Maribavir isomers, compositions, methods of making and methods of using

Abstract

The invention relates to novel compositions and methods of using maribavir which enhance its effectiveness in medical therapy, as well as to maribavir isomers and methods of use thereof for counteracting the potentially adverse effects of maribavir isomerization in vivo in the event it occurs.

What is claimed is: 
     
         1 . A method for treatment or prophylaxis of a herpes viral infection in a patient in need thereof comprising administering to said patient the compound 5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole, or an isomer of said compound, in an amount effective to counteract molecular conversion of said compound occurring in vivo, and thereby providing an anti-virally effective amount of said compound to said patient. 
     
     
         2 . A method according to  claim 1 , wherein said amount is greater than 200 mg per day. 
     
     
         3 . A method according to  claim 2 , wherein the amount administered is up to 6400 mg per day. 
     
     
         4 . A method according to  claim 1 , wherein said herpes viral infection is cytomegalovirus. 
     
     
         5 . A method according to  claim 4 , wherein said patient is a stem cell transplant recipient, a liver transplant recipient, or kidney transplant recipient. 
     
     
         6 . A method according to  claim 1 , wherein said compound is administered to said patient under fasted conditions. 
     
     
         7 . The method of  claim 1  wherein said compound is administered as a composition comprising a therapeutically acceptable adjuvant, excipient or carrier medium. 
     
     
         8 . The method of  claim 7  wherein said composition is an immediate release formulation, a delayed release formulation, a controlled release formulation or an intravenous formulation. 
     
     
         9 . The method of  claim 1 , wherein said compound is administered in combination with at least one of an antacid which is effective for neutralizing acid that catalyzes isomerization of maribavir, an antibiotic having activity against a microorganism that mediates isomerization of maribavir and an antagonist that inhibits metabolism that induces isomerization of maribavir, said isomerization producing a decrease in the therapeutic efficacy of said compound. 
     
     
         10 . A method for the treatment or prophylaxis of herpes viral infection in a patient in need thereof comprising administering to said patient one or more maribavir isomers. 
     
     
         11 . The method according to  claim 10 , wherein the prodrug of the maribavir isomers is administered to said patient. 
     
     
         12 . The method according to  claim 11 , wherein the prodrug is isomerized in vivo to produce one or more maribavir isomers. 
     
     
         13 . The method according to  claim 1 , wherein said compound comprises a pyranosyl analog of maribavir. 
     
     
         14 . The method according to  claim 7 , wherein said composition comprises a pyranosyl isomer of maribavir. 
     
     
         15 . A method for determining the therapeutic efficacy of the compound 5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole, or an isomer of said compound in the blood plasma of a patient administered said compound, comprising measuring the concentration of a therapeutically effective form of said compound in a blood plasma sample from said patient and comparing said measured concentration with the concentration(s) of at least one of a lesser therapeutically effective form of said compound or an isomer or analog thereof in same patient sample. 
     
     
         16 . The method according to  claim 15 , wherein said measurement and comparison is performed on patient samples during and within 12 hours of terminating treatment. 
     
     
         17 . The method according to  claim 15 , wherein said measurement(s) and comparison(s) determine the treatment protocol of said patient. 
     
     
         18 . The method according to  claim 17 , wherein said treatment protocol is the dosage amount of said compound administered to said patient, the dosage regimen for administration of said compound to said patient, the discontinuation of administration of said compound to said patient, or the initiation of other therapeutic intervention for said patient. 
     
     
         19 . A method of increasing the bioavailability of maribavir to a patient receiving maribavir therapy comprising administering to said patient an oral dose comprising about 200 mg to 800 mg of maribavir under fasted conditions, whereby said administration results in an increase of the maximum plasma concentration and the extent of absorption of maribavir relative to the plasma concentration and the extent of absorption for the corresponding administration of maribavir under fed conditions. 
     
     
         20 . A method of informing a patient receiving maribavir therapy that dosing of maribavir under fasted conditions results in an increase of the maximum plasma concentration as compared to the administration of maribavir under fed conditions, comprising providing to said patient a container of maribavir doses, said container being associated with prescription information that advises the patient that administration of a maribavir dose under fasted conditions results in said increase. 
     
     
         21 . A method of more effectively and safely using maribavir therapy comprising providing information and guidance in maribavir product packaging and promotional materials regarding the nature of in vivo isomerization of maribavir and related guidance on dosing and use of maribavir so as to mitigate any potential undesired effects from said in vivo maribavir isomerization. 
     
     
         22 . A method of making one or more maribavir isomers comprising the step of administering maribavir to a mammal, wherein said administration results in the in vivo isomerization of maribavir to one or more maribavir isomers. 
     
     
         23 . The method according to  claim 22 , wherein the said mammal is human that has a herpes virus infection. 
     
     
         24 . A composition for the treatment or prophylaxis of herpes viral infection comprising the compound 5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole and at least one of an antacid which is effective for neutralizing acid that catalyzes isomerization of maribavir, an antibiotic having activity against a microorganism that mediates isomerization of maribavir and an antagonist that inhibits metabolism that induces isomerization of maribavir, said isomerization producing a decrease in the therapeutic efficacy of said compound.