{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T20:32:24Z","timestamp":1789590744295,"version":"build-2803163510"},"reference-count":37,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,5,9]],"date-time":"2022-05-09T00:00:00Z","timestamp":1652054400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:p>PF\u201006835919 is a first\u2010in\u2010class ketohexokinase inhibitor (KHKi), recently under development for the treatment of metabolic and fatty liver diseases, which inhibited organic anion transporting polypeptide (OATP)1B1 <jats:italic>in vitro<\/jats:italic> and presented drug\u2013drug interaction (DDI) risk. This study aims to investigate the dose\u2010dependent effect of KHKi on OATP1B <jats:italic>in vivo<\/jats:italic> activity. We performed an open\u2010label study comparing pharmacokinetics of atorvastatin (OATP1B probe) dosed alone (20 mg single dose) and coadministered with two dose strengths of KHKi (50 and 280\u00a0mg once daily) in 12 healthy participants. Additionally, changes in exposure of coproporphyrin\u2010I (CP\u2010I), an endogenous biomarker for OATP1B, were assessed in the atorvastatin study (1.12\u2010fold and 1.49\u2010fold increase in area under the plasma concentration\u2010time profile (AUC) with once\u2010daily 50 and 280\u00a0mg, respectively), and a separate single oral dose study of KHKi alone (100\u2013600\u00a0mg, <jats:italic>n<\/jats:italic>\u00a0=\u00a06 healthy participants; up to a 1.80\u2010fold increase in AUC). Geometric mean ratios (90% confidence interval) of atorvastatin AUC following 50 and 280\u00a0mg KHKi were 1.14 (1.00\u20131.30) and 1.54 (1.37\u20131.74), respectively. Physiologically\u2010based pharmacokinetic modeling of CP\u2010I plasma exposure following a single dose of KHKi predicted <jats:italic>in vivo<\/jats:italic> OATP1B inhibition from about 13% to 70% over the 100 to 600\u00a0mg dose range, while using the <jats:italic>in vitro<\/jats:italic> inhibition potency (1.9\u00a0\u00b5M). Model\u2010based analysis correctly predicted \u201cno\u2010effect\u201d (AUC ratio &lt;\u00a01.25) at the low dose range and \u201cweak\u201d effect (AUC ratio &lt;\u00a02) on atorvastatin pharmacokinetics at the high dose range of KHKi. This study exemplified the utility of biomarker\u2010informed model\u2010based approach in discerning even small effects on OATP1B activity <jats:italic>in vivo<\/jats:italic>, and to project DDI risk at the clinically relevant doses.<\/jats:p>","DOI":"10.1002\/cpt.2593","type":"journal-article","created":{"date-parts":[[2022,3,31]],"date-time":"2022-03-31T06:34:32Z","timestamp":1648708472000},"page":"605-614","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Effect of a Ketohexokinase Inhibitor (PF\u201006835919) on <i>In Vivo<\/i> OATP1B Activity: Integrative Risk Assessment Using Endogenous Biomarker and a Probe Drug"],"prefix":"10.1111","volume":"112","author":[{"given":"David A.","family":"Tess","sequence":"first","affiliation":[{"name":"Pharmacokinetics, Dynamics and Metabolism, Medicine Design Worldwide Research &amp; Development Pfizer Inc  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emi","family":"Kimoto","sequence":"additional","affiliation":[{"name":"Pharmacokinetics, Dynamics and Metabolism, Medicine Design Worldwide Research &amp; Development Pfizer Inc.  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"King\u2010Ahmad","sequence":"additional","affiliation":[{"name":"Pharmacokinetics, Dynamics and Metabolism, Medicine Design Worldwide Research &amp; Development Pfizer Inc.  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoli","family":"Vourvahis","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Global Product Development Pfizer Inc  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. David","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Pharmacokinetics, Dynamics and Metabolism, Medicine Design Worldwide Research &amp; Development Pfizer Inc.  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Bergman","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Early Clinical Development Pfizer Inc.  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruolun","family":"Qui","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Early Clinical Development Pfizer Inc.  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veena","family":"Somayaji","sequence":"additional","affiliation":[{"name":"Clinical Biostatistics Early Clinical Development Pfizer Inc  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Weng","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Early Clinical Development Pfizer Inc.  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari R.","family":"Fonseca","sequence":"additional","affiliation":[{"name":"Pharmacokinetics, Dynamics and Metabolism, Medicine Design Worldwide Research &amp; Development Pfizer Inc  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Litchfield","sequence":"additional","affiliation":[{"name":"Pharmacokinetics, Dynamics and Metabolism, Medicine Design Worldwide Research &amp; Development Pfizer Inc  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manthena V. S.","family":"Varma","sequence":"additional","affiliation":[{"name":"Pharmacokinetics, Dynamics and Metabolism, Medicine Design Worldwide Research &amp; Development Pfizer Inc.  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,9]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-3002(51)90032-7"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1119908109"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26594"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c00944"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2021.101196"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.medj.2021.04.007"},{"key":"e_1_2_11_8_1","unstructured":"US Food and Drug Administration.Guidance for industry:in vitrodrug interaction studies \u2014 cytochrome P450 enzyme\u2010 and transporter\u2010mediated drug interactions<https:\/\/www.fda.gov\/media\/134582\/download> (2020)."},{"key":"e_1_2_11_9_1","volume-title":"Guideline on the investigation of drug interactions","author":"European Medicines Agency","year":"2012"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2434"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.723"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-014-0188-4"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.37"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1013"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1693"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-014-0156-z"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-012-0792-7"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.116.013326"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.116.234914"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.749"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.983"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12348"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.4155\/bio-2017-0270"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.119.257600"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12582"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2429"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12672"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13318-016-0383-9"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-015-1749-4"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.3109\/00498254.2015.1085111"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.118.081125"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI59526"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1042\/cs0400017"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(76)90426-5"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1695"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12625"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.120.000076"},{"issue":"17","key":"e_1_2_11_38_1","first-page":"198","article-title":"Multicompartment analysis of 14C\u2010labelled coproporphyrin and uroporphyrin kinetics in human beings","volume":"8","author":"Koskelo P.","year":"1976","journal-title":"Ann. 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