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

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 equiva...

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Bibliographic Details
Published in:Pharmaceutics 2021-04, Vol.13 (5), p.629
Main Authors: Huh, Ki Young, Hwang, Sejung, Park, Sang Yeob, Lim, Hye Jung, Jin, Miryung, Oh, Jaeseong, Yu, Kyung Sang, Chung, Jae Yong
Format: Article
Language:English
Subjects:
bioavailability
Bioequivalence
Confidence intervals
Electrocardiography
enterohepatic reabsorption
Medical laboratories
Monte Carlo simulation
Particle size
Pharmacokinetics
pharmacometrics
Plasma
Population
sorafenib
Vital signs
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Summary: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.
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics13050629