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Effect of everolimus on the pharmacokinetics of octreotide long‐acting repeatable in patients with advanced neuroendocrine tumors: An analysis of the randomized phase III RADIANT‐2 trial
Author(s) -
Pavel ME,
Becerra C,
Grosch K,
Cheung W,
Hasskarl J,
Yao JC
Publication year - 2017
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.559
Subject(s) - everolimus , octreotide , medicine , placebo , concomitant , pharmacokinetics , hazard ratio , neuroendocrine tumors , confidence interval , urology , gastroenterology , pharmacology , somatostatin , pathology , alternative medicine
In the RADIANT‐2 trial, addition of everolimus to octreotide long‐acting repeatable (LAR) exhibited a clinically meaningful 5.1‐month improvement in progression‐free survival (PFS) in patients with advanced functional neuroendocrine tumors. In this study, we characterized the effects of everolimus co‐administration on octreotide LAR pharmacokinetics and its relationship with efficacy and safety. At least one evaluable blood everolimus and plasma octreotide predose minimum concentration (C min ) was available for 182 patients and 294 patients, respectively. Concomitant everolimus administration increased octreotide C min with a geometric mean ratio (everolimus/placebo) of 1.47 (90% confidence interval [CI] = 1.32–1.64). Risk for progression was consistently reduced when everolimus C min was increased twofold, regardless of octreotide exposure (hazard ratio [HR] = 0.74; 95% CI = 0.46–1.18; HR = 0.54; 95% CI = 0.32–0.92 for 6 ng/mL and 4 ng/mL octreotide, respectively). Risk for pulmonary or metabolic events was associated with increased everolimus C min . Co‐administration of everolimus plus octreotide LAR increased octreotide C min , which did not impact efficacy.