{"id":26898,"date":"2012-06-15T08:08:43","date_gmt":"2012-06-15T12:38:43","guid":{"rendered":"http:\/\/piel-l.org\/blog\/?p=26898"},"modified":"2012-06-17T01:26:09","modified_gmt":"2012-06-17T05:56:09","slug":"pharmacokinetic-dose-scheduling-study-of-hedgehog-pathway-inhibitor-vismodegib-gdc-0449-in-patients-with-locally-advanced-or-metastatic-solid-tumors","status":"publish","type":"post","link":"https:\/\/piel-l.org\/blog\/26898","title":{"rendered":"Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors"},"content":{"rendered":"<p>Clin\u00a0Cancer Res.\u00a02011 Sep 1;17(17):5774-82. Epub 2011 Jul 13.\u00a0<em>Lorusso PM, Jimeno A, Dy G, Adjei A, Berlin J, Leichman L, Low JA, Colburn D, Chang I, Cheeti S, Jin JY, Graham RA.<\/em><\/p>\n<p><!--more--><\/p>\n<p><strong>Source<\/strong><\/p>\n<p>Karmanos Cancer Institute, Detroit, Michigan, USA.<\/p>\n<p><strong>Abstract<\/strong><\/p>\n<p><strong>PURPOSE<\/strong>:\u00a0<\/p>\n<p>This study was designed to evaluate whether less frequent dosing [three times per week (TIW) or once weekly (QW)] of 150 mg vismodegib following a loading dose [150 mg once daily (QD) for 11 days] would result in similar safety, tolerability, and steady-state levels of total and unbound vismodegib as continuous QD dosing.<\/p>\n<p><strong>EXPERIMENTAL DESIGN<\/strong>:<\/p>\n<p>Sixty-seven patients with advanced solid tumors were stratified by baseline plasma alpha 1-acid glycoprotein (AAG) levels and randomized to one of three vismodegib 150 mg regimens: QD (n = 23), TIW (n = 22), or QW (n = 22) for up to 42 days after an 11-day loading phase (150 mg QD). Total and unbound (dialyzed) plasma vismodegib concentrations were determined by LC-MS\/MS.<\/p>\n<p><strong>RESULTS<\/strong>:<\/p>\n<p>The most frequently reported adverse events were consistent with those in prior monotherapy trials, with similar incidence and severity regardless of dosing schedule. After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose. Mean total and unbound vismodegib steady-state concentrations were lower after TIW and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug. Mechanism-based PK model simulations accurately and prospectively predicted the PK results.<\/p>\n<p><strong>CONCLUSIONS<\/strong>:<\/p>\n<p>Vismodegib 150 mg TIW or QW failed to achieve unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a QD loading dose period. The 150 mg QD regimen is appropriate for vismodegib based on its clinical activity, tolerability, and favorable unbound concentrations.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Clin\u00a0Cancer Res.\u00a02011 Sep 1;17(17):5774-82. Epub 2011 Jul 13.\u00a0Lorusso PM, Jimeno A, Dy G, Adjei A, Berlin J, Leichman L, Low JA, Colburn D, Chang I, Cheeti S, Jin JY, Graham RA.<\/p>\n","protected":false},"author":16,"featured_media":26899,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[8,1],"tags":[],"class_list":["post-26898","post","type-post","status-publish","format-standard","has-post-thumbnail","","category-articulos-cientificos","category-generales"],"_links":{"self":[{"href":"https:\/\/piel-l.org\/blog\/wp-json\/wp\/v2\/posts\/26898","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/piel-l.org\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/piel-l.org\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/piel-l.org\/blog\/wp-json\/wp\/v2\/users\/16"}],"replies":[{"embeddable":true,"href":"https:\/\/piel-l.org\/blog\/wp-json\/wp\/v2\/comments?post=26898"}],"version-history":[{"count":0,"href":"https:\/\/piel-l.org\/blog\/wp-json\/wp\/v2\/posts\/26898\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/piel-l.org\/blog\/wp-json\/wp\/v2\/media\/26899"}],"wp:attachment":[{"href":"https:\/\/piel-l.org\/blog\/wp-json\/wp\/v2\/media?parent=26898"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/piel-l.org\/blog\/wp-json\/wp\/v2\/categories?post=26898"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/piel-l.org\/blog\/wp-json\/wp\/v2\/tags?post=26898"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}