F Jin1, M Robeson2, H Zhou3, G Hisoire4, S Ramanathan5. 1. Department of Clinical Pharmacology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA. feng.jin@gilead.com. 2. Department of Clinical Research, Gilead Sciences, Inc., Seattle, WA, USA. 3. Department of Biostatistics, CTI Biopharma, Seattle, WA, USA. 4. Department of Clinical Operations, Gilead Sciences, Inc., Foster City, CA, USA. 5. Department of Clinical Pharmacology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
Abstract
PURPOSE: 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.
PURPOSE: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: Remy B Verheijen; Huixin Yu; Jan H M Schellens; Jos H Beijnen; Neeltje Steeghs; Alwin D R Huitema Journal: Clin Pharmacol Ther Date: 2017-09-07 Impact factor: 6.875
Authors: Antonio Cuneo; Giovanni Barosi; Romano Danesi; Stefano Fagiuoli; Paolo Ghia; Alfredo Marzano; Marco Montillo; Venerino Poletti; Pierluigi Viale; Pier Luigi Zinzani Journal: Hematol Oncol Date: 2018-09-05 Impact factor: 5.271