{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T20:19:14Z","timestamp":1771877954459,"version":"3.50.1"},"reference-count":29,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2016,1,15]],"date-time":"2016-01-15T00:00:00Z","timestamp":1452816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100001003","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001003","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2016,3]]},"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>\n                      To quantify the effect of the sodium\u2010glucose co\u2010transporter 2 inhibitor, empagliflozin, on renal glucose reabsorption in patients with type 2 diabetes, and to evaluate covariate effects, using a mechanistic population pharmacokinetic\u2013pharmacodynamic (\n                      <jats:styled-content style=\"fixed-case\">PK\u2013PD<\/jats:styled-content>\n                      ) model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Four phase\n                      <jats:styled-content style=\"fixed-case\">I<\/jats:styled-content>\n                      \/\n                      <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>\n                      trials were used for model development. Empagliflozin's\n                      <jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>\n                      characteristics were characterized by a two\u2010compartmental model with sequential zero\u2010 and first\u2010order absorption. Urinary glucose excretion (\n                      <jats:styled-content style=\"fixed-case\">UGE<\/jats:styled-content>\n                      ) was described as dependent on renal glucose filtration and reabsorption; splay of the glucose reabsorption\/excretion curves was considered. The modelling assumed that empagliflozin lowers the maximum renal glucose reabsorption capacity and, thereby, the renal threshold for glucose (\n                      <jats:styled-content style=\"fixed-case\">RTg<\/jats:styled-content>\n                      ). Covariate effects were investigated using a full covariate modelling approach, emphasizing parameter estimation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:styled-content style=\"fixed-case\">PK\u2013PD<\/jats:styled-content>\n                      model provided a reasonable description of the\n                      <jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>\n                      characteristics of empagliflozin and its effects on\n                      <jats:styled-content style=\"fixed-case\">UGE<\/jats:styled-content>\n                      across a range of renal function levels. Its parameters are consistent with reported values for renal physiology. Using this model, the effect of empagliflozin on renal glucose reabsorption was quantified. Steady\u2010state empagliflozin doses (1, 5, 10 and 25\u2009mg) reduced\n                      <jats:styled-content style=\"fixed-case\">RTg<\/jats:styled-content>\n                      from 12.5\u2009mmol\/L [95% confidence interval (\n                      <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content>\n                      ) 12.0, 13.1] to 5.66 (95%\n                      <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content>\n                      4.62, 6.72), 3.01 (95%\n                      <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content>\n                      2.33, 3.69), 2.53 (95%\n                      <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content>\n                      1.83, 3.14) and 2.21 (95%\n                      <jats:styled-content style=\"fixed-case\">CI<\/jats:styled-content>\n                      1.47, 2.84)\u2009mg\/dl, respectively. Covariate analysis showed the effect of empagliflozin on\n                      <jats:styled-content style=\"fixed-case\">UGE<\/jats:styled-content>\n                      was not influenced, to a clinically relevant extent, by sex, age or race.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      A method for characterizing renal glucose reabsorption was developed that does not require complex glucose clamp experiments. These analyses indicate that empagliflozin provided concentration\u2010dependent\n                      <jats:styled-content style=\"fixed-case\">RTg<\/jats:styled-content>\n                      reductions, with 10 and 25\u2009mg providing near\u2010maximum\n                      <jats:styled-content style=\"fixed-case\">RTg<\/jats:styled-content>\n                      \u2010lowering.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.12597","type":"journal-article","created":{"date-parts":[[2015,10,29]],"date-time":"2015-10-29T03:51:30Z","timestamp":1446090690000},"page":"241-248","source":"Crossref","is-referenced-by-count":9,"title":["Mixed\u2010effects modelling to quantify the effect of empagliflozin on renal glucose reabsorption in patients with type 2 diabetes"],"prefix":"10.1111","volume":"18","author":[{"given":"J.","family":"Mondick","sequence":"first","affiliation":[{"name":"Metrum Research Group  Tariffville CT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Riggs","sequence":"additional","affiliation":[{"name":"Metrum Research Group  Tariffville CT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T.","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Nippon Boehringer Ingelheim Co. 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