Delving into the Latest Updates on Donafenib Tosylate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Donafenib, Donafenib tosilate, Zeprosen

+ [4]

Target

CRAF x PDGFR x VEGFR

Mechanism

CRAF inhibitors(C-Raf kinase inhibitors), PDGFR inhibitors(Platelet-derived growth factor receptor inhibitors), VEGFR antagonists(Vascular endothelial growth factor receptor antagonists)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [1]

Active Indication

Thyroid CancerHepatocellular CarcinomaAdvanced Bile Duct Carcinoma+ [2]

Inactive Indication

Advanced gastric carcinomaAdvanced Hepatocellular CarcinomaEsophageal Carcinoma+ [8]

Originator Organization

Suzhou Zelgen Biopharmaceuticals Co., Ltd.

Active Organization

Suzhou Zelgen Biopharmaceuticals Co., Ltd.

Fudan University

Inactive Organization

The First Affiliated Hospital, Zhejiang University School of Medicine

Drug Highest PhaseApproved

First Approval Date

CN (08 Jun 2021),

Hepatocellular Carcinoma

RegulationPriority Review (CN)

Login to view First Approval Timeline

Structure

Molecular FormulaC28H24ClF3N4O6S

InChIKeyIVDHYUQIDRJSTI-NIIDSAIPSA-N

CAS Registry1333386-17-6

Donafenib and sorafenib are small molecule chemotherapy drugs for the management of hepatocellular carcinoma, with donafenib being a deuterated derivative of sorafenib. To date, a high liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method that quantify donafenib, sorafenib, and their main metabolites has not yet been developed. The objective of this study was to establish a HPLC-MS/MS method for the simultaneous detection of donafenib, donafenib-N-oxide, sorafenib, and sorafenib-N-oxide and for the pharmacokinetic studies in rat. The extraction of all analytes was achieved by simple protein precipitation utilizing acetonitrile. The Waters XBridge C₁₈ column (2.1 × 100 mm, 3.5 µm) was selected, and the analytes could be efficiently separated and quantitated during a 2.8 min gradient elution procedure. The method was linear within the predefined quantification ranges and provided acceptable precision (%CV < 9.4%), reproducible extraction recovery (99.4%-111.5%), and low matrix effect (88.1%-98.6%). The hemolysis effect did not interfere with the quantification of all analytes, and similar results were obtained by changing the anticoagulant K₂-EDTA to heparin or sodium citrate. Plasma pharmacokinetics revealed that the values of t_1/2, C_max, and AUC_0-t of donafenib were 1.4-, 6.2-, and 3.1-fold higher than those of sorafenib, respectively. In conclusion, the proposed bioassay was successfully applied to pharmacokinetic studies in rat after administration of donafenib and sorafenib. Our work not only improves the bioanalytical method for determining the plasma concentrations of donafenib, sorafenib, and their N-oxide metabolites, but also provides a scientific reference for clinical pharmacokinetic studies.

01 Jun 2023·Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

In vivo assessment of the pharmacokinetic interactions between donafenib and dapagliflozin, donafenib and canagliflozin in rats

Article

Author: Guo, Caihui ; Li, Yajing ; Li, Ying ; Fu, Yuhao ; He, Xueru ; Wang, Zhi ; Xun, Xuejiao ; Dong, Zhanjun

