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We compared the pharmacokinetics (PKs) and pharmacodynamics of brand name versus two generic formulations (drugs 1 and 2) of metoprolol ER tablets with different time to maximum concentration (<jats:italic>T<\/jats:italic><jats:sub>max<\/jats:sub>) in adults with hypertension. Participants were randomized to equal drug doses (50\u2013150\u2009mg\/day) administered in one of two sequences (brand\u2010drug1\u2010brand\u2010drug2 or brand\u2010drug2\u2010brand\u2010drug1) and completed 24\u2010h PK, digital heart rate (HR), ambulatory blood pressure (BP), and HR studies after taking each formulation for greater than or equal to 7\u2009days. Metoprolol concentrations were determined by liquid chromatography tandem mass spectrometry, with noncompartmental analysis performed to obtain PK parameters in Phoenix WinNonlin. Heart rate variability (HRV) low\u2010to\u2010high frequency ratio was determined per quartile over the 24\u2010h period. Thirty\u2010six participants completed studies with the brand name and at least one generic product. Among 30 participants on the 50\u2009mg dose, the primary PK end points of area under the concentration\u2010time curve and <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> were similar between products; <jats:italic>T<\/jats:italic><jats:sub>max<\/jats:sub> was 6.1\u2009\u00b1\u20093.6 for the brand versus 3.5\u2009\u00b1\u20094.9 for drug 1 (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.019) and 9.6\u2009\u00b1\u20093.2 for drug 2 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). Among all 36 participants, 24\u2010h BPs and HRs were similar between products. Mean 24\u2010h HRV low\u2010to\u2010high ratio was also similar for drug 1 (2.04\u2009\u00b1\u20091.35), drug 2 (1.86\u2009\u00b1\u20091.35), and brand (2.04\u2009\u00b1\u20091.77), but was more sustained over time for the brand versus drug 1 (drug\u2009\u00d7\u2009quartile interaction <jats:italic>p<\/jats:italic>\u00a0=\u00a00.017). Differences in <jats:italic>T<\/jats:italic><jats:sub>max<\/jats:sub> between metoprolol ER products following repeated doses may have implications for drug effects on autonomic balance over the dosing interval.<\/jats:p>","DOI":"10.1111\/cts.13294","type":"journal-article","created":{"date-parts":[[2022,4,30]],"date-time":"2022-04-30T07:09:50Z","timestamp":1651302590000},"page":"1764-1775","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A randomized, cross\u2010over trial of metoprolol succinate formulations to evaluate <scp>PK<\/scp> and <scp>PD<\/scp> end points for therapeutic equivalence"],"prefix":"10.1111","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1460-4000","authenticated-orcid":false,"given":"Scott A.","family":"Mosley","sequence":"first","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine College of Pharmacy, University of Florida  Gainesville Florida USA"},{"name":"Department of Clinical Pharmacy University of Southern California  Los Angeles California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9179-0735","authenticated-orcid":false,"given":"Sarah","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy University of Florida  Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1652-3773","authenticated-orcid":false,"given":"Nihal","family":"El Rouby","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine College of Pharmacy, University of Florida  Gainesville Florida USA"},{"name":"Department of Pharmacy Practice and Administrative Sciences 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