{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T14:19:25Z","timestamp":1789654765058,"version":"4.0.1"},"reference-count":43,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T00:00:00Z","timestamp":1622764800000},"content-version":"unspecified","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2021,4,27]]},"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Dosing schemes of pembrolizumab (anti-programmed cell death protein 1 monoclonal antibody) are solely based on pharmacokinetic (PK) modelling derived from phase I\u2013III trials. The current study aimed to determine factors affecting PK and its relationship with clinical outcome in the real-world setting.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Advanced-stage cancer patients, who were treated with pembrolizumab monotherapy (2\u2009mg\/kg Q3W or 200\u2009mg flat Q3W), were prospectively included for serial sampling to obtain trough concentrations. A PK model was generated, covariate effects assessed and internally validated by a bootstrap procedure. PK parameters were related to overall survival (OS) and the occurrence of immune-related adverse events (irAEs).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>588 serum samples derived from 122 patients with (non-)small-cell lung cancer ([N]SCLC), malignant pleural mesothelioma (MPM), melanoma and urothelial cell cancer (UCC) were analyzed. Median follow-up was 2.2 years. A one-compartment PK model was generated: body surface area (BSA) and serum albumin had a significant effect on drug clearance (CL; covariate estimate 1.46 and \u22121.43, respectively), and serum lactate dehydrogenase (LDH) on the distribution volume(V<jats:sub>d<\/jats:sub>; 0.34). A significant inverse CL\u2013OS relationship was determined for NSCLC (HR:1.69; 95%CI1.07\u20132.68; p=0.024) and MPM (HR: 3.29; 95% CI 1.08 to 10.09; p=0.037), after correction for prognostic factors, which could not confirmed for melanoma (p=0.22) or UCC (p=0.34). No relationship could be determined between CL and grade <jats:underline>&gt;<\/jats:underline>3 irAEs (p=0.70).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>High interpatient variability of pembrolizumab PK is determined by BSA and serum albumin (on CL) and LDH (on V<jats:sub>d<\/jats:sub>). A strong inverse CL\u2013OS relationship was demonstrated for NSCLC and MPM, which could not be observed for melanoma and UCC. The findings suggest that personalized dosing should be prospectively explored.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2021-002344","type":"journal-article","created":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T11:37:50Z","timestamp":1622806670000},"page":"e002344","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["Prospective real-world study on the pharmacokinetics of pembrolizumab in patients with solid tumors"],"prefix":"10.1136","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8750-5188","authenticated-orcid":false,"given":"Daan P.","family":"Hurkmans","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands"},{"name":"Department of Pulmonology, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiaan D.T.","family":"Sassen","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5928-2899","authenticated-orcid":false,"given":"Karlijn","family":"de Joode","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisanne","family":"Putter","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin A.","family":"Basak","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemarie J.M.","family":"Wijkhuijs","sequence":"additional","affiliation":[{"name":"Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Joerger","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Hematology, Cantonal Hospital, St. Gallen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3649-807X","authenticated-orcid":false,"given":"Reno","family":"Debets","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit C.P.","family":"Koch","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cor H.","family":"Van der Leest","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Amphia Hospital, Breda, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco W.J.","family":"Schreurs","sequence":"additional","affiliation":[{"name":"Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid A.M.","family":"van der Veldt","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands"},{"name":"Department of Radiology & Nuclear Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim G.J.V.","family":"Aerts","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5667-5697","authenticated-orcid":false,"given":"Ron H.J.","family":"Mathijssen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stijn L.W.","family":"Koolen","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands"},{"name":"Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2021,6,4]]},"reference":[{"key":"2025100314534489000_9.6.e002344.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1810865"},{"key":"2025100314534489000_9.6.e002344.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1801005"},{"key":"2025100314534489000_9.6.e002344.3","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdv550"},{"key":"2025100314534489000_9.6.e002344.4","unstructured":"Pembrolizumab (Keytruda) . Highlights of prescribing information. Whitehouse station NJ: Merck & Co, 2020."},{"key":"2025100314534489000_9.6.e002344.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)01281-7"},{"key":"2025100314534489000_9.6.e002344.6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1606774"},{"key":"2025100314534489000_9.6.e002344.