{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T14:35:00Z","timestamp":1783780500260,"version":"3.55.0"},"reference-count":18,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,11,11]],"date-time":"2023-11-11T00:00:00Z","timestamp":1699660800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Tafolecimab, a novel fully human monoclonal antibody targeting PCSK9, has been assessed in Chinese healthy volunteers and patients with hypercholesterolemia. This analysis is to develop and qualify a population pharmacokinetics (PopPKs)\/LDL\u2010C model to characterize tafolecimab PK and LDL\u2010C profiles, evaluate the impact of potential covariates on tafolecimab, estimate individual predicted exposure, and LDL\u2010C decreasing, furthermore, explore exposure\u2013response relationship to support clinical use. Data from six clinical trials in China were used to develop the PopPK\/LDL\u2010C model. A Michaelis\u2013Menten approximation of the target\u2010mediated drug disposition (TMDD) model was used to describe PK data and indirect response (IDR) model was developed to estimate the LDL\u2010C profile. A stochastic approximation expectation maximization algorithm was applied to estimate PopPK\/LDL\u2010C parameters. The PK\/LDL\u2010C time course data for tafolecimab were well described by TMDD\/IDR model. Baseline covariates resulting in statistically significant changes in PK\/LDL\u2010C parameters included: body weight and sex on absorption rate constant; body weight, sex, and unbound PCSK9 on central volume; body weight and sex on clearance; baseline LDL\u2010C on first\u2010order rate constants for the removal of an effect); and disease and sex on maximum effect. However, the magnitudes of changes associated with these covariates do not necessitate dose adjustment. Exposure\u2013efficacy relationship indicated that the nadir of LDL\u2010C reduction achieved with the steady\u2010state trough plasma concentration (<jats:italic>C<\/jats:italic><jats:sub>trough<\/jats:sub>) of tafolecimab at 5\u2009\u03bcg\/mL, and no further LDL\u2010C decreasing with the increasing <jats:italic>C<\/jats:italic><jats:sub>trough<\/jats:sub>. There was no exposure dependency observed in exposure\u2010safety exploration. The PopPK\/LDL\u2010C model was successfully developed, validated, and predicted tafolecimab\/LDL\u2010C concentrations and individual exposures.<\/jats:p>","DOI":"10.1111\/cts.13674","type":"journal-article","created":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T11:11:23Z","timestamp":1698232283000},"page":"2791-2803","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Pharmacokinetic\/LDL\u2010C and exposure\u2013response analysis of tafolecimab in Chinese hypercholesterolemia patients: Results from phase I, II, and III studies"],"prefix":"10.1111","volume":"16","author":[{"given":"Shuling","family":"Yan","sequence":"first","affiliation":[{"name":"Innovent Biologics (Suzhou) Co. Ltd.  Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Peking University First Hospital  Beijing China"},{"name":"Institute of Clinical Pharmacology Peking University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiushi","family":"Xie","sequence":"additional","affiliation":[{"name":"Innovent Biologics (Suzhou) Co. Ltd.  Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijuan","family":"Du","sequence":"additional","affiliation":[{"name":"Innovent Biologics (Suzhou) Co. Ltd.  Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyang","family":"Ma","sequence":"additional","affiliation":[{"name":"Innovent Biologics (Suzhou) Co. Ltd.  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