Regimens of tafenoquine for prevention of malaria in malaria-naïve subjects

Patent metadata

Field	Value
Publication number	US-11744828-B2
Application number	US-202117145530-A
Country	US
Kind code	B2
Filing date	Jan 11, 2021
Priority date	Dec 2, 2014
Publication date	Sep 5, 2023
Grant date	Sep 5, 2023

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.

First claim

What is claimed is:

1. A method of prevention of symptomatic P. falciparum malaria in a human subject, comprising:
a) administering to the human subject three loading doses of tafenoquine, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising tafenoquine, wherein each loading dose comprises about 200 mg of tafenoquine and is administered once a day for three days prior to potential exposure of the subject to P. falciparum;
b) administering to the human subject a maintenance dose of tafenoquine, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising tafenoquine once per week during potential exposure of the subject to P. falciparum , wherein each maintenance dose comprises about 200 mg of tafenoquine; and
c) administering to the human subject a post-exposure dose of tafenoquine, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising tafenoquine once seven days after the last maintenance dose, wherein said post-exposure dose comprises about 200 mg of tafenoquine;
wherein the first maintenance dose is administered seven days after the third loading dose;
wherein the administering of said a), b), and/or c) is with food; and
wherein the human subject is malaria-naïve and does not have a Glucose-6-phosphate dehydrogenase (G6PD) deficiency.

2. 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 said tafenoquine 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 loading and maintenance doses.

3. 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 tafenoquine 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 loading and maintenance doses.

4. The method of claim 1 , wherein the human subject is an adult.

5. The method of claim 1 , wherein the human subject is a child.

6. The method of claim 1 , wherein the compound, the salt, or the pharmaceutical composition is administered orally or sublingually.

7. The method of claim 1 , wherein the pharmaceutically acceptable salt of a compound of tafenoquine is tafenoquine succinate.

8. The method of claim 1 , wherein the pharmaceutically acceptable salt of a compound of tafenoquine is a salt of tafenoquine or a salt having the following structure,

9. The method of claim 1 , wherein a Cmin serum or plasma concentration of at least about 80 ng/mL of tafenoquine is obtained prior to potential exposure to P. falciparum and is substantially maintained throughout potential exposure to P. falciparum in the human subject.

10. A kit comprising:
a) three loading doses comprising about 200 mg each of tafenoquine, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising tafenoquine;
b) a plurality of maintenance doses of tafenoquine, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising tafenoquine, wherein each maintenance dose comprises about 200 mg of tafenoquine;
c) one post-exposure dose comprising about 200 mg of tafenoquine, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising tafenoquine;
d) instructions for taking said three loading doses once a day for three days, wherein at least the first loading dose is taken prior to potential exposure of the subject to P. falciparum ; for taking said maintenance doses once per week during potential exposure of the subject to P. falciparum , wherein the first maintenance dose is administered seven days after the third loading dose; and for taking said post-exposure dose seven days after the last exposure dose.

Assignees

• 60 Degrees Pharmaceuticals Llc
• Us Gov Sec Army

Inventors

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

Classifications

• A61K31/4706 Primary

  4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine · CPC title

• A61P33/06

  Antimalarials · CPC title

• C07D215/40

  attached in position 8 · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title