F. Jin,1 H. Zhou,2 Y. Gao,3 X. Li,4 T. Newcomb,4 S. Ramanathan1; 1Gilead Sciences, Foster City, CA, 2CTI BioPharma Corp, Seattle, WA, 3Quantitative Solutions, Menlo Park, CA, 4Gilead Sciences, Seattle, WA

BACKGROUND: Zydelig™ (idelalisib) is the first PI3Kδ inhibitor approved for the treatment of indolent non-Hodgkin lymphoma (iNHL) and chronic lymphocytic leukemia (CLL). The objective of this analysis was to evaluate the effect of intrinsic and extrinsic factors on the pharmacokinetics (PK) of idelalisib and its inactive metabolite, GS-563117.
METHODS: A population PK model for idelalisib was developed based on data from studies in healthy volunteers and patients with hematologic malignancies. The effect of intrinsic and extrinsic factors (body weight, age, gender, race, baseline CLcr, AST, ALT, type of cancer, and background therapies) on idelalisib and GS-563117 PK were evaluated during covariate model building (forward addition then backward elimination, p<0.001) and posthoc procedures following establishment of popPK models.
RESULTS: Of the covariates evaluated, only body weight was identified as a significant PK covariate. In the posthoc assessment, the exposures of idelalisib were comparable for subjects across quartiles of the weight range; idelalisib exposures were also unaffected by disease type (Table 1). No other covariates had a relevant impact on idelalisib and GS-563117 exposures.
CONCLUSION: There are no clinically effects of intrinsic and extrinsic factors on idelalisib or GS-563117 pharmacokinetics.
Effect of Selected Intrinsic or Extrinsic Factors on Idelalisib PK Exposures (Mean (90% CI))
Type of CanceriNHL (N=212)CLL (N=258)Other (N=129)
AUCtau (ng*h/mL)10400 (5840, 16600)10400 (5670, 17500)11300 (6190, 17200)
Ctrough (ng/mL)1910 (999, 2980)1860 (862, 2870)2000 (953, 3460)
Cmax (ng/mL)349 (104, 702)357 (115, 731)402 (163, 773)
Body Weight QuartileQ1 (<68 kg) Q2-Q3 (68-90 kg)Q4 (>90 kg)
AUCtau (ng*h/mL)11600 (6330, 18300)10200 (5730, 16700)10300 (5600, 16000)
Ctrough (ng/mL)2180 (1080, 3490)1850 (903, 2890)1760 (909, 2730)
Cmax (ng/mL)390 (138, 776)345 (100, 696)368 (121, 711)