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Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Therapeutic drug monitoring (TDM) may optimize dosing of mycophenolate mofetil (MMF) in patients with nephrotic syndrome, but it is not routinely implemented. When performed, TDM typically relies on total mycophenolic acid (MPA) concentrations, although only unbound MPA is pharmacologically active. This study aimed to develop a population pharmacokinetic (PK) model characterizing the PK and pharmacodynamics (PD) of total and unbound MPA in plasma and saliva of paediatric nephrotic syndrome patients following oral MMF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>PK\/PD data from 62 children (47 full and 21 limited sampling curves) were analysed using nonlinear mixed-effects modelling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A two-compartment model with first-order absorption best describes unbound MPA PK. Protein binding was captured using a nonlinear saturable binding equation. The final population PK parameter estimates (for unbound MPA) were absorption rate constant (k\n                      <jats:sub>a<\/jats:sub>\n                      ), 1.81\u2009h\n                      <jats:sup>\u22121<\/jats:sup>\n                      (relative standard error (RSE): 8%); apparent clearance (Cl\/F), 2550\u2009L h\n                      <jats:sup>\u22121<\/jats:sup>\n                      (RSE: 8%); apparent central volume (V\n                      <jats:sub>c<\/jats:sub>\n                      \/F), 1590\u2009L (RSE: 27%); apparent peripheral volume (V\n                      <jats:sub>p<\/jats:sub>\n                      \/F), 239,000\u2009L (RSE: 52%); apparent intercompartmental clearance (Q\/F), 1940\u2009L h\n                      <jats:sup>\u22121<\/jats:sup>\n                      (RSE: 13%); maximal binding capacity (B\n                      <jats:sub>max<\/jats:sub>\n                      ), 196\u2009\u00b5mol (RSE: 44%); dissociation constant (K\n                      <jats:sub>d<\/jats:sub>\n                      ), 0.75\u2009\u00b5mol L\n                      <jats:sup>\u22121<\/jats:sup>\n                      (RSE: 49%). Saliva and unbound plasma MPA showed a proportional relationship (saliva\/plasma ratio: 1.34, RSE: 24%). The PK\u2013PD relationship between unbound MPA and inosine monophosphate dehydrogenase (IMPDH) activity was described by a sigmoid inhibitory effect model with a baseline parameter. The population estimates were baseline effect, 66.4 (RSE: 21%); unbound plasma concentration for 50% inhibition, 0.0251 (RSE: 27%); shape parameter, 0.559 (RSE:22%). A limited sampling strategy allowed acceptable prediction of unbound MPA area under the concentration\u2013time curve from 0 to 12\u2009hours (AUC\n                      <jats:sub>0\u201312\u2009h<\/jats:sub>\n                      ) but not IMPDH activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The developed model provides a foundation for model-informed precision dosing of MMF in children with nephrotic syndrome.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s43440-026-00885-z","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T14:16:32Z","timestamp":1785507392000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Population pharmacokinetics of total and free mycophenolic acid in plasma in paediatric patients with nephrotic syndrome including salivary concentrations and the pharmacodynamics"],"prefix":"10.1007","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0441-4514","authenticated-orcid":false,"given":"Astrid","family":"Heida","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1758-8587","authenticated-orcid":false,"given":"Danuta","family":"Ostalska-Nowicka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7365-553X","authenticated-orcid":false,"given":"Jacek","family":"Zachwieja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4524-9892","authenticated-orcid":false,"given":"Nynke G. 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These studies were approved by the Bioethical Committee at Poznan University of Medical Sciences (Decisions numbers 866\/15, 1147\/18, 158\/20, 773\/21, and 808\/22). The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.","order":1,"name":"Ethics","label":"Ethics approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Written informed consent was obtained for collection of the data for the studies from which the data was obtained","order":2,"name":"Ethics","label":"Consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable","order":3,"name":"Ethics","label":"Consent for Publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}]}}