Claims for Patent: 10,342,791

Summary for Patent: 10,342,791

Title:	Regimens of tafenoquine for prevention of malaria in malaria-naive subjects
Abstract:	Methods of prevention of symptomatic malaria in a malaria-naïve, 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-naïve 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-naïve, G6PD-normal subjects.
Inventor(s):	Bryan L Smith, John P Jones, Moshe Shmuklarsky, Budda Balasubrahmanyam
Assignee:	Tunnell Consulting Inc , 60 Degrees Pharmaceuticals Inc , United States Department of the Army
Application Number:	US15/532,280
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) over a period of 1-7 days, 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 100 mg to about 275 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 100 mg to about 275 mg per week, wherein the administration is sufficient to produce a Cmin 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, wherein the human subject is malaria-nave and Glucose-6-phosphate dehydrogenase (G6PD) normal, and wherein Formula (I) has the following structure, 2. The method of claim 1, wherein the amount of the compound of Formula (I) administered in each of said two or more initial doses is about 200 mg and said initial doses are administered once per day for three days, and wherein the total amount of the compound of Formula (I) administered through the exposure dose is about 200 mg once per week. 3. The method of claim 1, wherein the exposure dose is a daily dose of 25 mg. 4. The method of claim 1, wherein the initial doses are administered once per day for three days. 5. The method of claim 4, wherein the amount of the compound of Formula (I) administered in each of said initial doses is about 200 mg. 6. The method of claim 1, wherein the total amount of the compound of Formula (I) administered in the exposure dose(s) is about 200 mg per week. 7. The method of claim 1, wherein the exposure dose(s) are administered once per week. 8. The method of claim 1, wherein the initial dose is about 165 mg, about 180 mg, about 210 mg, about 240 mg, or about 270 mg of the compound of Formula (I) administered once per day for three days, and wherein the total administered amount of the exposure dose is about 100 mg per week, 150 mg per week, about 165 mg per week, about 180 mg per week, about 210 mg per week, or about 270 mg per week of the compound of Formula (I). 9. The method of claim 1, wherein the exposure dose is a daily dose of about 30 mg of the compound of Formula (I). 10. The method of claim 1, wherein the initial dose is administered three times. 11. The method of claim 1, wherein the exposure dose is administered once per day. 12. The method of claim 1, wherein the subject has low body weight or age, wherein the amount of the compound of Formula (I) in each of said two or more initial doses comprises about 1-5 mg/kg of body weight each day, and wherein the total weekly amount of the compound of Formula (I) in the exposure dose(s) comprises about 1-5 mg/kg of body weight each week. 13. The method of claim 1, wherein the combined total amount of the compound of Formula (I) administered in the two or more initial doses does not exceed about 600 mg, and the total amount of the compound of Formula (I) administered in the exposure doses does not exceed about 270 mg per week. 14. The method of claim 13, wherein the initial dose is about 80-100 mg of the compound of Formula (I) administered once per day for six days, and the exposure dose is about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg of the compound of Formula (I) administered once per day. 15. The method of claim 1, wherein the administration is sufficient to produce a Cmin 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. 16. The method of claim 1, wherein the human subject is an adult. 17. The method of claim 1, wherein the human subject is a child. 18. The method of claim 1, wherein the compound, the salt, or the pharmaceutical composition is administered orally or sublingually. 19. The method of claim 1, wherein the total combined amount of the compound of Formula (I) administered in said two or more initial doses is about 525-585 mg. 20. A kit comprising: a) two or more initial dose(s) of about 100 to about 270 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 amount of the exposure dose to be administered is about 100 to about 275 mg per week of the compound of Formula (I); and c) instructions for taking said two or more initial doses, 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, 21. The method of claim 1, wherein the pharmaceutically acceptable salt of a compound of Formula (I) is tafenoquine succinate. 22. 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, 23. The method of claim 1, wherein the exposure dose is administered one to seven times per week. 24. The method of claim 1, wherein each of the two or more initial doses is about 150 mg of the compound of Formula (I), wherein the initial doses are administered four times, and wherein the exposure doses are about 150 mg administered weekly. 25. The method of claim 1 further comprising administering to the human subject one of 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 150 mg to about 300 mg of the compound of Formula (I). 26. The method of claim 25, wherein the post-exposure dose is about 150 mg of the compound of Formula (I) and is administered once. 27. The method of claim 25, wherein the post-exposure dose is about 200 mg of the compound of Formula (I) and is administered once. 28. The method of claim 25, wherein the total combined post-exposure dose is about 300 mg of the compound of Formula (I) that is administered in one to three separate post-exposure doses. 29. The method of claim 25, wherein the total combined post-exposure dose is about 300 mg of the compound of Formula (I) that is administered in two separate post-exposure doses. 30. The method of claim 25, wherein each of the two or more initial doses is about 200 mg of the compound of Formula (I), wherein the initial doses are administered once per day for three days prior to potential exposure, wherein the exposure dose is about 200 mg of the compound of Formula (I) administered once per week during potential exposure, and wherein the post-exposure dose is about 200 mg of the compound of Formula (I) administered once. 31. The method of claim 1, wherein a Cmin 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.