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Eighteen metformin\u2010na\u00efve men and women with Type 2 Diabetes and creatinine clearance (CrCl) in the range 18\u201049\u00a0mL\/min (eGFR 15\u201029\u00a0mL\/min\/1.73\u00a0m<jats:sup>2<\/jats:sup>) were allocated to daily immediate\u2010release metformin of 250\u00a0mg, 500\u00a0mg, or 1000\u00a0mg. A first\u2010dose profile and trough concentrations for 4\u00a0weeks were taken on all patients. Pharmacokinetic (<jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content>) parameters were estimated by fitting a first\u2010order compartment model with absorption in a peripheral compartment to concentrations measured 24 hours post\u2013first dose. Single\u2010dose <jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content> parameters time to maximum concentration (<jats:italic>t<\/jats:italic><jats:sub>max<\/jats:sub>) and maximum concentration (<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>) were consistent with previous observations in patients with normal renal function (healthy and diabetic), as was the association between CrCl and apparent total oral clearance (<jats:italic>Cl\/F<\/jats:italic>). However, patients with a CrCl below 32\u00a0mL\/min had trough concentrations that were consistently above the steady\u2010state minimum implied by the population <jats:styled-content style=\"fixed-case\">PK<\/jats:styled-content> model. This suggests the model may not apply to patients with CrCl below 32\u00a0<jats:styled-content style=\"fixed-case\">mL<\/jats:styled-content>\/min. Metformin in doses of 500\u20101000\u00a0mg\/day could be taken by <jats:styled-content style=\"fixed-case\">CKD<\/jats:styled-content>\u20104 patients. However, the single\u2010compartment model breaks down as CrCl declines below 32\u00a0mL\/min suggesting that metformin levels should be monitored regularly in progressive stage 4 CKD.<\/jats:p>","DOI":"10.1002\/prp2.424","type":"journal-article","created":{"date-parts":[[2018,9,14]],"date-time":"2018-09-14T19:34:44Z","timestamp":1536953684000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Pharmacokinetics of metformin in patients with chronic kidney disease stage 4 and metformin\u2010na\u00efve type 2 diabetes"],"prefix":"10.1002","volume":"6","author":[{"given":"Ajith M.","family":"Dissanayake","sequence":"first","affiliation":[{"name":"Counties Manukau Health Auckland New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6897-9644","authenticated-orcid":false,"given":"Mark C.","family":"Wheldon","sequence":"additional","affiliation":[{"name":"Auckland University of Technology Auckland New Zealand"},{"name":"Middlemore Clinical Trials Middlemore Hospital Auckland New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher J.","family":"Hood","sequence":"additional","affiliation":[{"name":"Counties Manukau Health Auckland New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,9,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(98)07037-8"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.2165\/11534750-000000000-00000"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1463-1326.2001.00128.x"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.1992.00400230129023"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2010.03891.x"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.2337\/diab.32.2.181"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD002967.pub3"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.15298"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(15)00123-0"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2015.10.014"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdiacomp.2015.07.022"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1552-4604.1995.tb04033.x"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1463-1326.2012.01617.x"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc09-1284"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-013-0046-9"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2017.03.005"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200544070-00004"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1345\/aph.1S176"},{"key":"e_1_2_8_20_1","unstructured":"WalkerG.2015.Creatinine Clearance (Cockcroft\u2010Gault Equation) \u2010 MDCalc.http:\/\/www.mdcalc.com\/creatinine-clearance-cockcroft-gault-equation\/#about-equationRetrieved December 11 2015"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1875-9114.2012.01098.x"},{"key":"e_1_2_8_22_1","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Core Team","year":"2014"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-21706-2"},{"key":"e_1_2_8_24_1","volume-title":"An R Companion to Applied Regression, 2nd edn","author":"Fox J","year":"2011"},{"key":"e_1_2_8_25_1","unstructured":"PinheiroJ BatesD DebRoyS SarkarD.R Core Team.nlme: Linear and Nonlinear Mixed Effects Models.2014. 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