Pharmaceutics (Apr 2021)

Population Pharmacokinetic Modelling and Simulation to Determine the Optimal Dose of Nanoparticulated Sorafenib to the Reference Sorafenib

  • Ki-Young Huh,
  • Se-jung Hwang,
  • Sang-Yeob Park,
  • Hye-Jung Lim,
  • Mir-yung Jin,
  • Jae-seong Oh,
  • Kyung-Sang Yu,
  • Jae-Yong Chung

DOI
https://doi.org/10.3390/pharmaceutics13050629
Journal volume & issue
Vol. 13, no. 5
p. 629

Abstract

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Sorafenib, an oral multikinase inhibitor, exhibits a highly variable absorption profile due to enterohepatic reabsorption and poor solubility. SYO-1644 improved the solubility of sorafenib by nanoparticulation technology leading to enhanced bioavailability. To evaluate the pharmacokinetically equivalent dose of SYO-1644 to the reference Nexavar® 200 mg, a randomized, open-label, replicated two-period study was conducted in healthy volunteers. A total of 32 subjects orally received a single dose of the following assigned treatment under a fasted state in the first period and repeated once more in the second period with a two-week washout: SYO-1644 100, 150 and 200 mg and Nexavar® 200 mg. Pharmacokinetic (PK) samples were collected up to 168 h post-dose. The PK profile was evaluated by both non-compartmental analysis and population PK method. With the final model, 2 × 2 crossover trial scenarios with Nexavar® 200 mg and each dose of SYO-1644 ranging from 100 to 150 mg were repeated 500 times by Monte Carlo simulation, and the proportion of bioequivalence achievement was assessed. Transit absorption compartments, followed by a one-compartment model with first-order elimination and enterohepatic reabsorption components were selected as the final model. The simulation results demonstrated that the SYO-1644 dose between 120 and 125 mg could yielded the highest proportion of bioequivalence.

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