{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T07:52:35Z","timestamp":1768031555431,"version":"3.49.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010711","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T00:00:00Z","timestamp":1669593600000}}],"reference-count":82,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T00:00:00Z","timestamp":1668384000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"publisher","award":["Fondecyt 1181094"],"award-info":[{"award-number":["Fondecyt 1181094"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"publisher","award":["ACT210083"],"award-info":[{"award-number":["ACT210083"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"publisher","award":["Scholarship Program \/ DOCTORADO \/ 2019 \u2014 21191120"],"award-info":[{"award-number":["Scholarship Program \/ DOCTORADO \/ 2019 \u2014 21191120"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Blood pressure (BP) follows a circadian variation, increasing during active hours, showing a small postprandial valley and a deeper decrease during sleep. Nighttime reduction of 10\u201320% relative to daytime BP is defined as a dipper pattern, and a reduction of less than 10%, as a non-dipper pattern. Despite this BP variability, hypertension\u2019s diagnostic criteria and therapeutic objectives are usually based on BP average values. Indeed, studies have shown that chrono-pharmacological optimization significantly reduces long-term cardiovascular risk if a BP dipper pattern is maintained. Changes in the effect of antihypertensive medications can be explained by circadian variations in their pharmacokinetics (PK) and pharmacodynamics (PD). Nevertheless, BP circadian variation has been scarcely included in PK-PD models of antihypertensive medications to date. In this work, we developed PK-PD models that include circadian rhythm to find the optimal dosing time (<jats:italic>Ta<\/jats:italic>) of first-line antihypertensive medications for dipper and non-dipper patterns. The parameters of the PK-PD models were estimated using global optimization, and models were selected according to the lowest corrected Akaike information criterion value. Simultaneously, sensitivity and identifiability analysis were performed to determine the relevance of the parameters and establish those that can be estimated. Subsequently, <jats:italic>Ta<\/jats:italic> parameters were optimized to maximize the effect on BP average, BP peaks, and sleep-time dip. As a result, all selected models included at least one circadian PK component, and circadian parameters had the highest sensitivity. Furthermore, <jats:italic>Ta<\/jats:italic> with which BP&gt;130\/80 mmHg and a dip of 10\u201320% are achieved were proposed when possible. We show that the optimal <jats:italic>Ta<\/jats:italic> depends on the therapeutic objective, the medication, and the BP profile. Therefore, our results suggest making chrono-pharmacological recommendations in a personalized way.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010711","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T18:31:25Z","timestamp":1668450685000},"page":"e1010711","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Dosing time optimization of antihypertensive medications by including the circadian rhythm in pharmacokinetic-pharmacodynamic models"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1501-8081","authenticated-orcid":true,"given":"Javiera","family":"Cort\u00e9s-R\u00edos","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8853-5901","authenticated-orcid":true,"given":"Ram\u00f3n C.","family":"Hermida","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1966-2920","authenticated-orcid":true,"given":"Maria","family":"Rodriguez-Fernandez","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,11,14]]},"reference":[{"key":"pcbi.1010711.ref001","first-page":"1","article-title":"Hypertension","volume":"4","author":"S Oparil","year":"2018","journal-title":"Nat Rev Dis Prim 2018 41"},{"key":"pcbi.1010711.ref002","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.freeradbiomed.2017.11.024","article-title":"Circadian clock-mediated regulation of blood pressure","author":"LG Douma","year":"2018","journal-title":"Free Radical Biology and Medicine. 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