PII-028

A. Chang,1 Y. K. Pithavala,2 P. Bycott,2 A. Ingrosso,3 A. Ruiz2; 1University of California, San Diego, La Jolla, CA, 2Pfizer La Jolla, San Diego, CA, 3Pfizer Milan, Milan, Italy

BACKGROUND: Axitinib, an inhibitor of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3, is approved for use in 2nd-line renal cell carcinoma (RCC) patients (pts). The population pharmacokinetics (PPK) and pharmacodynamics (PD) of axitinib have been well characterized in RCC pts, but have yet to be described in thyroid cancer (TC). In this analysis, axitinib disposition and relevant covariates were evaluated in TC pts and compared to RCC pts.
METHODS: A PPK model was developed using pooled data from 46 healthy subjects and 98 pts with metastatic or unresectable locally-advanced TC. Non linear mixed effect model validity and stability was determined by goodness-of-fit diagnostic plots, visual predictive checks (VPC), and bootstrap analysis. Stepwise covariate method was used to explore potential covariates of interest.
RESULTS: A two-compartment model with first-order absorption and lag time (tlag) described axitinib PPK in TC; the estimated mean systemic clearance (CL) of axitinib was 14.3L/hr and central volume of distribution (Vc) was 54.6L. Parameter estimates for the base model were compared to those from RCC pts (Table).
CONCLUSION: Axitinib PK in TC is similar to previously described RCC pts and supports use of the same dose and frequency of administration.
Base model parameter estimates and patient demographics
ParametersBase structural model for TCBase structural model for RCC
Estimate% Relative Standard Error (RSE)Estimate%Relative Standard Error (RSE)
Clearance (CL) [L/hr]14.37.8%13.711%
Volume of distribution, central (Vc) [L]54.610%47.79.2%
Inter-compartmental CL (Q) [L/hr]4.0315%4.265.7%
Volume of distribution, peripheral (Vp) [L]34940%47013%
Absorption rate constant, fed (ka) [hr-1]0.4528.3%0.4815.4%
TC study population included in the PPK analysis
NRaceWhiteRaceBlackRaceAsianRaceOtherSex MaleSex FemaleAge (yrs)Median (range)Weight (kg)Median (range)
1441228771004453.5 (19-84)79.4 (43-143)