{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T14:50:59Z","timestamp":1788360659958,"version":"build-2803163510"},"reference-count":23,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Hydroxyurea (HU), a cornerstone treatment for sickle cell disease (SCD), exhibits marked interindividual pharmacokinetic\/pharmacodynamic (PK\/PD) variability that remains poorly understood. This study aimed to establish a population PK model using OPTIMDREP randomized trial data (NCT06464458), quantify parameter variability, and identify covariates influencing HU PK and hematological response. Methods: Plasma sampling data from 22 SCD patients (20 pediatric and 2 adult patients; median age: 11.2 years [range: 2.5\u201335.7]) on once-daily oral HU underwent a non-compartmental analysis (NCA) followed by nonlinear mixed-effects modeling (MonolixSuite\u00ae). PK variability covariates and PK\/PD correlations with the mean corpuscular volume (MCV), reticulocytes, fetal hemoglobin percentage (HbF%) and neutrophils were investigated. Results: NCA identified two absorption phenotypes (rapid\/slow), with higher maximum concentration values observed for rapid (36.5 \u00b1 18.8 mg\/L) compared to slow (22.3 \u00b1 8.4 mg\/L) (p = 0.0013) profiles but not statistically different total exposures, apparent clearances (Cl\/F) or volumes of distribution (Vd\/F). The population approach identified the one-compartment model (first-order absorption and linear elimination) and confirmed the absorption phenotype as the key absorption rate (ka) covariate (9.93 vs. 1.36 h\u22121), explaining half of the ka interindividual variability (IIV). The median-normalized body weight was retained for both the Cl\/F and Vd\/F, as it significantly reduced the objective function value. No hematological parameter was correlated to PK parameters. However, rapid absorbers showed a superior response on the MCV (\u0394 = 9.1 fL, p &lt; 0.0001), reticulocytes (\u0394 = \u221242.2 G\/L, p &lt; 0.01), and HbF% trend (\u0394 = 2.8%, p = 0.0835) but not on neutrophil counts (p = 0.8757). Conclusions: The absorption phenotype, a novel covariate explaining half of the ka IIV, predicts a superior erythropoietic response without toxicity in SCD patients. These findings support absorption phenotype integration into PK-guided dosing algorithms to optimize early-response biomarkers and personalize HU therapy.<\/jats:p>","DOI":"10.3390\/pharmaceutics18060654","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T12:31:56Z","timestamp":1779885116000},"page":"654","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Hydroxyurea Absorption Phenotype: A Key PK\/PD Determinant in Sickle Cell Disease Treatment"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3560-0166","authenticated-orcid":false,"given":"Amelia-Naomi","family":"Sabo","sequence":"first","affiliation":[{"name":"Laboratoire de Biochimie et Biologie Mol\u00e9culaire, P\u00f4le de Biologie-G\u00e9n\u00e9tique-Pathologie, H\u00f4pitaux Universitaires de Strasbourg, 67098 Strasbourg, France"},{"name":"Laboratoire de Pharmacologie et Toxicologie Neurocardiovasculaire, Unit\u00e9 de Recherche 7296, Facult\u00e9 de M\u00e9decine de Ma\u00efeutique et des Sciences de la Sant\u00e9, Centre de Recherche en Biom\u00e9decine de Strasbourg (CRBS), Universit\u00e9 de Strasbourg, 67085 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0710-7957","authenticated-orcid":false,"given":"Charlotte","family":"Nazon","sequence":"additional","affiliation":[{"name":"Centre de Comp\u00e9tence Pour les Maladies Constitutionnelles du Globule Rouge et de L\u2019\u00e9rythropo\u00ef\u00e8se, Service D\u2019h\u00e9matologie Oncologie P\u00e9diatrique, P\u00f4le de P\u00e9diatrie, H\u00f4pitaux Universitaires de Strasbourg, 67200 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Paillard","sequence":"additional","affiliation":[{"name":"Centre de Comp\u00e9tence Pour les Maladies Constitutionnelles du Globule Rouge et de L\u2019\u00e9rythropo\u00ef\u00e8se, Service D\u2019h\u00e9matologie Oncologie P\u00e9diatrique, P\u00f4le de P\u00e9diatrie, H\u00f4pitaux Universitaires de Strasbourg, 67200 Strasbourg, France"},{"name":"Laboratoire D\u2019immunoRhumatologie Mol\u00e9culaire, INSERM UMR_S 1109, LabEx Transplantex, F\u00e9d\u00e9ration de M\u00e9decine Translationnelle de Strasbourg, Universit\u00e9 de Strasbourg, 67085 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4680-4293","authenticated-orcid":false,"given":"V\u00e9ronique","family":"Kemmel","sequence":"additional","affiliation":[{"name":"Laboratoire de Biochimie et Biologie Mol\u00e9culaire, P\u00f4le de Biologie-G\u00e9n\u00e9tique-Pathologie, H\u00f4pitaux Universitaires de Strasbourg, 67098 Strasbourg, France"},{"name":"Laboratoire de Pharmacologie et Toxicologie Neurocardiovasculaire, Unit\u00e9 de Recherche 7296, Facult\u00e9 de M\u00e9decine de Ma\u00efeutique et des Sciences de la Sant\u00e9, Centre de Recherche en Biom\u00e9decine de Strasbourg (CRBS), Universit\u00e9 de Strasbourg, 67085 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"ref_1","first-page":"CD002202","article-title":"Hydroxyurea (Hydroxycarbamide) for Sickle Cell Disease","volume":"9","author":"Nevitt","year":"2022","journal-title":"Cochrane Database Syst. 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Rep."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/6\/654\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T12:47:47Z","timestamp":1779886067000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/6\/654"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,27]]},"references-count":23,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["pharmaceutics18060654"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18060654","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,27]]}}}