{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T04:30:10Z","timestamp":1778301010523,"version":"3.51.4"},"reference-count":64,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T00:00:00Z","timestamp":1641772800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>The aims of this study are (i) to develop a population pharmacokinetic model of enzyme activity in Gaucher\u2010type 1 (GD1) patients after intravenous administration of enzyme replacement therapy (ERT), and (ii) to establish an exposure\u2013efficacy relationship for bone marrow infiltration to propose dose adjustments according to patient covariate values.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A prospective follow\u2010up, semi\u2010experimental multi\u2010centre study was conducted in four hospitals to evaluate the pharmacokinetics, efficacy and safety of ERT in GD1 patients. Twenty\u2010five individuals with 266 glucocerebrosidase (GCase) observations in plasma and leukocytes and 14 individuals with 68 Spanish magnetic resonance imaging (S\u2010MRI) observations were enrolled.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A two concatenated compartment model with zero\u2010order endogenous production and first\u2010order distribution (CL<jats:sub>1<\/jats:sub>\u2009=\u20093.85\u2009\u00d7\u200910<jats:sup>\u22121<\/jats:sup> L\/d) and elimination (CL<jats:sub>2<\/jats:sub>\u2009=\u20091.25\u2009L\/d) allowed GCase observations in plasma and leukocytes to be described, respectively. An exponential time dependency (k<jats:sub>T<\/jats:sub>\u2009=\u20096.14\u2009\u00d7\u200910<jats:sup>\u22121<\/jats:sup> d<jats:sup>\u22121<\/jats:sup>) effect on CL<jats:sub>1<\/jats:sub> was incorporated. The final exposure\u2013efficacy model was a longitudinal logistic regression model with a first\u2010order Markov element. An <jats:italic>E<\/jats:italic><jats:sub>max<\/jats:sub> function (EC<jats:sub>50<\/jats:sub>\u2009=\u200915.73\u2009U\/L and <jats:italic>E<\/jats:italic><jats:sub>max<\/jats:sub>\u2009=\u20092.33) linked steady\u2010state concentrations of GCase in leukocytes to the probability of transition across the different S\u2010MRI stages.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>A population pharmacokinetic model successfully characterized the leukocyte activity\u2013time profiles of GCase following intravenous administration of ERT in GD1 patients together with an exposure\u2013efficacy relationship in bone marrow using Markovian elements. The information obtained from this study could be of high clinical relevance in individualization of ERT in GD1 patients, as this could lead to anticipative decision\u2010making regarding clinical response in bone and optimal dosing strategy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15198","type":"journal-article","created":{"date-parts":[[2021,12,27]],"date-time":"2021-12-27T01:48:16Z","timestamp":1640569696000},"page":"2727-2737","source":"Crossref","is-referenced-by-count":3,"title":["Quantitative assessment of the exposure\u2013efficacy relationship of glucocerebrosidase using Markovian elements in Gaucher patients treated with enzyme replacement therapy"],"prefix":"10.1111","volume":"88","author":[{"given":"Elena","family":"Gras\u2010Colomer","sequence":"first","affiliation":[{"name":"Pharmacy Department Hospital Manises of Valencia  Valencia 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