai, Seite 616-626 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gibbs, John P [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 29.08.2017 Date Revised 04.12.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/jcph.840 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM266329837 |
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| 100 | 1 | |a Gibbs, John P |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a 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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| 500 | |a Date Completed 29.08.2017 | ||
| 500 | |a Date Revised 04.12.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2016, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology. | ||
| 520 | |a 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 (IC50 ) 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 | ||
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a LDL-C | |
| 650 | 4 | |a PCSK9 | |
| 650 | 4 | |a monoclonal antibody | |
| 650 | 4 | |a pharmacokinetic/pharmacodynamic | |
| 650 | 4 | |a pharmacokinetics | |
| 650 | 4 | |a target-mediated drug disposition | |
| 650 | 7 | |a Antibodies, Monoclonal |2 NLM | |
| 650 | 7 | |a Antibodies, Monoclonal, Humanized |2 NLM | |
| 650 | 7 | |a Cholesterol, LDL |2 NLM | |
| 650 | 7 | |a PCSK9 Inhibitors |2 NLM | |
| 650 | 7 | |a evolocumab |2 NLM | |
| 650 | 7 | |a LKC0U3A8NJ |2 NLM | |
| 700 | 1 | |a Doshi, Sameer |e verfasserin |4 aut | |
| 700 | 1 | |a Kuchimanchi, Mita |e verfasserin |4 aut | |
| 700 | 1 | |a Grover, Anita |e verfasserin |4 aut | |
| 700 | 1 | |a Emery, Maurice G |e verfasserin |4 aut | |
| 700 | 1 | |a Dodds, Michael G |e verfasserin |4 aut | |
| 700 | 1 | |a Gibbs, Megan A |e verfasserin |4 aut | |
| 700 | 1 | |a Somaratne, Ransi |e verfasserin |4 aut | |
| 700 | 1 | |a Wasserman, Scott M |e verfasserin |4 aut | |
| 700 | 1 | |a Blom, Dirk |e verfasserin |4 aut | |
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