Claims for Patent: 10,888,558

Summary for Patent: 10,888,558

Title:	Regimens of tafenoquine for prevention of malaria in malaria-naive subjects
Abstract:	Methods of prevention of symptomatic malaria in a malaria-naive, G6PD-normal human subject comprising administering to the human subject a compound of Formula (I), a pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising a compound of Formula (I). A compound of Formula (I) can be administered prior to potential exposure of a species of Plasmodium, during potential exposure of a species of Plasmodium, and after potential exposure of a species of Plasmodium. The methods of the invention also pertains to kits comprising specific doses of Formula (I), a pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising a compound of Formula (I), and instructions for administration of dosing quantity and frequency. The methods of the invention also pertain to determining doses of Formula (I) that meet the general regulatory requirement for a drug to be efficacious in the prevention of malaria in malaria-naive subjects. The methods of the invention further pertain to using the described algorithm to derive dosing regimens which can provide protection against symptomatic malaria in malaria-naive, G6PD-normal subjects. ##STR00001##
Inventor(s):	Dow; Geoffrey S. (Washington, DC), Smith; Bryan L. (Chevy Chase, MD), Jones; John P. (Richmond, VA), Shmuklarsky; Moshe (Bethesda, MD), Balasubrahmanyam; Budda (Richmond, VA)
Assignee:	60 Degrees Pharmaceuticals LLC (Washington, DC) The Government Of The United States As Represented By The Secretary Of The Army (Fort Detrick, MD)
Application Number:	16/504,533
Patent Claims:	1. A method of prevention of symptomatic P. falciparum malaria in a human subject, comprising: a) administering to the human subject two or more initial doses of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), wherein at least the first initial dose is administered prior to potential exposure of the subject to P. falciparum; and b) administering to the human subject an exposure dose of said compound or composition one or more times per week during potential exposure of the subject to P. falciparum; wherein about 75 to about 299 mg of said compound of Formula (I) is administered in each of said two or more initial doses, wherein the total combined amount of said compound of Formula (I) administered in said initial doses is about 500 mg to about 900 mg, wherein the total amount of said compound of Formula (I) administered through said exposure dose(s) is about 75 to about 299 mg per week, wherein the human subject is malaria-nave and Glucose-6-phosphate dehydrogenase (G6PD) normal, and wherein Formula (I) has the following structure, ##STR00013## 2. The method of claim 1, wherein the initial dose is administered once per day for three days. 3. The method of claim 1, wherein the exposure dose(s) are administered once per week. 4. The method of claim 1, wherein the initial dose is administered three or four times. 5. The method of claim 1, wherein the exposure dose is administered once per day. 6. The method of claim 1, wherein the exposure dose is administered one to seven times per week. 7. The method of claim 1, wherein the administration is sufficient to produce a C min serum or plasma concentration of at least about 80 ng/mL of said compound of Formula (I) prior to potential exposure to P. falciparum and to substantially maintain that serum or plasma concentration throughout to P. falciparum in more than 50% of individuals administered the given initial and exposure doses. 8. The method of claim 1, wherein the administration is sufficient to produce a C min serum or plasma concentration of at least about 80 ng/mL of the compound of Formula (I) prior to potential exposure to P. falciparum and to substantially maintain that serum or plasma concentration throughout potential exposure to P. falciparum in 95% or more of a population of subjects administered the given initial and exposure doses. 9. The method of claim 1, wherein the human subject is an adult. 10. The method of claim 1, wherein the human subject is a child. 11. The method of claim 1, wherein the compound, the salt, or the pharmaceutical composition is administered orally or sublingually. 12. The method of claim 1, wherein the pharmaceutically acceptable salt of a compound of Formula (I) is tafenoquine succinate. 13. The method of claim 1, wherein the pharmaceutically acceptable salt of a compound of Formula (I) is a salt of tafenoquine or a salt having the following structure, ##STR00014## 14. The method of claim 1, further comprising administering to the human subject one or more post-exposure dose(s) of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), within 1-10 days after the risk of continued exposure to P. falciparum has substantially ended, wherein each said post-exposure dose comprises 40 mg to about 399 mg of the compound of Formula (I). 15. The method of claim 14, wherein the post-exposure dose is administered one to three times. 16. The method of claim 1, wherein a C min serum or plasma concentration of at least about 80 ng/mL of the compound of Formula (I) is obtained prior to potential exposure to P. falciparum and is substantially maintained throughout potential exposure to P. falciparum in the human subject. 