PII-086 - POPULATION PHARMACOKINETIC MODELING OF FAMITINIB IN PATIENTS WITH VARIOUS CANCER TYPES INCLUDING METASTATIC CERVICAL CANCER

W. Yuan¹, M. Zhu², X. Li¹, S. Li¹, Z. Zhu¹, N. DJEBLI³, K. Shen¹; ¹Jiangsu Hengrui Pharmaceuticals, Shanghai, China, Jiangsu Hengrui Pharmaceuticals, Shanghai, China, ²Jiangsu Hengrui Pharmaceuticals, Shanghai, China, Jiangsu Hengrui Pharmaceuticals, Shanghai, , China, ³Luzsana / Hengrui, Luzsana Biotechnology (subsidiary of Jiangsu Hengrui Pharmaceutical), Basel, Switzerland.

Background: Famitinib, a small molecule, is a multi-targeted receptor tyrosine kinase inhibitor that inhibits tumor invasion and metastasis. It is being developed as monotherapy or in combination with the anti PD-L1/PD-1 antibody Camrelizumab for the treatment of solid tumors, including recurrent or metastatic Cervical Cancer (mCC). The purpose of this analysis was to characterize via Non-Linear Mixed Effect Modeling (NLME), the pharmacokinetics (PK) of Famitinib in various solid tumors and healthy subjects, and assess the covariates’ effects on the PK using data from multiple clinical studies.

Methods: The population PK (PopPK) analysis included 685 subjects (253 health subjects and 431 cancer patients) and 8709 PK samples. The dataset was pooled using SAS (version9.4), the PopPK performed using NLME with NONMEM software (version 7.4) and the exploratory analysis, simulations and graphical analyses performed using R (version 4.1.2).

Results: The PopPK of Famitinib was described by a two-compartment model with parallel zero- and first-order absorption and linear elimination. The fraction of the first-order absorption process was estimated at 40.9% with a first-order rate constant (Ka) of 0.327/h. The remaining zero-order fraction was estimated with a duration of 5.97 h. The typical values for apparent clearance (CL/F) was 18.6 (L/h), central volume of distribution (Vc/F) was 955 L and peripheral (Vp/F) was 122 L. The final parameters’-covariates relationships were as follows: the relative bioavailability (rF) of Famitinib in gastric cancer patients is 27.1% lower as compared to remaining individuals. The Ka of Famitinib is 33.1% lower in metastatic cancer patients, however, only slightly impacted exposures (5% to 9% on Cmax and AUC, respectively). Individuals with high total cholesterol have a lower CL/F with an impact of up to 16% increase in the exposure of Famitinib. Finally, the combination with camrelizumab was associated with approximately 9% lower CL/F, although this translated in a modest increase of exposures (i.e. 11% and 13% for Cmax and AUCss, respectively), as illustrated in Figure 1.

Conclusion: The present analysis described the PopPK of Famitinib in cancer patients and healthy subjects and illustrates the impact of the identified covariates on the exposures of Famitinib.