Enhanced treatment regimens using mTOR inhibitors
Inventors
Liu, Yi • Bui, Lynne • Martin, Michael • Wilson, Troy Edward • Rommel, Christian
Assignees
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Publication Number
US-9669032-B2
Publication Date
2017-06-06
Expiration Date
Abstract
The present invention provides for methods and pharmaceutical compositions comprising inhibitors of mTorC1 and/or mTorC2. In some aspects, the invention provides for treatment regimens resulting in enhanced treatment efficacy and better tolerability.
Core Innovation
The disclosure provides a dosage form comprising a therapeutically effective amount of an mTorC1/mTorC2 inhibitor for administration to a subject in need thereof. The dosage form is formulated to provide a Cmax of greater than about 200 nM to the subject, and the mTorC1/mTorC2 inhibitor is the inhibitor or a pharmaceutically acceptable salt thereof.
The dosage form is further defined by quantitative constraints on the therapeutically effective amount and on plasma exposure. It provides a plasma concentration of said mTorC1/mTorC2 inhibitor greater than about 100 nM for at least about 20 hours over a 7-day period of administration, and the therapeutically effective amount is about 45, 50, 55, 60, 70, or 75 mg or less.
The disclosure includes permitted administration routes and dosage-form types for delivering the mTorC1/mTorC2 inhibitor. The mTorC1/mTorC2 inhibitor is administered parenterally, orally, intraperitoneally, intravenously, intraarterially, transdermally, intramuscularly, liposomally, via local delivery by catheter or stent, subcutaneously, intraadiposally, or intrathecally, and the dosage form is one of capsule, tablet, pill, powder, solution, or suspension.
The subject matter also includes structural embodiments and biological characterization of mTorC1/mTorC2 inhibitor compounds, with defined substituent options such as X1 being CH or N and V being cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, or N-morpholino. The disclosure further identifies treatment of one of a specified set of cancers, including renal cancer and other listed cancer types.
Claims Coverage
The claim coverage centers on one independent claim directed to a dosage form comprising an mTorC1/mTorC2 inhibitor with a defined systemic exposure threshold. The independent claim is supported by dependent claims that refine the therapeutically effective amount, plasma concentration and exposure duration, permitted administration routes, dosage-form types, and cancer treatment indications, giving a total of six inventive features.
Dosage form with Cmax above about 200 nM
A dosage form comprising a therapeutically effective amount of an mTorC1/mTorC2 inhibitor for administration to a subject in need thereof, formulated to provide a Cmax of greater than about 200 nM, wherein the mTorC1/mTorC2 inhibitor is the inhibitor or a pharmaceutically acceptable salt thereof.
Upper bound on therapeutically effective amount
The therapeutically effective amount of the mTorC1/mTorC2 inhibitor is about 45, 50, 55, 60, 70, or 75 mg or less.
Plasma concentration above about 100 nM for at least about 20 hours over a 7-day period
The dosage form provides a plasma concentration of said mTorC1/mTorC2 inhibitor greater than about 100 nM for at least about 20 hours over a 7-day period of administration.
Permitted administration routes
The mTorC1/mTorC2 inhibitor is administered parenterally, orally, intraperitoneally, intravenously, intraarterially, transdermally, intramuscularly, liposomally, via local delivery by catheter or stent, subcutaneously, intraadiposally, or intrathecally.
Dosage-form types
The dosage form is one of capsule, tablet, pill, powder, solution, or suspension.
Cancer treatment indications
The dosage form is for treating one of a specified set of cancers, including renal cancer and other listed cancer types.
Overall, the claims define a dosage form of an mTorC1/mTorC2 inhibitor configured to achieve a Cmax greater than about 200 nM, with dependent refinements that set an upper bound on therapeutically effective amount, require a plasma concentration greater than about 100 nM for at least about 20 hours over a 7-day period, specify allowable administration routes and dosage-form types, and identify cancer treatment indications including renal cancer.
Stated Advantages
Provides a dosage form formulated to provide a Cmax greater than about 200 nM.
Provides a plasma concentration greater than about 100 nM for at least about 20 hours over a 7-day period of administration.
Improved efficacy and tolerability versus equivalent once-daily dosing.
Enables treatment of a specified set of cancers, including renal cancer.
Documented Applications
Administration of an mTorC1/mTorC2 inhibitor dosage form to a subject in need thereof.
Treatment of cancers including renal cancer and other explicitly listed cancer types.
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