Donafenib (DONA), a deuterium derivative of sorafenib, is used for advanced hepatocellular carcinoma (HCC). Dapagliflozin (DAPA) and canagliflozin (CANA) are sodium-glucose co-transporter 2 (SGLT2) inhibitors used for T2DM, which is frequently comorbid with HCC. Three drugs are substrates of UGT1A9 isoenzyme. This study aimed to evaluate donafenib-dapagliflozin and donafenib-canagliflozin pharmacokinetic interactions and explore the potential mechanisms. Rats were divided into seven groups (n = 6) that received donafenib (1), dapagliflozin (2), canagliflozin (3), dapagliflozin and donafenib (4), canagliflozin and donafenib (5), donafenib and dapagliflozin (6), donafenib and canagliflozin (7). The concentrations of drugs were determined by an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. The messenger RNA (mRNA) expressions were measured by quantitative RT-PCR. Multiple doses of dapagliflozin caused donafenib maximum plasma concentration (C_max) to increase 37.01%. Canagliflozin increased donafenib C_max 1.77-fold and the area under the plasma concentration-time curves (AUC_0-t and AUC_inf) 1.39- and 1.41-fold, respectively, while reducing the apparent clearance (CL_z) 28.38%. Multiple doses of donafenib increased dapagliflozin AUC_0-t 1.61-fold, AUC_inf 1.77-fold, whereas its CL_z reduced 40.50%. Furthermore, donafenib caused similar changes in canagliflozin pharmacokinetics. The PCR results demonstrated that dapagliflozin inhibited the mRNA expression of Ugt1a7 in liver and donafenib decreased the expression of Ugt1a7 mRNA in liver and intestine. Increased exposure to these drugs may be due to their metabolism inhibition mediated by Ugt1a7. These pharmacokinetic interactions observed in this study may be of clinical significance, which may help adjust dose properly and avoid toxicity effects in patients with HCC and T2DM.

01 Jan 2023·Frontiers in pharmacology

Development of a UPLC-MS/MS method for simultaneous therapeutic drug monitoring of anti-hepatocellular carcinoma drugs and analgesics in human plasma.

Article

Author: Li, Guofei ; Zhao, Mingming ; Lu, Shijia ; Zhao, Limei

In hepatocellular carcinoma treatment, sorafenib, oxaliplatin, 5-fluorouracil, capecitabine, lenvatinib, and donafenib are first-line drugs; regorafenib, apatinib, and cabozantinib are second-line drugs; and oxycodone, morphine, and fentanyl are commonly used analgesics. However, the high degree of inter- and intra-individual variability in the efficacy and toxicity of these drugs remains an urgent issue. Therapeutic drug monitoring (TDM) is the most reliable technical means for evaluating drug safety and efficacy. Therefore, we developed an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous TDM of three chemotherapy drugs (5-fluorouracil, oxaliplatin, and capecitabin), six targeted drugs (sorafenib, donafenib, apatinib, cabozantinib, regorafenib, and lenvatinib), and three analgesics (morphine, fentanyl, and oxycodone). We extracted 12 analytes and isotope internal standards (ISs) from plasma samples by magnetic solid phase extraction (mSPE) and separated them using a ZORBAX Eclipse Plus C18 column with water containing 0.1% formic acid and methanol containing 0.1% formic acid as the mobile phase. The analytical performance of our method in terms of sensitivity, linearity, specificity, carryover, precision, limit of quantification, matrix effect, accuracy, dilution integrity, extraction recovery, stability, and crosstalk of all the analytes under different conditions met all the criteria stipulated by the guidelines of the Chinese Pharmacopoeia and U.S. Food and Drug Administration. The response function was estimated at 10.0-10 000.0 ng/mL for sorafenib, donafenib, apatinib, cabozantinib, regorafenib, and lenvatinib, and 20.0-20 000.0 ng/mL for 5-fluorouracil, oxaliplatin, capecitabin, morphine, fentanyl, and oxycodone, with a correlation of > 0.9956 for all compounds. The precision and accuracy of all analytes were < 7.21% and 5.62%, respectively. Our study provides empirical support for a simple, reliable, specific, and suitable technique for clinical TDM and pharmacokinetics.

