Abstract #5437: Population pharmacokinetic model of PI-88, a heparanase inhibitor
Authors: Susan Hudachek, Daniel Gustafson, S. Eckhardt, Barbara Hicks
Journal: Cancer Research (2009)

PI-88 (phosphomannopentose sulfate) is an anticancer agent currently undergoing clinical trials in patients with advanced malignancies. In vitro and in vivo studies have shown PI-88 to be a potent inhibitor of tumor growth, metastasis and angiogenesis by virtue of its ability to inhibit heparan sulfate cleavage by heparanase and antagonize the interaction between proangiogenic growth factors and heparan sulfate. Three Phase I clinical trials were conducted by Progen Pharmaceuticals Ltd. (Brisbane, Australia) to evaluate the subcutaneous administration of fixed PI-88 doses. These studies involved a total of 76 subjects, including 18 healthy subjects and 58 patients with solid malignancies. The pharmacokinetics (PK) of PI-88 showed low intra-individual variability but considerably higher inter-patient variability. Thus, the purpose of this work was to develop and validate a population PK model for PI-88 and to identify the patient covariates that impact PK variability. The covariates evaluated included weight, age, creatinine clearance, body surface area (BSA), body mass index (BMI), sex, cancer, concurrent docetaxel administration, prior chemotherapy, prior investigational therapy, prior radiotherapy and prior surgery. The relationship between PI-88 concentration versus time data and the covariates was analyzed by nonlinear mixed effects modeling using NONMEM. This method included the identification of an appropriate base model, calculation of the empirical Bayes estimates of the primary PK parameters, covariate screening, forward stepwise addition of covariates using the likelihood ratio test as a model selection criteria and backwards elimination of covariates to obtain the final model. In the final population PK model, BSA and cancer significantly affected clearance (CL), BSA significantly affected volume of distribution (V) and BMI significantly affected the absorption rate constant (KA). The inter-individual variability of CL was reduced from 30.6% in the base model to 20.2% in the final model, showing that BSA and cancer account for 34.0% of the inter-subject variability in CL. The inter-individual variability of V was reduced from 31.4% in the base model to 20.7% in the final model, showing that BSA accounts for 34.1% of the inter-subject variability in V. The inter-individual variability of KA was reduced from 52.6% in the base model to 46.2% in the final model, showing that BMI accounts for 12.2% of the inter-subject variability in KA. Interestingly, we found that cancer significantly affected CL; the model estimated the final value of CL for a healthy subject (noncancer) with the study average BSA of 1.9 and the study average BMI of 25.7 to be 3,440 mL/hr whereas for a cancer patient with the same BSA and BMI, the CL was estimated to be 2,573 mL/hr. In conclusion, the present model may be used to optimize treatment with PI-88 by developing a dosing strategy based on BSA and BMI.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5437.