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US-12616689-B2 - Regimens of tafenoquine for prevention of malaria in malaria-naive subjects

US12616689B2US 12616689 B2US12616689 B2US 12616689B2US-12616689-B2

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.

Inventors

  • Geoffrey S. DOW
  • Bryan L. Smith
  • John P. Jones
  • Moshe Shmuklarsky
  • Budda Balasubrahmanyam

Assignees

  • 60 DEGREES PHARMACEUTICALS, INC.
  • THE GOVERNMENT OF THE UNITED STATES AS REPRESENTED BY THE SECRETARY OF THE ARMY

Dates

Publication Date
20260505
Application Date
20230830

Claims (20)

  1. 1 . A method of prevention of symptomatic 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 at least one species of Plasmodium ; 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 at least one species of Plasmodium; 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 at least one species of Plasmodium is P. vivax, P. falciparum, P. ovale, P. knowlsi, P. malariae, and/or P. berghei, wherein the human subject is malaria-naïve and Glucose-6-phosphate dehydrogenase (G6PD) normal, and wherein Formula (I) has the following structure,
  2. 2 . The method of claim 1 , wherein the initial dose is administered once per day for three days.
  3. 3 . The method of claim 1 , wherein the exposure dose(s) are administered once per week.
  4. 4 . The method of claim 1 , wherein the initial dose is administered three or four times.
  5. 5 . The method of claim 1 , wherein the exposure dose is administered once per day.
  6. 6 . The method of claim 1 , wherein the exposure dose is administered one to seven times per week.
  7. 7 . 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 at least one species of Plasmodium and is substantially maintained throughout potential exposure to at least one species of Plasmodium in the human subject.
  8. 8 . The method of claim 1 , wherein the human subject is an adult.
  9. 9 . The method of claim 1 , wherein the compound, the salt, or the pharmaceutical composition is administered orally or sublingually.
  10. 10 . The method of claim 1 , wherein the pharmaceutically acceptable salt of a compound of Formula (I) is tafenoquine succinate.
  11. 11 . 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,
  12. 12 . 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 one week after the risk of continued exposure to at least one species of Plasmodium has substantially ended, wherein each said post-exposure dose comprises 40 mg to about 399 mg of the compound of Formula (I).
  13. 13 . The method of claim 12 , wherein the post-exposure dose is administered one to three times.
  14. 14 . 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.
  15. 15 . The method of claim 14 , wherein the first exposure dose is administered seven days after the third initial dose.
  16. 16 . The method of claim 12 , 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.
  17. 17 . The method of claim 16 , 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.
  18. 18 . A method of prevention of symptomatic 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 at least one species of Plasmodium ; 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 one week after the risk of continued exposure to at least one species of Plasmodium 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 at least one species of Plasmodium is P. vivax, P. falciparum, P. ovale, P. knowlsi, P. malariae, and/or P. berghei, wherein the human subject is malaria-naïve and Glucose-6-phosphate dehydrogenase (G6PD) normal, and wherein Formula (I) has the following structure,
  19. 19 . The method of claim 18 , wherein the primary dose is administered three times.
  20. 20 . The method of claim 18 , wherein the human subject is an adult.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a Continuation application of U.S. patent application Ser. No. 17/145,530, filed on Jan. 11, 2021, and issued as U.S. Pat. No. 11,744,828 on Sep. 5, 2023, which is a Continuation application of U.S. patent application Ser. No. 16/504,533, filed on Jul. 8, 2019, and issued as U.S. Pat. No. 10,888,558 on Jan. 12, 2021, which is Continuation application of U.S. patent application Ser. No. 15/532,280, filed on Jun. 1, 2017, and issued as U.S. Pat. No. 10,342,791 on Jul. 9, 2019, which is a U.S. National Stage Application pursuant to 35 U.S.C. § 371 of International Patent Application PCT/US2015/063425, filed on Dec. 2, 2015, and published as WO 2016/089995 on Jun. 9, 2016, which claims priority to U.S. Provisional Patent Application 62/086,355, filed on Dec. 2, 2014, all of which are incorporated herein by reference in their entireties for all purposes. BACKGROUND OF THE INVENTION There are 217,000,000 cases of malaria and 627,000 deaths annually in tropical countries (http://www.who.int/gho/malaria/epidemic/en/). The disease is caused by five species of Plasmodium: P. vivax, P. falciparum, P. ovale, P. knowlsi, and P. malariae, all protozoan parasites transmitted by mosquitoes. The symptoms of malaria are caused by the amplification of the parasite in red blood cells, after an initial cycle of replication in the liver. Individuals who reside in areas of heavy malaria transmission develop a partial immunity to the disease after repeated exposure to the parasites which prevents the development of symptoms in response to new infection. Travelers from temperate countries, who have not been exposed to malaria, are termed ‘non-immune individuals’ or ‘marlaria-naïve,’ are at high risk of severe clinical disease and death if they contract malaria during a visit to a tropical country. These individuals, to prevent malaria, are often administered a course of ‘prophylactic’ antimalarial drugs (e.g., mefloquine, chloroquine, doxycycline, primaquine, or atovaquone-proguanil) that maintain a minimum protective level of active drug in their blood during travel. Upon return, these individuals must take a 14-day course of primaquine to kill the latent stages of P. vivax and P. ovale and/or continue to maintain active blood levels of drug to suppress any remaining viable blood stage parasites of all species. An appropriate prophylactic antimalarial drug, dosed in a manner to maintain therapeutic levels indefinitely, could protect a non-immune individual from contracting symptomatic malaria, caused by any human species of Plasmodia, during the period of exposure to malaria vectors if it killed (i) 100% of developing liver schizonts upon entry into the liver after a mosquito bite, or (ii) 100% of merozoites upon their entry from the liver into the blood stream. In the special case of relapsing malaria parasites such as P. vivax and P. ovale, a hypothetical malaria drug would have to exhibit any of the aforementioned inhibitory properties, plus, in addition, kill developing liver schizonts after the activation of latent hypnozoites. However, in order to maintain high levels of clinical protective efficacy, 100% killing of merozoites emerging from the liver is an absolute requirement if a drug does not kill 100% of developing liver schizonts (originating from either sporozoites or hypnozoites). Tafenoquine is an 8-aminoquinoline analog of primaquine, the approved drug that is primarily used to eliminate the latent liver stages of P. vivax (Shanks and Edstein 2005). Tafenoquine is known to exhibit a potent inhibitory effect on developing liver schizonts. Tafenoquine is generally presumed to also exhibit antihypnocytocidal effects against P. vivax. The inhibitory effect of tafenoquine on asexual blood stage parasites is also known. The drug is active against the blood stages of P. falciparum in vitro, P. berghei in mice in vivo, and cured both chloroquine sensitive and resistant P. vivax infections in Aotus monkeys. Tafenoquine is being developed for the complete, also known as radical, cure of P. vivax malaria, and for the chemoprophylaxis (i.e., prevention) of malaria in malaria-naïve travelers. Structural features installed to block metabolic sites on the core 8-aminoquinoline scaffold provide the drug with an extremely long half-life (weeks) relative to primaquine (hours). Tafenoquine's long half-life makes it suitable for weekly administration, making it an ideal replacement for other weekly drugs such as chloroquine (limited efficacy due to resistance) and mefloquine (no longer commonly prescribed due to its association with adverse neurologic effects). The capacity for weekly administration (better compliance) and utility against the dormant, hypnozoites of P. vivax (14-day treatment with primaquine not required) confer superior utility to tafenoquine relative to daily prophylactic drugs such as doxycycline and atovaquone-proguanil. Glucose-6-phosphate dehydrogenase d