{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T17:27:39Z","timestamp":1780594059299,"version":"3.54.1"},"reference-count":54,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2019,7,12]],"date-time":"2019-07-12T00:00:00Z","timestamp":1562889600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Rituximab is standard care in a number of lymphoma subtypes, including follicular lymphoma (FL), although many patients are resistant to rituximab, or develop resistance with repeated treatment, and a high proportion relapse. Obinutuzumab is a novel anti\u2010CD20 monoclonal antibody with improved efficacy over rituximab. It is approved for previously untreated chronic lymphocytic leukaemia (CLL), and for use with bendamustine in patients with rituximab\u2010relapsed\/refractory FL.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using a previously described population pharmacokinetic (PK) model of obinutuzumab in patients with non\u2010Hodgkin lymphoma and CLL, we conducted an exposure\u2010response analysis using data from 6 clinical trials in patients with CD20+ B\u2010cell malignancies (CLL11, GADOLIN, GATHER, GAUDI, GAUGUIN and GAUSS) to describe the PK properties of obinutuzumab, identify covariates influencing exposure, and explore how exposure affects safety, efficacy and pharmacodynamics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A 2\u2010compartment model with linear and time\u2010dependent clearance described obinutuzumab PK. Disease type and subtype, body weight, baseline tumour size, and sex had the largest effects on PK. Obinutuzumab exposure was not associated with occurrence or severity of adverse events, but higher exposure appeared to be associated with greater efficacy, particularly longer progression\u2010free survival. However, in multivariate Cox regression analysis, progression\u2010free survival benefit in the obinutuzumab plus bendamustine arm was independent of exposure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The updated population PK model reported here accurately describes the PK of obinutuzumab patients with non\u2010Hodgkin lymphoma and CLL. The selected obinutuzumab dosing regimen offers clinical benefit in a majority of rituximab\u2010refractory FL patients treated with bendamustine, irrespective of variability in exposure, whilst minimising adverse events.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.13974","type":"journal-article","created":{"date-parts":[[2019,5,3]],"date-time":"2019-05-03T12:53:48Z","timestamp":1556888028000},"page":"1935-1945","source":"Crossref","is-referenced-by-count":11,"title":["Pharmacokinetics, exposure, efficacy and safety of obinutuzumab in rituximab\u2010refractory follicular lymphoma patients in the GADOLIN phase III study"],"prefix":"10.1111","volume":"85","author":[{"given":"Ekaterina","family":"Gibiansky","sequence":"first","affiliation":[{"name":"QuantPharm LLC  North Potomac MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonid","family":"Gibiansky","sequence":"additional","affiliation":[{"name":"QuantPharm LLC  North Potomac MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Buchheit","sequence":"additional","affiliation":[{"name":"Pharma Research and Early Development Roche Innovation Center Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Frey","sequence":"additional","affiliation":[{"name":"Pharma Research and Early Development Roche Innovation Center Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Brewster","sequence":"additional","affiliation":[{"name":"Clinical Development Roche Innovation Center Welwyn  Welwyn Garden City UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcnter","family":"Fingerle\u2010Rowson","sequence":"additional","affiliation":[{"name":"Pharma Development Clinical Oncology F. Hoffmann\u2010La Roche Ltd  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7018-9687","authenticated-orcid":false,"given":"Candice","family":"Jamois","sequence":"additional","affiliation":[{"name":"Pharma Research and Early Development Roche Innovation Center Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,7,12]]},"reference":[{"key":"e_1_2_11_2_1","first-page":"7","article-title":"Individualized management of follicular lymphoma","volume":"4","author":"Bai B","year":"2015","journal-title":"Chin Clin Oncol"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-03-491514"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation-2014.1.169"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-014-0058-4"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-08-3175"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-01-0016"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.06.4618"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)62175-7"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-04-1323"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.26.5827"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2015.11.001"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00448"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-09-305847"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-06-225979"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.4161\/mabs.22771"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.46.9718"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-01-404368"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.46.9585"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-02-408773"},{"issue":"1","key":"e_1_2_11_21_1","first-page":"1267","article-title":"Greater efficacy and potency of obinutuzumab compared with rituximab in chronic lymphocytic leukemia patients confirmed by a semi\u2010mechanistic pharmacokinetic\/pharmacodynamic model","volume":"130","author":"Kamisoglu K","year":"2017","journal-title":"Blood"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2014.42"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1313984"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-01-481341"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.46.9718"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.59.2139"},{"issue":"22","key":"e_1_2_11_27_1","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1182\/blood.V128.22.615.615","article-title":"Obinutuzumab plus bendamustine followed by obinutuzumab maintenance prolongs overall survival compared with bendamustine alone in patients with rituximab\u2010refractory indolent non\u2010Hodgkin lymphoma: updated results of the GADOLIN study","volume":"128","author":"Cheson BD","year":"2016","journal-title":"Blood"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2018.1515940"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1012299115260"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30097-3"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-016-2878-5"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-011-9228-y"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1011555016423"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-006-9067-5"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-005-0016-4"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2014.42"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1121"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13882"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270011430506"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270005277075"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2010.28.15_suppl.e13108"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-01-330357"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.2165\/11531280-000000000-00000"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/9780470485408.ch19"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2015.133421"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20021829"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.4161\/onci.26333"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-10-744292"},{"key":"e_1_2_11_49_1","unstructured":"KaagedalM ClaretL MarchardM et al.Herceptin in HER2\u2010positive gastric cancer: evaluation of exposure\u2010response with two dose levels. Population Approach Group in Europe (PAGE)2017; 26: Abstract 7329."},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-010-0674-x"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1998.16.7.2332"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.21.3991"},{"key":"e_1_2_11_53_1","unstructured":"Clinical study data request. Available from:www.clinicalstudydatarequest.com. Accessed April 2019."},{"key":"e_1_2_11_54_1","unstructured":"Clinical study data request: Roche sponsor specific details. Available from:https:\/\/clinicalstudydatarequest.com\/Study\u2010Sponsors\/Study\u2010Sponsors\u2010Roche.aspx. Accessed April 2019."},{"key":"e_1_2_11_55_1","unstructured":"Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents. Available from:https:\/\/www.roche.com\/research_and_development\/who_we_are_how_we_work\/clinical_trials\/our_commitment_to_data_sharing.htm. Accessed April 2019."}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.13974","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bcp.13974","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.13974","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,10]],"date-time":"2023-09-10T01:32:34Z","timestamp":1694309554000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bcp.13974"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,12]]},"references-count":54,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2019,9]]}},"alternative-id":["10.1111\/bcp.13974"],"URL":"https:\/\/doi.org\/10.1111\/bcp.13974","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,12]]}}}