Regimens of tafenoquine for prevention of malaria in malaria-naïve subjects
Inventors
DOW, Geoffrey S. • Smith, Bryan L. • Jones, John P. • Shmuklarsky, Moshe • Balasubrahmanyam, Budda
Assignees
60 Degrees Pharmaceuticals Inc • United States Department of the Army
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Publication Number
US-11744828-B2
Publication Date
2023-09-05
Expiration Date
2035-12-02
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.
Core Innovation
The invention provides novel dosing regimens for tafenoquine for the prevention of symptomatic malaria in malaria-naïve, Glucose-6-phosphate dehydrogenase (G6PD) normal human subjects. These regimens involve administering an initial dose of tafenoquine prior to potential exposure to Plasmodium species, followed by one or more exposure doses during potential exposure, and optionally one or more post-exposure doses after potential exposure. The invention specifies achieving and maintaining a serum or plasma concentration of at least about 80 ng/mL of tafenoquine prior to, during, and for at least three weeks following potential exposure to malaria.
The problem addressed is the lack of antimalarial drugs that can be administered once weekly, are effective worldwide, and are active against latent liver stages of Plasmodium vivax. Current regimens do not optimally balance tolerability with maintaining therapeutic steady state concentrations of tafenoquine to effectively prevent symptomatic malaria in malaria-naïve, G6PD normal individuals. Existing prophylactic methods require combinations of drugs and prolonged dosing periods to cover latent stages and potential late exposures, which are inconvenient and less effective or have safety concerns.
The invention also pertains to kits comprising specific dosing quantities of tafenoquine, providing instructions for administration related to timing, frequency, and amounts to ensure protective plasma levels. The dosing regimens can be adapted based on variables such as age, weight, and timing relative to exposure, and are supported by pharmacokinetic and pharmacodynamic modeling incorporating data from multiple clinical studies. The methods enable achieving required regulatory efficacy benchmarks, such as 95% effectiveness in prevention of symptomatic malaria in malaria-naïve, G6PD-normal subjects.
Claims Coverage
The patent contains one independent claim related to a method of preventing symptomatic P. falciparum malaria using specific dosing regimens of tafenoquine in malaria-naïve, G6PD-normal human subjects.
Specific dosing regimen for malaria prophylaxis
Administering three loading doses of about 200 mg tafenoquine once daily for three days prior to potential exposure, followed by weekly maintenance doses of about 200 mg during potential exposure, and a post-exposure dose of about 200 mg administered one week after the last maintenance dose.
Administration in food and subject conditions
The method requires administration with food and is specifically for malaria-naïve subjects without G6PD deficiency; the method applies to adults and children and includes oral or sublingual routes of administration.
Achieving protective plasma concentration levels
The dosing regimen is sufficient to produce and maintain a Cmin serum or plasma concentration of at least about 80 ng/mL tafenoquine prior to and throughout potential exposure in more than 50%, and in some embodiments 95% or more, of individuals.
Pharmaceutically acceptable salt forms and kit composition
Use of pharmaceutically acceptable salts of tafenoquine, including tafenoquine succinate, is claimed. The invention also claims kits comprising loading doses, maintenance doses, post-exposure doses, and instructions for regimen administration as specified.
The claims cover the method of malaria prevention in malaria-naïve, G6PD-normal humans using a defined tafenoquine dosing schedule with loading, maintenance, and post-exposure doses designed to maintain protective plasma concentrations, including forms of tafenoquine salts and kits containing doses and instructions for use.
Stated Advantages
Tafenoquine's long half-life enables weekly administration, improving compliance relative to daily prophylactic drugs.
The dosing regimens achieve and maintain plasma concentrations above a threshold (80 ng/mL) required for protection against symptomatic malaria in malaria-naïve, G6PD-normal individuals.
The invention provides a single drug solution effective against all Plasmodium species, including the latent liver stages of P. vivax, which current drugs do not fully address.
The invention optimizes tolerability by balancing dose size and frequency to reduce adverse events while maintaining efficacy.
Post-exposure dosing regimens provided reduce the risk of malaria from late exposure or latent liver stages, improving convenience over current multiple-drug regimens.
Documented Applications
Prevention of symptomatic malaria caused by any species of human Plasmodium including P. falciparum, P. vivax, P. ovale, P. knowlesi, and P. malariae in malaria-naïve, G6PD-normal human subjects.
Prophylaxis and post-exposure prophylaxis of malaria in travelers or deployed military personnel entering malaria-endemic regions.
Use in malaria-naïve adult and pediatric populations to provide protection before, during, and after potential exposure to Plasmodium species.
Development of pharmaceutical kits that provide appropriate dosing to individuals based on body weight, age, and exposure timing for effective malaria prevention.
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