964P - Modeling and Impact of Organ Function on the Population Pharmacokinetics (PK) of Niraparib, a Selective Poly (ADP-Ribose) Polymerase (PARP)-1 and -...

Date 09 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Anti-Cancer Agents & Biologic Therapy
Ovarian Cancer
Pharmacology
Gynaecologic Malignancies
Presenter Zhi-Yi Zhang
Citation Annals of Oncology (2017) 28 (suppl_5): v330-v354. 10.1093/annonc/mdx372
Authors Z. Zhang1, X. Wang2, J. Wang2, H.S. Pentikis3, V. Kansra2
  • 1Clinical Pharmacology, TESARO, Inc., 02451 - Waltham/US
  • 2Clinical Pharmacology, TESARO, Inc., Waltham/US
  • 3Clinical Pharmacology, SAJE Consulting LLC, Baltimore/US

Abstract

Background

Niraparib (ZEJULA™) is a selective PARP-1 and -2 inhibitor approved for maintenance treatment in adults with recurrent ovarian cancer in complete or partial response to platinum-based chemotherapy. We developed a population PK (PPK) model for niraparib and determined the impact of hepatic and renal organ impairment on niraparib exposure.

Methods

Data from the phase 1 dose escalation and expansion (dose ranging from 30 to 400 mg once daily [qd]) and phase 3 ENGOT-OV16/NOVA (300 mg qd) studies were modeled using a compartmental population approach within nonlinear mixed-effects modeling (NONMEM). Patients (pts) who received a dose of niraparib were included in the PK analysis. The PPK base model was built using NONMEM techniques from the phase 1 study. The impact of pt variables (age, race, ethnicity, body weight), renal impairment (normal, mild, or moderate, based on serum creatinine clearance) and hepatic function (baseline serum alanine and aspartate aminotransferase, albumin, total bilirubin) on niraparib PK parameters was evaluated. A step-wise elimination procedure for each covariate was used to develop the final model. Model evaluation was performed via a visual predictive check.

Results

512 pts (33–83 years old) were available for PK analysis (4109 measurements) from the phase 1 (n = 104) and phase 3 (n = 408) studies. A 2-compartment model (2CM) with first-order absorption and elimination best described the niraparib PK. In the base model, the typical value for niraparib apparent clearance was 16.2 L/h, with interindividual variability of 52.6%. The estimated volume of distribution was 1074 L (290 L central and 784 L peripheral compartment. Model diagnostics showed good agreement between predicted and observed individual niraparib plasma concentrations. No patient variables impacted niraparib PK. Neither the mild to moderate renal impairment nor the mild hepatic impairment significantly altered niraparib PK.

Conclusions

Niraparib disposition was best described by a 2-compartment model with moderate to high interindividual variability. Mild to moderate organ impairment did not significantly impact niraparib PK; no dose adjustments are recommended.

Clinical trial identification

NCT01847274

Legal entity responsible for the study

Tesaro, Inc.

Funding

Tesaro, Inc.

Disclosure

Z-Y. Zhang, X. Wang, J. Wang, V. Kansra: Employment: Tesaro; Stock: Tesaro. H.S. Pentikis: Advisory board or board of directors: Tesaro; Consulting: Tesaro.