{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T06:00:13Z","timestamp":1785218413785,"version":"3.55.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Organic Anion Transporting Polypeptide (OATP) 1B1\/3 inhibition can lead to clinically significant drug-drug interactions (DDIs). Coproporphyrin-I (CP-I) is an established endogenous biomarker for assessing the OATP1B inhibitory activity of new chemical entities. However, current physiologically based pharmacokinetic (PBPK) models for CP-I are restricted to proprietary software, limiting widespread adoption and collaboration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We developed and qualified an open-source PBPK model for CP-I using the Open Systems Pharmacology (OSP) Suite. The model describes the endogenous synthesis and OATP1B1\/MRP2-mediated disposition of CP-I. It was integrated into a DDI network comprising the precipitants rifampicin, probenecid, and cyclosporine A, and the object drugs atorvastatin, pitavastatin, and rosuvastatin. A key methodological feature was the estimation of\n                      <jats:italic>in vivo<\/jats:italic>\n                      inhibition constants (K\n                      <jats:sub>i,OATP1B<\/jats:sub>\n                      ) for precipitants based on clinical CP-I data rather than relying solely on\n                      <jats:italic>in vitro<\/jats:italic>\n                      measurements.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The CP-I model successfully captured baseline plasma concentration-time profiles with a Geometric Mean Fold Error (GMFE) of 1.15. In the DDI network analysis, using CP-I-derived\n                      <jats:italic>in vivo<\/jats:italic>\n                      K\n                      <jats:sub>i,OATP1B<\/jats:sub>\n                      values for the strong OATP1B inhibitors rifampicin and cyclosporine yielded superior predictive accuracy compared to\n                      <jats:italic>in vitro<\/jats:italic>\n                      values, with most predicted DDI ratios for statins falling within the 2-fold acceptance range. Specifically for cyclosporine, the model required an adjustment of the endogenous CP-I synthesis rate to account for baseline differences in the specific study population; incorporating this allowed for the estimation of an\n                      <jats:italic>in vivo<\/jats:italic>\n                      K\n                      <jats:sub>i,OATP1B<\/jats:sub>\n                      (4.7\u00a0nM) that accurately predicted interactions with pitavastatin and rosuvastatin. Notably, probenecid, a weak OATP1B inhibitor, showed an\n                      <jats:italic>in vivo<\/jats:italic>\n                      K\n                      <jats:sub>i,OATP1B<\/jats:sub>\n                      estimate within a similar range of its\n                      <jats:italic>in vitro<\/jats:italic>\n                      measured value. Consequently, the scaling factor between\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      K\n                      <jats:sub>i,OATP1B<\/jats:sub>\n                      appears to be a compound-specific parameter requiring independent identification for each precipitant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study presents a qualified, freely available PBPK framework for CP-I. It demonstrates that calibrating participant models using early clinical biomarker data enables reliable prospective prediction of OATP1B-mediated DDIs. This workflow supports model-informed drug development (MIDD) strategies, potentially reducing the need for dedicated clinical DDI studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1828033","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T05:35:25Z","timestamp":1785216925000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Coproporphyrin I PBPK model in the open systems pharmacology suite enables precise prediction of OATP 1B- mediated drug interactions through calibrated In vivo inhibition constants"],"prefix":"10.3389","volume":"17","author":[{"given":"Tobias","family":"Kanacher","sequence":"first","affiliation":[{"name":"Pharmetheus AB","place":["Uppsala, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moriah","family":"Pellowe","sequence":"additional","affiliation":[{"name":"Pharmetheus AB","place":["Uppsala, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Kovar","sequence":"additional","affiliation":[{"name":"Pharmetheus AB","place":["Uppsala, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Eriksson","sequence":"additional","affiliation":[{"name":"Pharmetheus AB","place":["Uppsala, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wu","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma Inc.","place":["Ridgefield, CT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Busse","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH & Co. 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