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Phase I pharmacokinetic study of an oral, small-molecule MEK inhibitor tunlametinib in patients with advanced NRAS mutant melanoma

Affiliation
Clinical Pharmacology Research Center ,Peking Union Medical College Hospital ,Chinese Academy of Medical Sciences & Peking Union Medical College ,State Key Laboratory of Complex Severe and Rare Diseases ,NMPA Key Laboratory for Clinical Research and Evaluation of Drug ,Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs ,Beijing ,China
Zhao, Qian;
Affiliation
Clinical Pharmacology Research Center ,Peking Union Medical College Hospital ,Chinese Academy of Medical Sciences & Peking Union Medical College ,State Key Laboratory of Complex Severe and Rare Diseases ,NMPA Key Laboratory for Clinical Research and Evaluation of Drug ,Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs ,Beijing ,China
Wang, Teng;
Affiliation
Clinical Pharmacology Research Center ,Peking Union Medical College Hospital ,Chinese Academy of Medical Sciences & Peking Union Medical College ,State Key Laboratory of Complex Severe and Rare Diseases ,NMPA Key Laboratory for Clinical Research and Evaluation of Drug ,Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs ,Beijing ,China
Wang, Huanhuan;
Affiliation
Clinical Pharmacology Research Center ,Peking Union Medical College Hospital ,Chinese Academy of Medical Sciences & Peking Union Medical College ,State Key Laboratory of Complex Severe and Rare Diseases ,NMPA Key Laboratory for Clinical Research and Evaluation of Drug ,Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs ,Beijing ,China
Cui, Cheng;
Affiliation
Clinical Pharmacology Research Center ,Peking Union Medical College Hospital ,Chinese Academy of Medical Sciences & Peking Union Medical College ,State Key Laboratory of Complex Severe and Rare Diseases ,NMPA Key Laboratory for Clinical Research and Evaluation of Drug ,Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs ,Beijing ,China
Zhong, Wen;
Affiliation
Clinical Pharmacology Research Center ,Peking Union Medical College Hospital ,Chinese Academy of Medical Sciences & Peking Union Medical College ,State Key Laboratory of Complex Severe and Rare Diseases ,NMPA Key Laboratory for Clinical Research and Evaluation of Drug ,Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs ,Beijing ,China
Fu, Diyi;
Affiliation
Clinical Pharmacology Research Center ,Peking Union Medical College Hospital ,Chinese Academy of Medical Sciences & Peking Union Medical College ,State Key Laboratory of Complex Severe and Rare Diseases ,NMPA Key Laboratory for Clinical Research and Evaluation of Drug ,Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs ,Beijing ,China
Xi, Wanlin;
Affiliation
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) ,Department of Renal Cancer and Melanoma ,Peking University Cancer Hospital and Research Institute ,Beijing ,China
Si, Lu;
Affiliation
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) ,Department of Renal Cancer and Melanoma ,Peking University Cancer Hospital and Research Institute ,Beijing ,China
Guo, Jun;
Affiliation
Shanghai KeChow Pharma, Inc. ,Shanghai ,China
Cheng, Ying;
Affiliation
Shanghai KeChow Pharma, Inc. ,Shanghai ,China
Tian, Hongqi;
Affiliation
Clinical Pharmacology Research Center ,Peking Union Medical College Hospital ,Chinese Academy of Medical Sciences & Peking Union Medical College ,State Key Laboratory of Complex Severe and Rare Diseases ,NMPA Key Laboratory for Clinical Research and Evaluation of Drug ,Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs ,Beijing ,China
Hu, Pei

Background: Malignant melanoma is an aggressive disease. Tunlametinib (HL-085) is a potent, selective, and orally bioavailable MEK1/2 inhibitor. The objective of this study was to determine the pharmacokinetics (PK) of tunlametinib and its main metabolite M8 in patients with NRAS -mutant melanoma following a single dose and multiple doses in a phase I safety and PK study. Methods: A multiple-center phase I study was performed in patients with melanoma including dose-escalation phase and dose-expansion phase. PK following a single oral dose and multiple doses of 0.5–18 mg twice daily was assessed. Results: A total of 30 participants were included in the dose escalation phase and then 11 patients were included in the dose-expansion phase (12 mg twice daily). Tunlametinib plasma concentration rapidly increased after dosing, with a T max of 0.5–1 h. Mean elimination half-life (t 1/2 ) was dose-independent and had a range from 21.84 to 34.41 h. Mean apparent clearance (CL/F) and distribution volume (V/F) were 28.44–51.93 L/h and 1199.36–2009.26 L, respectively. The average accumulation ratios of AUC and C max after the multiple administration of tunlametinib were 1.64–2.73 and 0.82–2.49, respectively. Tunlametinib was rapidly transformed into the main metabolite M8 and M8 reached the peak concentration about 1 h after administration. Mean t 1/2 of M8 was 6.1–33.54 h. The body exposure of M8 in plasma was 36%–67% of that of tunlametinib. There were general dose-proportional increases in maximum concentration (C max ) and area under the curve (AUC) of tunlametinib and M8 both in the single dose phase and in the multiple doses phase. Conclusion: Tunlametinib was absorbed rapidly and eliminated at a medium speed after drug withdrawal. Pharmacokinetic body exposure increased in general dose-proportional manner from 0.5 mg up to 18 mg. Slight accumulation was found after multiple oral doses. The pharmacokinetics of tunlametinib and its metabolite suggest that twice daily dosing is appropriate for tunlametinib.

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License Holder: Copyright © 2022 Zhao, Wang, Wang, Cui, Zhong, Fu, Xi, Si, Guo, Cheng, Tian and Hu.

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