{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T12:04:01Z","timestamp":1780920241175,"version":"3.54.1"},"reference-count":24,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["accpjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacotherapy"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Drug interactions involving immunosuppressants can compromise transplant outcomes. Although repeated ketamine administration induces hepatic enzymes in experimental models, clinical reports of induced clearance of cytochrome P450 (CYP) substrates are lacking. Continuous subcutaneous ketamine infusions are increasingly used for acute pain management. We present a case of difficult\u2010to\u2010maintain tacrolimus and sirolimus concentrations in the context of subcutaneous ketamine infusion for acute pain management.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A 55\u2010year\u2010old male heart transplant recipient received continuous subcutaneous ketamine (5.2\u201310.4\u2009mg\/h) for pain management following lower limb thrombectomy. Tacrolimus and sirolimus concentrations were monitored throughout hospitalization and rehabilitation. Population pharmacokinetic modeling with Bayesian estimation characterized temporal clearance changes, incorporating inter\u2010occasion variability across six periods (pre\u2010, during\u2010, and weekly post\u2010ketamine administration for 4\u2009weeks).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Following ketamine initiation, tacrolimus and sirolimus concentrations remained subtherapeutic despite dose escalations of 1.8\u2010fold and 5\u2010fold, respectively. Pharmacokinetic modeling revealed approximately 2\u2010fold clearance increases during ketamine administration, peaking 1\u2009week after initiation. Following ketamine discontinuation, tacrolimus and sirolimus concentrations progressively increased over 3\u2009weeks, consistent with enzyme induction and recovery. Drug Interaction Probability Scale assessment indicated probable interaction (score\u2009+\u20095). Brief concomitant flucloxacillin use may have contributed to the observed changes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This case provides preliminary evidence of potential interaction between ketamine and CYP3A4\u2010metabolized immunosuppressants. Clinicians should consider increased therapeutic drug monitoring when using ketamine with narrow therapeutic range medications, continuing approximately 3\u2009weeks post\u2010discontinuation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/phar.70150","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T01:31:38Z","timestamp":1778549498000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Continuous Subcutaneous Ketamine Infusion May Induce Tacrolimus and Sirolimus Clearance: A Case Report"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4812-5745","authenticated-orcid":false,"given":"Jana","family":"Stojanova","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology and Toxicology St Vincent's Hospital  Sydney Australia"},{"name":"School of Clinical Medicine St Vincent's Healthcare Clinical Campus, Faculty of Medicine and Health, UNSW Sydney  Sydney Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7791-3025","authenticated-orcid":false,"given":"Bridin","family":"Murnion","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Toxicology St Vincent's Hospital  Sydney Australia"},{"name":"School of Clinical Medicine St Vincent's Healthcare Clinical Campus, Faculty of Medicine and Health, UNSW Sydney  Sydney Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fay","family":"Burrows","sequence":"additional","affiliation":[{"name":"Pharmacy Department St. Vincent's Hospital  Sydney Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilibeth","family":"Carlos","sequence":"additional","affiliation":[{"name":"Pharmacy Department St. Vincent's Hospital  Sydney Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8471-9826","authenticated-orcid":false,"given":"Tomoyuki","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Division of Translational and Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"},{"name":"Department of Pediatrics University of Cincinnati College of Medicine  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanobu","family":"Nadai","sequence":"additional","affiliation":[{"name":"Division of Translational and Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Irie","sequence":"additional","affiliation":[{"name":"Division of Translational and Clinical Pharmacology Cincinnati Children's Hospital Medical Center  Cincinnati Ohio 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