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Population pharmacokinetic modeling of idelalisib, a novel PI3Kδ inhibitor, in healthy subjects and patients with hematologic malignancies

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Abstract

Purpose

Idelalisib is a potent PI3Kδ inhibitor that was recently approved for treating hematologic malignancies. The objective of this analysis was to develop a population pharmacokinetic model for idelalisib and its inactive metabolite GS-563117 and to evaluate the impact of covariates on idelalisib/GS-563117 PK.

Methods

Data from 10 phase I or II studies in healthy volunteers or patients with hematologic malignancies (n = 736) were analyzed using NONMEM. Stepwise forward addition followed by backward elimination was implemented in the covariate (age, gender, race, body weight, baseline CLcr, AST, ALT, disease status, and type of cancer) model building process. Various model assessment methods were used to evaluate the models.

Results

Idelalisib plasma PK was best described by a two-compartment model with first-order absorption, first-order elimination from the central compartment, and a lag time. A nonlinear relationship between dose and relative bioavailability was included in the final model. Two statistically significant covariates were identified and incorporated into the final model: health status (healthy vs. patient) on CL/F and Q/F and body weight on CL/F. Despite being a statistically significant covariate, the effect of body weight on idelalisib exposures was weak, as evidenced by minor changes of steady-state exposure (C trough: 16 %; AUC and C max: 10 %) for a patient with extreme body weight (5th and 95th percentile) relative to the typical patient, and not considered to be clinically relevant.

Conclusions

PopPK models were developed to adequately describe the plasma concentrations of idelalisib and GS-563117. There were no covariate that had a clinically meaningful impact on idelalisib or GS-563117 exposure.

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Acknowledgments

The results of this study were presented in part at the 2014 American Conference of Pharmacometric (ACOP) (October 13, 2014, Las Vegas, NV). Financial support for this study was provided by Gilead Sciences, Inc.

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Authors and Affiliations

  1. Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, USA

    Feng Jin & Srini Ramanathan

  2. Quantitative Solutions, LP., Menlo Park, CA, USA

    Yuying Gao

  3. CTI Biopharma, Seattle, WA, USA

    Huafeng Zhou

  4. Onyx Pharmaceuticals, South San Francisco, CA, USA

    Lorna Fang

  5. Gilead Sciences, Inc., Seattle, WA, USA

    Xiaoming Li

Authors
  1. Feng Jin
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  2. Yuying Gao
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  5. Xiaoming Li
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  6. Srini Ramanathan
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Corresponding author

Correspondence to Feng Jin.

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Jin, F., Gao, Y., Zhou, H. et al. Population pharmacokinetic modeling of idelalisib, a novel PI3Kδ inhibitor, in healthy subjects and patients with hematologic malignancies. Cancer Chemother Pharmacol 77, 89–98 (2016). https://doi.org/10.1007/s00280-015-2891-8

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  • DOI: https://doi.org/10.1007/s00280-015-2891-8

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