Dosing of Cabozantinib Formulations

a technology of cabozantinib and formulation, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, sexual disorders, etc., can solve problems such as cellular properties being altered, and achieve the effect of pharmacokinetic and pharmacodynamic effects

Inactive Publication Date: 2019-03-14
EXELIXIS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]These and other needs are met by the present invention, which is directed to various of pharmaceutical formulations of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (cabozantinib) a c-Met inhibitor, and its metabolites, to achieve desired pharmacokinetic and pharmacodynamic effects.

Problems solved by technology

Since protein kinases and their ligands play critical roles in various cellular activities, deregulation of protein kinase enzymatic activity can lead to altered cellular properties, such as uncontrolled cell growth associated with cancer.

Method used

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  • Dosing of Cabozantinib Formulations
  • Dosing of Cabozantinib Formulations
  • Dosing of Cabozantinib Formulations

Examples

Experimental program
Comparison scheme
Effect test

embodiments

Embodiment 1

[0110]A pharmaceutical formulation comprising a physiologically effective amount of cabozantinib, wherein oral administration of said composition to a selected human subject group produces in said selected human subject group:

[0111]an average cabozantinib plasma area under the curve (average AUC) of at least 60,000 ng·h / mL per each 140 mg dosage of cabozantinib delivered;

[0112]an average maximum cabozantinib blood plasma concentration (average Cmax) of at least 1000 ng / mL per each 140 mg dosage of cabozantinib delivered; and

[0113]a ratio of AUC(cabozantinib) to the AUC of the sum of cabozantinib plus measured cabozantinib metabolites:

AUC(Cabozantinib) / AUC(Cabozantinib+Measured Metabolites)

of at least 0.25;

[0114]wherein the AUC is measured from time zero to the time of last measurable concentration.

embodiment 2

[0115]A pharmaceutical formulation comprising a physiologically effective amount of cabozantinib, wherein oral administration of said pharmaceutical formulation to a selected human subject group produces in said selected human subject group:

[0116]a steady state area under the curve for cabozantinib (average AUC) of at least 35,000 ng·h / mL for a formulation comprising 100 mg of cabozantinib delivered once daily;

[0117]an average maximum cabozantinib blood plasma concentration (average Cmax) of at least 2400 ng / mL per each 100 mg dosage of cabozantinib delivered;

[0118]an average minimum cabozantinib blood plasma concentration (average Cmax) of at least 1100 ng / mL per each 100 mg dosage of cabozantinib delivered; and

[0119]a ratio of AUC(cabozantinib) to the AUC of the sum of cabozantinib plus measured cabozantinib metabolites:

AUC(Cabozantinib) / AUC(Cabozantinib+Measured Metabolites)

of at least 0.35;

[0120]wherein the AUC is measured on day 22.

embodiment 3

[0121]The pharmaceutical formulation of embodiments 1-2, wherein the measured metabolites are selected from the group consisting of:

wherein GA is a glucuronic acid moiety,

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Abstract

The invention relates to administration of various pharmaceutical formulations of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (cabozantinib) a c-Met inhibitor, and its metabolites, to achieve desirable pharmacokinetic and pharmacodynamic effects.

Description

PRIORITY CLAIM[0001]This application claims priority to U.S. Application Ser. No. 61 / 954,352, filed Mar. 17, 2014. The entire contents of the aforementioned application are incorporated herein by reference.TECHNICAL FIELD[0002]The invention relates to administration of various pharmaceutical formulations of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophnyl)cyclopropane-1,1-dicarboxamide, (cabozantinib) a c-Met inhibitor, and its metabolites, to achieve desirable pharmacokinetic and pharmacodynamic effects.BACKGROUND[0003]Traditionally, dramatic improvements in the treatment of cancer are associated with identification of therapeutic agents acting through novel mechanisms. One mechanism that can be exploited in cancer treatment is the modulation of protein kinase activity because signal transduction through protein kinase activation is responsible for many of the characteristics of tumor cells. Protein kinase signal transduction is of particular relevance in, for e...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/47A61K9/00A61K9/20
CPCA61K9/0053A61K9/2054A61K31/47A61P1/04A61P1/16A61P1/18A61P11/00A61P13/12A61P15/00A61P17/00A61P19/08A61P35/00A61P35/02
Inventor AFTAB, DANA T.NAGANATHAN, SRIRAMXU, WEILACY, STEVEN
Owner EXELIXIS INC
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