1

News (Medical) associated with Donafenib Tosylate

04 Aug 2021

·www.mobihealthnews.com

Digital health platform 111 signs deal to build online liver cancer management platform

Nasdaq-listed 111, a Chinese healthcare platform, has entered into a strategic cooperation agreement with Jiangsu-based drug R&D firm Suzhou Zelgen Biopharmaceuticals Co. to build a virtual platform for liver cancer patients. WHAT IT DOES 111 operates an internet hospital offering virtual health consultations, an electronic prescription service, and a patient management service. It also runs one of China's largest retail pharmacy networks serving over 320,000 pharmacies, as well as a medicine marketplace where pharmacies can source products. Moreover, 111 provides an omnichannel commercialisation platform for pharmaceutical firms. WHY IT MATTERS 111 claims that its upcoming online disease management platform will offer liver cancer patients with integrated services, including online consultations and information on diseases, medications and therapies. Additionally, this latest partnership will see Zelgen's flagship product Zeprosyn – a drug for treating unresectable hepatocellular carcinoma, marketed through the platform. Liver cancer is the second leading cause of cancer deaths in China. Data from the WHO's International Agency for Research on Cancer shows that liver cancer accounts for about 410,000 new cancer cases in China last year, causing around 390,000 deaths. THE LARGER TREND In May, 111 also made a similar deal with another biotech firm, BeiGene, to launch an online oncology management platform leveraging its internet hospital capabilities. 111 said it has so far made 360 direct partnerships with pharma companies, such as Eli Lilly and Bayer Healthcare. ON THE RECORD "The cooperation with Zelgen in the field of liver cancer is an important deployment of our digital platform in health management services directed toward a leading cause of cancer death in China. By harnessing the power of the internet, we can break the limitations of time and space, and this new virtual platform will bring together specialists and patients online to efficiently carry out diagnoses, treatment education, follow-up visits and prescription renewals. These functions not only expand the service radius of doctors but also help medicines like Zeprosyn reach more patients," Dr Yu Gang, co-founder and executive chairman of 111, stated. "Through this partnership, we will be able to take advantage of 111's online diagnosis, treatment, multi-channel platform and health management services to further increase the availability of new drugs and, in turn, provide greater benefits to patients," Zelgen Chairman and General Manager Dr Sheng Zelin also commented.

Collaborate

100 Deals associated with Donafenib Tosylate

Login to view more data

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	L01X	DB15414

R&D Status

Approved

10 top approved records.

Login

to view more data

Indication	Country/Location	Organization	Date
Thyroid Cancer	CN	Suzhou Zelgen Biopharmaceuticals Co., Ltd.	10 Aug 2022
Hepatocellular Carcinoma	CN	Suzhou Zelgen Biopharmaceuticals Co., Ltd.	08 Jun 2021

Developing

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Refractory Thyroid Gland Carcinoma	Phase 3	CN	Suzhou Zelgen Biopharmaceuticals Co., Ltd.	29 Aug 2018
Refractory Differentiated Thyroid Gland Carcinoma	Phase 3	CN	Suzhou Zelgen Biopharmaceuticals Co., Ltd.	26 Jul 2018
Metastatic Colorectal Carcinoma	Phase 3	CN	Suzhou Zelgen Biopharmaceuticals Co., Ltd.	28 Dec 2016
Advanced Hepatocellular Carcinoma	Phase 3	CN	Suzhou Zelgen Biopharmaceuticals Co., Ltd.	01 Mar 2016
Advanced Malignant Solid Neoplasm	Phase 2	CN	Suzhou Zelgen Biopharmaceuticals Co., Ltd.	10 May 2024
Advanced Bile Duct Carcinoma	Phase 2	CN	Fudan University	18 Oct 2022
Secondary malignant neoplasm of pancreas	Phase 2	CN	Fudan University	01 Dec 2021
Biliary Tract Neoplasms	Phase 2	CN	Suzhou Zelgen Biopharmaceuticals Co., Ltd.	01 Dec 2020
Nasopharyngeal Carcinoma	Phase 2	CN	Suzhou Zelgen Biopharmaceuticals Co., Ltd.	08 Feb 2017
Metastatic gastric adenocarcinoma	Phase 2	CN	Suzhou Zelgen Biopharmaceuticals Co., Ltd.	16 May 2016

