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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\u2010density lipoprotein cholesterol (LDL\u2010C). Data were pooled from 2 clinical studies: a single\u2010dose escalation study in healthy subjects (7\u2010420\u00a0mg SC; n = 44) and a multiple\u2010dose escalation study in statin\u2010treated hypercholesterolemic patients (14 mg weekly to 420\u00a0mg 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\u2010C reduction was described by an indirect response model with the elimination rate of LDL\u2010C being modulated by unbound PCSK9. The concentration of unbound PCSK9 associated with half\u2010maximal inhibition (IC<jats:sub>50<\/jats:sub>) of LDL\u2010C elimination was 1.46 nM. Based on simulations, 140 mg every 2 weeks (Q2W) and 420\u00a0mg QM were predicted to achieve a similar time\u2010averaged effect of 69% reduction in LDL\u2010C in patients on statin therapy, suggesting that an approximate 3\u2010fold dose increase is required for a 2\u2010fold extension in the dosing interval. Evolocumab dosing regimens of 140 mg Q2W or 420\u00a0mg QM were predicted to result in comparable reductions in LDL\u2010C over a monthly period, consistent with results from recently completed phase 3 studies.<\/jats:p>","DOI":"10.1002\/jcph.840","type":"journal-article","created":{"date-parts":[[2016,11,16]],"date-time":"2016-11-16T18:09:15Z","timestamp":1479319755000},"page":"616-626","source":"Crossref","is-referenced-by-count":41,"title":["Impact of Target\u2010Mediated Elimination on the Dose and Regimen of Evolocumab, a Human Monoclonal Antibody Against Proprotein Convertase Subtilisin\/Kexin Type 9 (PCSK9)"],"prefix":"10.1002","volume":"57","author":[{"given":"John P.","family":"Gibbs","sequence":"first","affiliation":[{"name":"Amgen Inc  Thousand Oaks CA, USA"},{"name":"Current affiliation: AbbVie  North Chicago IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameer","family":"Doshi","sequence":"additional","affiliation":[{"name":"Amgen Inc  Thousand 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