{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T20:15:26Z","timestamp":1761164126115,"version":"build-2065373602"},"reference-count":39,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T00:00:00Z","timestamp":1696982400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accpjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacotherapy"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Study Objective<\/jats:title>\n                    <jats:p>Levocarnitine (L\u2010carnitine) has shown promise as a metabolic\u2010therapeutic for septic shock, where mortality approaches 40%. However, high\u2010dose (\u2265 6 grams) intravenous supplementation results in a broad range of serum concentrations. We sought to describe the population pharmacokinetics (PK) of high\u2010dose L\u2010carnitine, test various estimates of kidney function, and assess the correlation of PK parameters with pre\u2010treatment metabolites in describing drug response for patients with septic shock.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Population PK analysis was done with baseline normalized concentrations using nonlinear mixed effect models in the modeling platform Monolix. Various estimates of kidney function, patient demographics, dose received, and organ dysfunction were tested as population covariates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Data Source<\/jats:title>\n                    <jats:p>We leveraged serum samples and metabolomics data from a phase II trial of L\u2010carnitine in vasopressor\u2010dependent septic shock. Serum was collected at baseline (T0); end\u2010of\u2010infusion (T12); and 24, 48, and 72 h after treatment initiation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Patients and Intervention<\/jats:title>\n                    <jats:p>Patients were adaptively randomized to receive intravenous L\u2010carnitine (6 grams, 12 grams, or 18 grams) or placebo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>The final dataset included 542 serum samples from 130 patients randomized to L\u2010carnitine. A two\u2010compartment model with linear elimination and a fixed volume of distribution (17.1 liters) best described the data and served as a base structural model. Kidney function estimates as a covariate on the elimination rate constant (k) reliably improved model fit. Estimated glomerular filtration rate (eGFR), based on the 2021 Chronic Kidney Disease Epidemiology collaboration (CKD\u2010EPI) equation with creatinine and cystatin C, outperformed creatinine clearance (Cockcroft\u2010Gault) and older CKD\u2010EPI equations that use an adjustment for self\u2010identified race.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>High\u2010dose L\u2010carnitine supplementation is well\u2010described by a two\u2010compartment population PK model in patients with septic shock. Kidney function estimates that leverage cystatin C provided superior model fit. Future investigations into high\u2010dose L\u2010carnitine supplementation should consider baseline metabolic status and dose adjustments based on renal function over a fixed or weight\u2010based dosing paradigm.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/phar.2882","type":"journal-article","created":{"date-parts":[[2023,9,30]],"date-time":"2023-09-30T00:50:51Z","timestamp":1696035051000},"page":"1240-1250","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Kidney function as a key driver of the pharmacokinetic response to high\u2010dose L\u2010carnitine in septic shock"],"prefix":"10.1002","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2496-6374","authenticated-orcid":false,"given":"Theodore S.","family":"Jennaro","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, College of Pharmacy University of Michigan  Ann Arbor Michigan 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