Application of mechanism-based PKPD model to identify optimal dosing regimens for future development of oraxol.

Abstract

e13505 Background: Paclitaxel (PTX) is a widely used potent anticancer drug that blocks mitosis by stabilization of microtubules. Previous attempts for oral administration of PTX have been unsuccessful at least partly due to its affinity for the efflux pump, P-gp. Oraxol is an oral formulation of PTX combined with a novel potent P-gp inhibitor, HM30181A, to maximize absorption of paclitaxel without itself being systemically absorbed. A population PK/PD model was developed to characterize the temporal relationship between PTX exposure and neutropenia, and subsequently model-based simulations were utilized to determine the optimal dosing strategy for oraxol. Methods: Oraxol was administered to 68 (51M/17F) patients with various malignancies. Oraxol dose levels ranged from 60 to 420 mg/m2 QW, and 90-150 QWx2 for 3/4 weeks. Population PKPD modeling was performed with the following patient factors: [BSA (1.29-2.15 m2), ECOG PS scores (97% pts ≤ 1), age (36-81.4 yrs), CrCL (39.6-132.8 ml/min), ALB (2.3-4.8 mg/dL), ALT (6-61 IU/L), TBIL (0.2-1.6 mg/dL), and smoking status (NS:57%)]; followed by model validation. Simulations assessed the influence of dose and schedule on the time course and the extent of neutropenia. Results: A precursor-dependent indirect PKPD response model, including three transit compartments was employed to describe the time course of ANC after oraxol administration. Mean predicted (%SEM) baseline ANC and MTT of neutrophils in plasma were 3.6 (3.9) x109 cells/L and 6.3 (4.2) days. The magnitude of the inhibition on marrow cells was 3.3% per 100 ng/mL of PTX. Model validation results showed excellent concordance with the observed and simulated ANC profiles at the 150 mg/m2 dose level. Simulations showed that severity of neutropenia was dose- and schedule-dependent. The optimal dosing scenarios for oraxol 150 mg/m2QDx3 and QDx5 showed the incidence of grade ³3 neutropenia to be 53.8% and 58%, respectively. Simulated grade 4 neutropenia was 25 and 34.6% for the same regimens; similar to IV PTX. Conclusions: A PKPD model quantifying the neutropenic effect of oraxol has been developed. The model predicts that the QDx3 or QDx5 oraxol dosing 3/4 weeks may optimize efficacy with manageable toxicity.