Regimens of tafenoquine for prevention of malaria in malaria-naive subjects
Inventors
Smith, Bryan L • Jones, John P • Shmuklarsky, Moshe • Balasubrahmanyam, Budda
Assignees
Tunnell Consulting Inc • 60 Degrees Pharmaceuticals Inc • United States Department of the Army
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Publication Number
US-10342791-B2
Publication Date
2019-07-09
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 pertains to methods and dosing regimens of tafenoquine, a compound of Formula (I), for the prevention of symptomatic malaria in malaria-naïve, Glucose-6-phosphate dehydrogenase (G6PD) normal human subjects. The methods involve the administration of an initial dose prior to potential exposure to Plasmodium species, exposure doses during potential exposure, and post-exposure doses after potential exposure, maintaining a serum or plasma concentration of at least 80 ng/mL of the compound to provide protection against symptomatic malaria.
The problem addressed is that existing tafenoquine regimens do not optimize the balance between tolerability and achieving therapeutic steady state concentrations sufficient to prevent symptomatic malaria in malaria-naïve, G6PD-normal individuals. Additionally, there was a lack of antimalarial drugs that could be administered once weekly, act against latent liver stages of P. vivax, and provide effective prophylaxis globally. The invention also solves the clinical need for dosing regimens that meet regulatory efficacy requirements of at least 95% protection while minimizing adverse events such as hemolytic anemia in G6PD-normal individuals.
The innovation includes specifying dosing regimens that maintain protective plasma concentrations of tafenoquine prior to, during, and for at least three weeks following potential exposure to Plasmodium. These regimens can include initial loading doses, exposure dosing with frequencies from daily to weekly, and post-exposure dosing schedules. The invention also encompasses kits comprising specified doses and instructions for administration. Further, pharmacokinetic modeling was employed to derive these regimens, optimize dosing amounts and intervals, and predict efficacy and tolerability. The invention also addresses dose adjustments by body weight and age to maintain protective plasma levels.
Claims Coverage
The patent includes one independent claim focused on a method for preventing symptomatic P. falciparum malaria in a human subject. The claim specifies dosing regimens involving initial and exposure doses of a compound of Formula (I), with defined dose ranges, dosing schedules, and pharmacokinetic targets.
Method of preventing symptomatic P. falciparum malaria with specified dosing regimen
Administering two or more initial doses of a compound of Formula (I) over 1-7 days prior to potential exposure, with each initial dose about 100 mg to 275 mg and a total initial dose of about 500 mg to 900 mg, followed by exposure doses of about 100 mg to 275 mg per week during potential exposure. The administration produces a Cmin serum or plasma concentration of at least about 80 ng/mL prior to exposure and maintains it in more than 50% of individuals, with the subject being malaria-naïve and G6PD-normal.
The claims focus on dosing regimens of tafenoquine for malaria prophylaxis that specify initial loading doses and exposure doses to achieve and maintain effective plasma concentrations for prevention of symptomatic malaria in malaria-naïve, G6PD-normal human subjects. The claims also cover varying dosing amounts, frequencies, and include kits with dosing instructions.
Stated Advantages
Tafenoquine’s long half-life enables weekly administration offering improved compliance compared to daily drugs.
The dosing regimens provide protection against symptomatic malaria by maintaining minimum plasma concentrations above therapeutic thresholds prior to, during, and after potential Plasmodium exposure.
Specified regimens balance tolerability and efficacy, minimizing adverse events such as hemolytic anemia in G6PD-normal subjects.
Tafenoquine can replace combinations of drugs used for prophylaxis and post-exposure prophylaxis, simplifying treatment with monotherapy.
Documented Applications
Prevention and prophylaxis of symptomatic malaria in malaria-naïve, G6PD-normal human subjects during and after potential exposure to Plasmodium species including P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi.
Post-exposure prophylaxis to maintain protective tafenoquine concentrations following travel or deployment to malaria-endemic regions.
Use in kits containing specified initial, exposure, and post-exposure doses with instructions for administration as malaria prophylaxis in travelers, military personnel, and other at-risk malaria-naïve populations.
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