Ki Young Huh (1), Sang Yeob Park (2), Hye Jung Lim (2), Miryung Jin (2), Jaeseong Oh (1), Kyung-Sang Yu (1), Jae-Yong Chung (3)
(1) Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea. (2) Samyang Biopharmaceuticals Corp., Gyeonggi-do, Republic of Korea. (3) Department of Clinical Pharmacology and Therapeutics Seoul National University and Bundang Hospital, Gyeonggi-do, Republic of Korea.
Objectives: Sorafenib is an oral multi-kinase inhibitor approved for the treatment of advanced hepatocellular carcinoma and renal cell carcinoma. However, the low solubility of sorafenib has been a source of high variability in absorption, which could lead to suboptimal treatment. Nanoparticulated sorafenib (SYO-1644) using fat and supercritical fluid technology enhanced the bioavailability in beagle dogs [1], but bioavailability data in human have not been reported yet. In this study, we conducted a clinical trial in healthy subjects and estimated the optimal dose of nanoparticulated sorafenib that was expected to show equivalent exposure to reference sorafenib using population pharmacokinetic (PK) modelling and simulation.
Methods: Pharmacokinetic data from previous SYO-1644 study was used for the analysis. (ClinicalTrials.gov Identifier: NCT03674060) A total of 32 healthy subjects were assigned to one of the following treatment groups: SYO-1644 100, 150, 200 mg and Nexavar® 200 mg). Each subject received a single dose of assigned study medication in the first period and blood PK samples were collected at pre-dose and 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 168 hours post-dose. After the two-week washout period, each subject received the same study medication and underwent identical PK blood sampling as in the first period. A total of 32 subjects were included in the PK analysis, among whom 2 subjects (treatment 100 and 150 mg group) completed only the first period.
Sorafenib concentration exhibited multiple peak phenomenon which implied known enterohepatic circulation. To model the absorption profile of sorafenib enterohepatic recirculation models described in the literature [2] was evaluated. Population PK analysis was conducted using nonlinear mixed effect modelling (NONMEM) software version 7.4.4 with first-order conditional estimation method. Goodness-of-fit plots and visual predictive check results were evaluated to assess the model performance. With the final model, of 2×2 comparative PK trial with SYO-1644 ranging from 100 mg to 150 mg and Nexavar® 200 mg was simulated. Each trial consisted of 36 subjects and was repeated for 500 times. Proportion of achieving bioequivalence was estimated for each dose of SYO-1644.
Results: To describe the irregular absorption and enterohepatic recirculation, transit compartments absorption, one central compartment combined with gall bladder compartment, and first-order elimination model [3] was finally adopted. The transit compartments were parameterized with mean transit time, number of transit compartments, and absorption rate constant (ka) which were estimated to 3.24 h, 1.72, and 1.6 h-1, respectively. The central compartment volume of distribution (V/F) and clearance (CL/F) were estimated to 8.17 L and 3.33 L/h. Enterohepatic recirculation fraction was estimated to 0.215. Bile secretion was parameterized with the early and late gall bladder emptying time with steep slope sigmoidal function similar to bile secretion switch function in the previous literature. [3] The early and the delayed gall bladder emptying time were estimated to 8.14 h and 12.2 h, respectively, which could appropriately fit multiple peaks observed in our study. The relative bioavailability ratio of SYO-1644 drug to Nexavar® was estimated to 1.62. Inter-individual variability on ka, CL/F, and V/F were estimated to 75.3%, 21.2%, and 25.7% of coefficient of variation, respectively. Inter-occasional variability on CL/F improved model performance and estimated to 8.9% of coefficient of variation. In the simulation of comparative PK trials, SYO-1644 between 120 mg and 125 mg showed highest bioequivalence achivement propotion with Nexavar® 200 mg.
Conclusions: The model described the enterohepatic recirculation profile of sorafenib well and was able to estimate the optimal dose for nanoparticulated sorafenib. We estimated that approximately 120 to 125 mg of SYO-1644 would be the optimal dose for SYO-1644 to show bioequivalence with Nexavar® 200 mg.
References:
[1] Park SY, Kang Z, Thapa P, Jin YS, Park JW, Lim HJ, et al. Development of sorafenib loaded nanoparticles to improve oral bioavailability using a quality by design approach. Int J Pharm. 2019;566:229–238.
[2] Okour M, Brundage RC. Modeling enterohepatic circulation. Curr Pharmacol Rep. 2017;3(5):301–313.
[3] Jain L, Woo S, Gardner ER, Dahut WL, Kohn EC, Kummar S, et al. Population pharmacokinetic analysis of sorafenib in patients with solid tumours. Br J Clin Pharmacol. 2011;72(2):294–305.
Reference: PAGE () Abstr 9416 [www.page-meeting.org/?abstract=9416]
Poster: Drug/Disease Modelling - Oncology