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASCO2024	Not Applicable	Hepatocellular Carcinoma First line HBV infection	102	D+TACE/HAIC	gfhkhcfigj(lcaqjpcgin) = qgzeiraosp edaldkgyzd (wcdyqxaqxm ) View more	Positive	24 May 2024
				D+TACE/HAIC+ICI	gfhkhcfigj(lcaqjpcgin) = kdgxvgkfqe edaldkgyzd (wcdyqxaqxm ) View more
ASCO2024	Not Applicable	Hepatocellular Carcinoma	-	Donafenib 100mg bid	sfzonxgaty(lcbxpisbqv) = AEs occurred in 44 patients, including 39 with grade 1 or 2 AEs and 5 with grade 3 AEs. The most common AEs included hand-foot skin reaction, decreased platelet count, and diarrhea cogbwtmakr (nazpibjaav )	-	24 May 2024
ZGDH3 (ASCO2024)	Phase 3	Unresectable Hepatocellular Carcinoma First line	48	Donafenib combined with anti-PD-1 antibodies	dxcwcdhstc(rcmflpevec) = detbjupbme zceivaikxn (ksjrracppk, 8.9 - NA) View more	Positive	24 May 2024
ASCO2024	Not Applicable	Hepatocellular Carcinoma Adjuvant AFP \| PIVKA-II	82	Donafenib	gfekdbqavc(amazgogqdk) = tgezozrkeb nditudnjgg (wgrjdaetdq ) View more	Positive	24 May 2024
NCT04418401 (PATH study, ASCO2024)	Phase 1	Hepatocellular Carcinoma Adjuvant	30	Donafenib plus anti-PD-1 antibody	rzaykzwcii(kyqgzdpywj) = zfcmmkfqzh grhgjqbssa (yfpkquoohx, 70.6% - 96.7)	Positive	24 May 2024
ASCO2024	Not Applicable	Advanced Hepatocellular Carcinoma	87	Dona-TACE + Regorafenib	twvvcfpqhb(ylxymsednr) = The Dona-TACE group received regorafenib sequentially had a lowest incidence of grade 3-4 AEs (39.1%, P<0.05) jvzsblfctu (iblagsxauw ) View more	Positive	24 May 2024
				Sora-TACE + Regorafenib
ChiCTR2100054041 (ESMO_TAT2024) Manual	Phase 4	Advanced Hepatocellular Carcinoma First line	27	donafenib	rezgjpjvsl(ihslbfxpah) = not reached pnqrjbiigx (vhdevxbref ) View more	Positive	26 Feb 2024
NCT05166772 (DoHAICs, ESMO2023) Manual	Phase 2	Unresectable Hepatocellular Carcinoma	30	donafenib + sintilimab +oxaliplatin + leucovorin +fluorouracil	woqecxmdqg(dacpcwxguv) = dyqihppccn zzjlddiltm (bvrdityskq ) View more	Positive	23 Oct 2023
				donafenib + sintilimab +oxaliplatin + leucovorin +fluorouracil (received hepatectomy)	fsgmcdvihe(xijwpruvgn) = kjnnpzejfc ieozcearwd (gwgdaogogs ) View more
ESMO2023	Not Applicable	Unresectable Hepatocellular Carcinoma First line	-	TACE+DP	meikwwsaxd(nnsdyvfzlx) = There was no significant difference in the incidence and severity of adverse events in the TACE+DP and TACE+D groups (any grade, 92.9% vs. 94.6%, P=0.270; grade 3 or 4, 33.8% vs. 37.3%, P=0.253) yqngzgtmzu (emdbbotbws )	Positive	23 Oct 2023
				TACE+D
NCT02645981 (ZGDH3, ASCO2023) Manual	Phase 2/3	Advanced Hepatocellular Carcinoma First line	668	Donafenib	qydwvljhen(flqyzabumc) = wcviptjvcy oorcktrnmz (erurabnsaa ) View more	Positive	31 May 2023
				Sorafenib	qydwvljhen(flqyzabumc) = qynoflmboi oorcktrnmz (erurabnsaa ) View more