{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T06:25:27Z","timestamp":1793773527390,"version":"4.6.1"},"reference-count":31,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T00:00:00Z","timestamp":1684800000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["EB022015"],"award-info":[{"award-number":["EB022015"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:sec><jats:title>Aim<\/jats:title><jats:p>Pharmacokinetics have historically been assessed using drug concentration data obtained via blood draws and bench\u2010top analysis. The cumbersome nature of these typically constrains studies to at most a dozen concentration measurements per dosing event. This, in turn, limits our statistical power in the detection of hours\u2010scale, time\u2010varying physiological processes. Given the recent advent of in vivo electrochemical aptamer\u2010based (EAB) sensors, however, we can now obtain hundreds of concentration measurements per administration. Our aim in this paper was to assess the ability of these time\u2010dense datasets to describe time\u2010varying pharmacokinetic models with good statistical significance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used seconds\u2010resolved measurements of plasma tobramycin concentrations in rats to statistically compare traditional one\u2010 and two\u2010compartmental pharmacokinetic models to new models in which the proportional relationship between a drug's plasma concentration and its elimination rate varies in response to changing kidney function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that a modified one\u2010compartment model in which the proportionality between the plasma concentration of tobramycin and its elimination rate falls reciprocally with time either meets or is preferred over the standard two\u2010compartment pharmacokinetic model for half of the datasets characterized. When we reduced the impact of the drug's rapid distribution phase on the model, this one\u2010compartment, time\u2010varying model was statistically preferred over the standard one\u2010compartment model for 80% of our datasets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results highlight both the impact that simple physiological changes (such as varying kidney function) can have on drug pharmacokinetics and the ability of high\u2010time resolution EAB sensor measurements to identify such impacts.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15756","type":"journal-article","created":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T01:16:02Z","timestamp":1682558162000},"page":"2798-2812","source":"Crossref","is-referenced-by-count":13,"title":["Using seconds\u2010resolved pharmacokinetic datasets to assess pharmacokinetic models encompassing time\u2010varying physiology"],"prefix":"10.1111","volume":"89","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5931-124X","authenticated-orcid":false,"given":"Matthew H.","family":"McDonough","sequence":"first","affiliation":[{"name":"Department of Statistics and Applied Probability University of California Santa Barbara  Santa Barbara California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2114-587X","authenticated-orcid":false,"given":"Sophie L.","family":"Stocker","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Faculty of Medicine and Health University of Sydney  New South Wales Sydney Australia"},{"name":"St Vincent's Clinical School University of New South Wales  Sydney Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tod E.","family":"Kippin","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences University of California Santa Barbara  Santa Barbara California USA"},{"name":"The Neuroscience Research Institute and Department of Molecular Cellular and Developmental Biology University of California Santa Barbara  Santa Barbara California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Meiring","sequence":"additional","affiliation":[{"name":"Department of Statistics and Applied Probability University of California Santa Barbara  Santa Barbara California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin W.","family":"Plaxco","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry University of California Santa Barbara  Santa Barbara California USA"},{"name":"Biological Engineering Graduate Program University of California Santa Barbara  California Santa Barbara USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,5,23]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsptsci.8b00033"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1613458114"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00691.2009"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.636048"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088\u2010200443110\u201000005"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095\u2010021\u201003114\u20109"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2010019\u201000816\u20107"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u20102125.2004.02170.x"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12406"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1445\u20105994.1997.tb00948.x"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1445\u20105994.1998.tb02973.x"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200500989"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acssensors.7b00787"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acssensors.9b01616"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9SC01495K"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2019.00069"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010022\u201009070\u20107"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/acssensors.1c01183"},{"key":"e_1_2_8_20_1","volume-title":"Guide for the care and use of laboratory animals","author":"National Research Council (US)","year":"2011"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acssensors.2c01894"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.38.1.79"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1159\/000139106"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978\u20100\u201012\u2010801411\u20100.00009\u20103"},{"key":"e_1_2_8_25_1","volume-title":"The essentials of linear state\u2010space systems","author":"Aplevich JD","year":"2000"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1109\/SPMB.2014.7002952"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/9780471722199"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1214\/aos\/1176344136"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11538\u2010019\u201000589\u2010x"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781118856406.app5"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1109\/TAC.1974.1100705"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.38.1.54"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.15756","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T12:17:37Z","timestamp":1754914657000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bcp.15756"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,23]]},"references-count":31,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2023,9]]}},"alternative-id":["10.1111\/bcp.15756"],"URL":"https:\/\/doi.org\/10.1111\/bcp.15756","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,23]]}}}