Abstract CT204: The pharmacokinetics and safety of idelalisib in subjects with severe renal impairment
Authors: Jin Feng , Robeson Michelle , Zhou Huafeng , Hisoire Grace , Ramanathan Srini 
Published: May 2015

Background: Idelalisib (IDELA) is a novel, potent inhibitor of PI3Kδ, which has been shown to be prominently expressed in cells of hematopoietic origin. Renal elimination plays a minor role on elimination of IDELA in humans (∼ 15% of dose excreted in urine). The objective of the present study was to evaluate the PK and safety of IDELA and GS-563117 (primary metabolite) in subjects with severe renal impairment (RI) following a single oral dose of IDELA.

Methods: Subjects with severe RI (eGFR 15 - 29 ml/min) and healthy matched controls (eGFR ≥ 80 ml/min) received IDELA 150 mg single dose. Blood and urine samples were collected over 6 days and IDELA/GS-563117 levels were measured using a validated LC/MS/MS method. Geometric least-squares mean ratio and 90% confidence interval of PK exposure parameters in the RI group versus matched controls were calculated, with clinically relevant exposure change defined as ≥ two-fold increase. Safety assessments were performed throughout the study.

Results: A total of 12 subjects were enrolled in the study. The majority of subjects were female, white, and of non-Hispanic/Latino ethnicity, and the median age was similar between the 2 groups. Study treatments were generally well tolerated. All AEs were Grade 1 in severity. No clinically significant abnormal changes were observed in vital signs and ECG results from baseline.

The AUClast, AUCinf, and Cmax geometric least-squares mean ratio were 127%, 127%, and 105% for IDELA and 124%, 124%, and 96% for GS-563117, respectively, for subjects with severe renal impairment vs matched control subjects (Table 1). There were no relevant relationships between IDELA or GS-563117 exposures and baseline eGFR.

Conclusion: There were no clinically relevant differences in the PK of IDELA or GS-563117 between subjects with severe RI vs matched healthy control subjects following a single oral dose of IDELA 150 mg. Dose adjustments for IDELA are not considered necessary in subjects with mild, moderate, or severe renal impairment.

PK Parameters in Severe RI and Matched Healthy SubjectsPK ParameterMean (%CV)% Geometric Least Squares Means Ratio(90% CI)Matched Control Group(N = 6)Severe Renal Impairment Group(N = 6)IDELACmax (ng/mL)2530 (27)2680 (28)105 (77, 143)Tmax (h)2.50 (2.00, 3.00)3.00 (2.00, 3.00)t1/2 (h)9.48 (7.37, 10.2)12.1 (6.25, 23.1)AUClast (ng·h/mL)11700 (20)15500 (37)127 (91, 176)AUCinf (ng·h/mL)11800 (20)15700 (37)127 (92, 176)GS-563117Cmax (ng/mL)2590 (21)2570 (37)96 (69, 134)Tmax (h)4.00 (3.00, 4.00)4.00 (4.00, 6.00)t1/2 (h)11.4 (10.9, 12.1)15.8 (8.87, 21.7)AUClast (ng·h/mL)35800 (31)50300 (60)124 (71, 215)AUCinf (ng·h/mL)36000 (30)50800 (61)124 (72, 215)

Tmax and T1/2 expressed as median (Q1, Q3)

Citation Format: Feng Jin, Michelle Robeson, Huafeng Zhou, Grace Hisoire, Srini Ramanathan. The pharmacokinetics and safety of idelalisib in subjects with severe renal impairment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT204. doi:10.1158/1538-7445.AM2014-CT204