Therapeutic combinations of orally administered paclitaxel and a p-gp inhibitor for the treatment of angiosarcoma

A technology of angiosarcoma and paclitaxel, which is applied in the field of compounds for the treatment of angiosarcoma, and can solve problems such as inability to inject paclitaxel intravenously and reluctance to accept it

Pending Publication Date: 2021-02-09
ATHENEX THERAPEUTICS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These benefits are attractive to patients, many of whom are elderly who would be unwilling or p

Method used

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  • Therapeutic combinations of orally administered paclitaxel and a p-gp inhibitor for the treatment of angiosarcoma
  • Therapeutic combinations of orally administered paclitaxel and a p-gp inhibitor for the treatment of angiosarcoma
  • Therapeutic combinations of orally administered paclitaxel and a p-gp inhibitor for the treatment of angiosarcoma

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[3574] Example 1 - Combination of Orally Administered Paclitaxel and Compound A in Vivo in a Tumor Cell Implanted Mouse Model anticancer activity

[3575] The ability of orally administered paclitaxel in combination with Compound A to inhibit the growth of different human tumor xenograft cell lines was investigated in 7 in vivo experiments in mice. Paclitaxel administered intravenously (IV) or intraperitoneally (IP) alone served as a control. A summary and results of the study are provided in Table 1 below.

[3576] Table 1: Summary and results of the in vivo anticancer activity of orally administered Paclitaxel in combination with Compound A in a tumor cell implanted mouse model

[3577]

[3578]

[3579] In these studies, tumor inhibition rate (IR%) was calculated as ([1 - relative tumor growth in treatment group / relative tumor growth in control group] x 100). Tumor regression was calculated as (mean tumor weight 治疗结束 / average tumor weight 治疗开始 )x100. Thus, a ...

Embodiment 2

[3582] Example 2 - Dose-Dependence of Orally Administered Paclitaxel

[3583] In rats and dogs orally administered paclitaxel in combination with Compound A, paclitaxel C max and AUC increased in a greater than dose proportional manner, as shown in Tables 2 and 3 below.

[3584] Table 2: Dose dependence of paclitaxel in rat pharmacokinetics after single oral administration in combination with compound A

[3585]

[3586] Table 3: Dose Dependence of Paclitaxel in Dog Pharmacokinetics Following Single-Dose Oral Administration in Combination with Compound A

[3587]

Embodiment 3

[3588] Example 3 - Determination of the Bioavailability of Orally Administered Paclitaxel in Combination with Compound A in Subjects with Cancer Utilization rate

[3589] The study was designed to determine the absolute bioavailability of orally administered paclitaxel in combination with Compound A in subjects with cancer. Eligible subjects were instructed to take 80mg / m2 once a week over 1 hour 2 Dosage of intravenous paclitaxel (eg, or use Adults treated with paclitaxel formulated together.

[3590] The first 6 subjects received the following treatment approximately 1 week apart: 80 mg / m 2 Intravenous paclitaxel (as or generic drug) via 1 hour infusion (on day 1 or day 8) plus premedication according to standard local practice; or 15mg Compound A + 270mg (approximately 150mg / m 2 ) paclitaxel administered orally (days 1 and 2 or days 8 and 9). Compound A was administered 1 hour before oral administration of paclitaxel. Premedication is not permitted during this...

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Abstract

The application pertains to pharmaceutical combinations of orally administered paclitaxel and a P-gp inhibitor. The pharmaceutical combinations are suitable for the treatment of an angiosarcoma in a subject and for reducing or preventing toxicity, hypersensitivity-type infusion reactions, and other negative outcomes resulting from or associated with intravenously administered paclitaxel (e.g., Taxol or paclitaxel formulated with Cremophor) therapy in a subject suffering from an angiosarcoma.

Description

[0001] related application [0002] This application claims priority to and benefit of U.S. Provisional Application No. 62 / 657,444, filed April 13, 2018, the contents of which are incorporated herein by reference in their entirety. Background technique [0003] Paclitaxel can treat many types of cancer. However, paclitaxel's affinity for the p-glycoprotein pump (P-gp) results in paclitaxel's efflux back into the intestinal lumen, so the drug is not bioavailable when administered orally. Its poor absorption through the intestinal epithelium, as well as its unfavorable solubility, necessitated intravenous administration of paclitaxel. Excipients for intravenous administration (e.g. ) often cause tolerability problems such as anaphylaxis-type infusion reactions. Paclitaxel administered intravenously (eg, or with Paclitaxel, formulated together) requires premedication, which has its own set of side effects. In addition, predosing introduces potential drug-drug interaction...

Claims

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Application Information

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IPC IPC(8): A61K31/4725A61K31/337A61K9/00A61P35/00
CPCA61K31/337A61K31/4725A61P35/00A61K9/0053A61P39/00A61K9/4858A61K9/2004A61K2300/00
Inventor M.P.斯莫林斯基M-F.R.关J.Y-N.劳W.K.陈
Owner ATHENEX THERAPEUTICS LTD
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