17. A kit comprising: a) one or more initial dose(s) of about 75 to about 299 mg of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I); b) a plurality of exposure doses of the compound, salt, or composition, wherein the total administered amount of the exposure dose is about 75 to 299 mg per week of the compound of Formula (I); c) instructions for taking said one or more initial dose(s), wherein at least the first initial dose is taken prior to potential exposure of the subject to P. falciparum, and for taking said exposure doses one or more times per week during potential exposure of the subject to P. falciparum, wherein Formula (I) has the following structure, ##STR00015## 18. The kit of claim 17, further comprising: d) one or more post-exposure dose(s) of about 40 to about 399 mg of the compound of Formula (I); wherein said instructions include taking said post-exposure dose(s) one or more times after potential exposure of the subject to P. falciparum. 19. The method of claim 1, wherein the initial doses is about 200 mg and administered once a day for three days, and wherein the exposure doses is about 200 mg and is administered once a week. 20. The method of claim 19, wherein the first exposure dose is administered seven days after the third initial dose. 21. The method of claim 14, wherein the initial doses is about 200 mg and administered once a day for three days, wherein the exposure doses is about 200 mg and is administered once a week, and wherein the post-exposure dose is administered once. 22. The method of claim 21, wherein the first exposure dose is administered seven days after the third initial dose, and wherein the post-exposure dose is administered seven days after the last exposure dose. 23. A method of prevention of symptomatic P. falciparum malaria in a human subject, comprising: a) administering to the human subject two or more primary doses of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), wherein at least the first primary dose is administered prior to potential exposure of the subject to P. falciparum; and b) administering to the human subject one or more post-exposure dose(s) of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), within 1-10 days after the risk of continued exposure to P. falciparum has substantially ended, wherein each said post-exposure dose comprises 75 mg to about 399 mg of the compound of Formula (I), wherein about 75 mg to about 399 mg of said compound of Formula (I) is administered in each of said two or more primary doses, wherein said primary doses are administered for about 1-21 days, wherein the human subject is malaria-nave and Glucose-6-phosphate dehydrogenase (G6PD) normal, and wherein Formula (I) has the following structure, ##STR00016## 24. The method of claim 23, wherein the primary dose is administered three times. 25. The method of claim 23, wherein the administration is sufficient to produce a C min serum or plasma concentration of at least about 80 ng/mL of said compound of Formula (I) prior to potential exposure to P. falciparum and to substantially maintain that serum or plasma concentration throughout to P. falciparum in more than 50% of individuals administered the given primary doses. 26. The method of claim 23, wherein the administration is sufficient to produce a C min serum or plasma concentration of at least about 80 ng/mL of the compound of Formula (I) prior to potential exposure to P. falciparum and to substantially maintain that serum or plasma concentration throughout potential exposure to P. falciparum in 95% or more of a population of subjects administered the given primary doses. 27. The method of claim 23, wherein the human subject is an adult. 28. The method of claim 23, wherein the human subject is a child. 29. The method of claim 23, wherein the compound, the salt, or the pharmaceutical composition is administered orally or sublingually. 30. The method of claim 23, wherein the pharmaceutically acceptable salt of a compound of Formula (I) is tafenoquine succinate. 31. The method of claim 23, wherein the pharmaceutically acceptable salt of a compound of Formula (I) is a salt of tafenoquine or a salt having the following structure, ##STR00017## 32. The method of claim 23, wherein a C min serum or plasma concentration of at least about 80 ng/mL of the compound of Formula (I) is obtained prior to potential exposure to P. falciparum and is substantially maintained throughout potential exposure to P. falciparum in the human subject. 33. A kit comprising: a) two or more primary doses of about 75 to about 399 mg of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I); b) one or more post-exposure dose(s) of about 75 to about 399 mg of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I); instructions for taking at least one primary dose prior to potential exposure of P. falciparum and taking said post-exposure dose(s) one or more times within 1-10 days after the risk of continued exposure to P. falciparum has substantially ended, wherein Formula (I) has the following structure, ##STR00018##