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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| Online Access: | https://www.mdpi.com/1999-4923/13/5/629 |
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| author | Ki-Young Huh Se-jung Hwang Sang-Yeob Park Hye-Jung Lim Mir-yung Jin Jae-seong Oh Kyung-Sang Yu Jae-Yong Chung |
| author_facet | Ki-Young Huh Se-jung Hwang Sang-Yeob Park Hye-Jung Lim Mir-yung Jin Jae-seong Oh Kyung-Sang Yu Jae-Yong Chung |
| author_sort | Ki-Young Huh |
| collection | DOAJ |
| description | 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<sup>®</sup> 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<sup>®</sup> 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<sup>®</sup> 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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| id | doaj.art-b83714689b4e42ab951a97c2c592d462 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T11:52:23Z |
| publishDate | 2021-04-01 |
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| series | Pharmaceutics |
| spelling | doaj.art-b83714689b4e42ab951a97c2c592d4622023-11-21T17:36:17ZengMDPI AGPharmaceutics1999-49232021-04-0113562910.3390/pharmaceutics13050629Population Pharmacokinetic Modelling and Simulation to Determine the Optimal Dose of Nanoparticulated Sorafenib to the Reference SorafenibKi-Young Huh0Se-jung Hwang1Sang-Yeob Park2Hye-Jung Lim3Mir-yung Jin4Jae-seong Oh5Kyung-Sang Yu6Jae-Yong Chung7Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul National University, Seoul 03080, KoreaDepartment of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul National University, Seoul 03080, KoreaSamyang Biopharmaceuticals Corp., Gyeonggi-do 13488, KoreaSamyang Biopharmaceuticals Corp., Gyeonggi-do 13488, KoreaSamyang Biopharmaceuticals Corp., Gyeonggi-do 13488, KoreaDepartment of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul National University, Seoul 03080, KoreaDepartment of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul National University, Seoul 03080, KoreaDepartment of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Gyeonggi-do 13620, KoreaSorafenib, 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<sup>®</sup> 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<sup>®</sup> 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<sup>®</sup> 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.https://www.mdpi.com/1999-4923/13/5/629sorafenibpharmacokineticsbioavailabilitypharmacometricsenterohepatic reabsorption |
| spellingShingle | Ki-Young Huh Se-jung Hwang Sang-Yeob Park Hye-Jung Lim Mir-yung Jin Jae-seong Oh Kyung-Sang Yu Jae-Yong Chung Population Pharmacokinetic Modelling and Simulation to Determine the Optimal Dose of Nanoparticulated Sorafenib to the Reference Sorafenib Pharmaceutics sorafenib pharmacokinetics bioavailability pharmacometrics enterohepatic reabsorption |
| title | Population Pharmacokinetic Modelling and Simulation to Determine the Optimal Dose of Nanoparticulated Sorafenib to the Reference Sorafenib |
| title_full | Population Pharmacokinetic Modelling and Simulation to Determine the Optimal Dose of Nanoparticulated Sorafenib to the Reference Sorafenib |
| title_fullStr | Population Pharmacokinetic Modelling and Simulation to Determine the Optimal Dose of Nanoparticulated Sorafenib to the Reference Sorafenib |
| title_full_unstemmed | Population Pharmacokinetic Modelling and Simulation to Determine the Optimal Dose of Nanoparticulated Sorafenib to the Reference Sorafenib |
| title_short | Population Pharmacokinetic Modelling and Simulation to Determine the Optimal Dose of Nanoparticulated Sorafenib to the Reference Sorafenib |
| title_sort | population pharmacokinetic modelling and simulation to determine the optimal dose of nanoparticulated sorafenib to the reference sorafenib |
| topic | sorafenib pharmacokinetics bioavailability pharmacometrics enterohepatic reabsorption |
| url | https://www.mdpi.com/1999-4923/13/5/629 |
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