Assessment of Dosing Strategies for Anticancer Drugs via Nonlinear Mixed Model

• Activity Number: 652
• Type: Topic Contributed
• Date/Time: Thursday, August 4, 2011 : 10:30 AM to 12:20 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Guohui Liu*+ and Xuedong Chi
• Companies: Millennium: The Takeda Oncology Company and Millennium Pharmaceuticals
• Keywords: non-linear mixed model ; oncology ; simulation ; body surface area

Abstract

Unlike other therapeutic areas, body surface area (BSA) - based dosing is commonly used in oncology with the assumption that patients with different body sizes should receive the ideal doses, i.e., maximum effective given tolerable toxicity, adjusted by BSA. However, the assumption may not always be held as the inter-individual variation in the pharmacokinetics (PK) may not be reduced by use of BSA. Hence, it is critical to decide what dosing strategy would be applied from the early development of the compound. Here we explored two alternative strategies, binned dosing and flat dosing in addition to BSA-based dosing in one compound under development. In detail, a non-linear mixed model was constructed to identify statistically significant covariates (such as BSA, weight, age, and race) and the first-order conditional estimation method with interaction between inter-and intra-individual variability (FOCEI) was used for parameter estimation. Once the optimal model was determined, two PK parameters, area under the curve (AUC) and maximum concentration (Cmax), were simulated to make comparison among different dosing strategies. A case study is presented to illustrate the process.