title: The pharmacokinetics and safety of idelalisib in subjects with severe renal impairment.
abstract: OBJECTIVE
  Idelalisib is a novel, potent inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ), which is prominently expressed in cells of hematopoietic origin. Renal excretion plays a minor role in elimination of idelalisib in humans (~15 % of the dose is excreted in urine). This study evaluated the pharmacokinetics (PK) and safety of idelalisib and GS-563117 (its inactive primary metabolite) in subjects with severe renal impairment and healthy subjects.
  
  
  METHODS
  Subjects with severe renal impairment were matched in age, sex, and body mass index with healthy subjects who had normal renal function. Each subject received a single oral dose of idelalisib at 150 mg, and safety assessments and PK analyses were performed.
  
  
  RESULTS
  Compared with healthy subjects, the geometric least-squares mean ratio of area under the concentration-time curve from zero to last PK observation (AUC(last)), area under the concentration-time curve from zero to infinity (AUC(inf)), and maximum observed plasma concentration (C(max)) were 127, 127, and 105 % for idelalisib and 124, 124, and 96 % for GS-563117, respectively, in subjects with severe renal impairment.
  
  
  CONCLUSIONS
  There were no clinically relevant changes of idelalisib or GS-563117 PK in subjects with severe renal impairment versus matched healthy controls. No relevant relationships were identified between idelalisib or GS-563117 exposures and baseline creatinine clearance. Idelalisib dosing was generally well tolerated with most treatment-emergent adverse events and laboratory abnormalities assessed as grade 1 or 2 in severity. Accordingly, dose adjustments for idelalisib are not necessary in subjects with mild, moderate, or severe renal impairment.
authors.affiliation: Department of Clinical Pharmacology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA. feng.jin@gilead.com.
authors.forename: F
authors.initials: F
authors.lastname: Jin
authors.affiliation: Department of Clinical Research, Gilead Sciences, Inc., Seattle, WA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Robeson
authors.affiliation: Department of Biostatistics, CTI Biopharma, Seattle, WA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Clinical Operations, Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Hisoire
authors.affiliation: Department of Clinical Pharmacology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ramanathan
mesh_terms: D000368:Aged; D019540:Area Under Curve; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines / Q000009:adverse effects / Q000493:pharmacokinetics*; D052999:Quinazolinones / Q000009:adverse effects / Q000493:pharmacokinetics*; D051437:Renal Insufficiency / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; D058543:Class Ia Phosphatidylinositol 3-Kinase; C552946:idelalisib
keywords: Idelalisib; PI3Kδ; Pharmacokinetics; Renal impairment; Safety