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)60958-2"},{"key":"2025100314534489000_9.6.e002344.8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1503093"},{"key":"2025100314534489000_9.6.e002344.9","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ejca.2020.02.016","article-title":"A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation","volume":"131","author":"Lala","year":"2020","journal-title":"Eur J Cancer"},{"key":"2025100314534489000_9.6.e002344.10","doi-asserted-by":"crossref","unstructured":"Zhao X , Gopalakrishnan M , Shen J . A model-based exposure\u2013response (ER) assessment of a nivolumab 4-weekly (Q4W) dosing schedule across multiple tumor types. Proceedings of the AACR Annual Meeting, 2017.","DOI":"10.1158\/1538-7445.AM2017-CT101"},{"key":"2025100314534489000_9.6.e002344.11","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-017-0242-5"},{"key":"2025100314534489000_9.6.e002344.12","doi-asserted-by":"crossref","unstructured":"Lala M , Akala O , Chartash E . CT042 - Pembrolizumab 400 mg Q6W dosing: First clinical outcomes data from Keynote-555 cohort B in metastatic melanoma patients. AACR Annual Meeting 2020, 2020.","DOI":"10.1158\/1538-7445.AM2020-CT042"},{"key":"2025100314534489000_9.6.e002344.13","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-2607"},{"key":"2025100314534489000_9.6.e002344.14","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdw174"},{"key":"2025100314534489000_9.6.e002344.15","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1412082"},{"key":"2025100314534489000_9.6.e002344.16","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1200690"},{"key":"2025100314534489000_9.6.e002344.17","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.53.0105"},{"key":"2025100314534489000_9.6.e002344.18","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ejca.2018.12.008","article-title":"Correlation between nivolumab exposure and treatment outcomes in non-small-cell lung cancer","volume":"109","author":"Basak","year":"2019","journal-title":"Eur J Cancer"},{"key":"2025100314534489000_9.6.e002344.19","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-019-0669-y"},{"key":"2025100314534489000_9.6.e002344.20","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-0415"},{"key":"2025100314534489000_9.6.e002344.21","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1002\/psp4.12139","article-title":"Model-Based characterization of the pharmacokinetics of pembrolizumab: a humanized anti-PD-1 monoclonal antibody in advanced solid tumors","volume":"6","author":"Ahamadi","year":"2017","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"2025100314534489000_9.6.e002344.22","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1002\/psp4.12143","article-title":"Model-Based population pharmacokinetic analysis of nivolumab in patients with solid tumors","volume":"6","author":"Bajaj","year":"2017","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"2025100314534489000_9.6.e002344.23","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1002\/psp4.12132","article-title":"Using Model-Based \"Learn and Confirm\" to Reveal the Pharmacokinetics-Pharmacodynamics Relationship of Pembrolizumab in the KEYNOTE-001 Trial","volume":"6","author":"Elassaiss-Schaap","year":"2017","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"2025100314534489000_9.6.e002344.24","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s10928-017-9528-y","article-title":"Time dependent pharmacokinetics of pembrolizumab in patients with solid tumor and its correlation with best overall response","volume":"44","author":"Li","year":"2017","journal-title":"J Pharmacokinet Pharmacodyn"},{"key":"2025100314534489000_9.6.e002344.25","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1097\/FTD.0000000000000534","article-title":"Development of an enzyme-linked immune sorbent assay to measure nivolumab and pembrolizumab serum concentrations","volume":"40","author":"Basak","year":"2018","journal-title":"Ther Drug Monit"},{"key":"2025100314534489000_9.6.e002344.26","doi-asserted-by":"publisher","DOI":"10.1097\/00000421-198212000-00014"},{"key":"2025100314534489000_9.6.e002344.27","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198710223171718"},{"key":"2025100314534489000_9.6.e002344.28","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2010.462"},{"key":"2025100314534489000_9.6.e002344.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026"},{"key":"2025100314534489000_9.6.e002344.30","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2015.467"},{"key":"2025100314534489000_9.6.e002344.31","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-014-1528-9"},{"key":"2025100314534489000_9.6.e002344.32","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.4059"},{"key":"2025100314534489000_9.6.e002344.33","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0127"},{"key":"2025100314534489000_9.6.e002344.34","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-13-0133"},{"key":"2025100314534489000_9.6.e002344.35","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(15)00083-2"},{"key":"2025100314534489000_9.6.e002344.36","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1002\/cam4.2024","article-title":"Pretreatment lactate dehydrogenase may predict outcome of advanced non small-cell lung cancer patients treated with immune checkpoint inhibitors: a meta-analysis","volume":"8","author":"Zhang","year":"2019","journal-title":"Cancer Med"},{"key":"2025100314534489000_9.6.e002344.37","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1001\/jamaoncol.2019.1747","article-title":"Prognostic value of the lung immune prognostic index for patients treated for metastatic Non\u2013Small cell lung cancer","volume":"5","author":"Kazandjian","year":"2019","journal-title":"JAMA Oncol"},{"key":"2025100314534489000_9.6.e002344.38","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1007\/s40262-019-00748-2","article-title":"Clinical pharmacokinetics and pharmacodynamics of immune checkpoint inhibitors","volume":"58","author":"Centanni","year":"2019","journal-title":"Clin Pharmacokinet"},{"key":"2025100314534489000_9.6.e002344.39","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1403014"},{"key":"2025100314534489000_9.6.e002344.40","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.5.3266"},{"key":"2025100314534489000_9.6.e002344.41","doi-asserted-by":"publisher","DOI":"10.2165\/11531280-000000000-00000"},{"key":"2025100314534489000_9.6.e002344.42","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.01.109"},{"key":"2025100314534489000_9.6.e002344.43","doi-asserted-by":"crossref","first-page":"iv264","DOI":"10.1093\/annonc\/mdy162","article-title":"Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up","volume":"29","author":"Haanen","year":"2018","journal-title":"Ann Oncol"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2021-002344","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T21:53:55Z","timestamp":1759528435000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2021-002344"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6]]},"references-count":43,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6,4]]},"published-print":{"date-parts":[[2021,6]]}},"alternative-id":["10.1136\/jitc-2021-002344"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2021-002344","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6]]}}}