Novel Regimens of Tafenoquine for Prevention of Malaria in Malaria-Naive Subjects
20170360768 · 2017-12-21
Assignee
Inventors
- Bryan L Smith (Chevy Chase, MD, US)
- John Paul Jones (Richmond, VA, US)
- Moshe Shmuklarsky (Bethesda, MD, US)
- Budda Balasubrahmanyam (Richmond, VA, US)
Cpc classification
Y02A50/30
GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
International classification
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.
##STR00001##
Claims
1. A method of prevention of symptomatic malaria in a human subject after potential exposure of the subject to mosquitoes carrying malaria, the method comprising: a) administering to the human subject a primary dose of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I); and b) administering to the human subject a post-exposure dose of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), wherein said post-exposure dose is administered after administration of said primary dose and after potential exposure to at least one species of Plasmodium, wherein said primary dose comprises one or more individual doses sufficient to achieve a serum or plasma concentration of at least about 80 ng/mL of a compound of Formula (I), and wherein said post-exposure dose comprises one or more individual doses sufficient to maintain for at least three weeks after potential exposure of the subject to at least one species of Plasmodium, a serum or plasma concentration of at least about 80 ng/mL of a compound of Formula (I), wherein the human subject is malaria-naïve and Glucose-6-phosphate dehydrogenase (G6PD) normal, and wherein Formula (I) has the following structure, ##STR00013##
2. The method of claim 1, wherein the serum or plasma concentration of at least about 80 ng/mL of a compound of Formula (I) is measured in the individual human subject.
3. The method of claim 1, wherein the serum or plasma concentration of at least about 80 ng/mL of a compound of Formula (I) is measured as the median Cmin of a population of subjects administered the given dose of a compound of Formula (I).
4. The method of claim 1, wherein each primary dose is about 75 to about 299 mg and wherein each post-exposure dose is about 75 to about 299 mg.
5. The method of claim 4, wherein the post-exposure dose comprises three individual doses.
6. The method of claim 5, wherein the individual post-exposure doses are given on three consecutive days.
7. The method of claim 5, wherein the individual post-exposure doses are given once per week for three consecutive weeks.
8. A method of prevention of symptomatic malaria in a human subject, comprising: a) administering to the human subject an initial dose of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), one or more times prior to potential exposure of the subject to at least one species of Plasmodium; b) administering to the human subject an exposure dose of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), one or more times per week during potential exposure of the subject to at least one species of Plasmodium; and c) administering to the human subject a post-exposure dose of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), one or more times after potential exposure of the subject to at least one species of Plasmodium, wherein a serum or plasma concentration of at least about 80 ng/mL of Formula (I) is attained prior to potential exposure, maintained during potential exposure, and maintained for at least three weeks after potential exposure of the subject to at least one species of Plasmodium, wherein the human subject is malaria-naïve and Glucose-6-phosphate dehydrogenase (G6PD) normal, and wherein Formula (I) has the following structure, ##STR00014##
9. The method of claim 8, wherein each said initial dose is about 75 to about 299 mg, wherein the total administered amount of the exposure dose is about 75 to about 299 mg per week, and wherein each said post-exposure dose is about 75 to about 299 mg.
10. The method of claim 9, wherein the total administered amount of the exposure dose is between about 75 and about 175 mg per week.
11. The method of claim 9, wherein the exposure dose is a daily dose of 25 mg.
12. The method of claim 8, wherein the initial dose is administered once per day for three days prior to potential exposure, and the post-exposure does is administered once per week for three weeks after potential exposure.
13. The method of claim 12, wherein the initial dose is about 150 mg, the total administered amount of the exposure dose is about 150 mg per week, and the post-exposure dose is about 150 mg.
14. The method of claim 12, wherein the initial dose is between about 75 and about 175 mg, the total administered amount of exposure dose is between about 75 and about 175 mg per week, and the post-exposure dose is between about 75 and about 175 mg.
15. The method of claim 8, wherein the initial dose is administered once per day for three days prior to potential exposure, and the post-exposure dose is administered once per day for three days.
16. The method of claim 15, wherein the initial dose is about 150 mg, the total administered amount of the exposure dose is about 150 mg per week, and the post-exposure dose is about 150 mg.
17. The method of claim 15, wherein the initial dose is between about 75 and about 175 mg, the total administered amount of exposure dose is between about 75 and about 175 mg, and the post-exposure dose is between about 75 and about 175 mg.
18. The method of claim 8, wherein the initial dose is administered three times and the post-exposure dose is administered once per week for three weeks.
19. The method of claim 18, wherein the initial dose is about 150 mg, the total administered amount of the exposure dose is about 150 mg per week, and the post-exposure dose is about 150 mg.
20. The method of claim 18, wherein the initial dose is between about 75 and about 175 mg, the total administered amount of exposure dose is between about 75 and about 175 mg per week, and the post-exposure dose is between about 75 and about 175 mg.
21. The method of claim 8, wherein the initial dose is administered three times and the post-exposure dose is administered once per day for three days.
22. The method of claim 21, wherein the initial dose is about 150 mg, the total administered amount of the exposure dose is about 150 mg per week, and the post-exposure dose is about 150 mg.
23. The method of claim 21, wherein the initial dose is between about 75 and about 175 mg, the total administered amount of exposure dose is between about 75 and about 175 mg per week, and the post-exposure dose is between about 75 and about 175 mg.
24. The method of claim 8, wherein the subject has low body weight or age and the compound of Formula (I) is administered in a suitable formulation of about 75 to about 299 mg or about 1-5 mg/kg.
25. The method of claim 8, wherein the total amount of the initial dose administered does not exceed about 600 mg prior to potential exposure of at least one species of Plasmodium, and the total administered amount of the exposure dose does not exceed about 200 mg per week.
26. The method of claim 25, wherein the initial dose is about 40-100 mg administered once per day for six days, and the exposure dose is about 10 mg, about 12 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg administered once per day.
27. The method of claim 25, wherein the initial dose is about 100 mg administered once per day for six days, and the exposure dose is about 100 mg administered every four days.
28. The method of claim 8, wherein the total pre-exposure dose is about 240-600 mg, and the exposure dose does not exceed 299 mg per week, and wherein the exposure dose is about 10 mg, about 12, mg, about 15 mg, about 20 mg, about 30 mg, about 35 mg, about 40 mg, or about 42 mg administered once per day.
29. The method of claim 8, wherein the serum or plasma concentration of at least about 80 ng/mL of a compound of Formula (I) is measured in the individual human subject.
30. The method of claim 8, wherein the Cmin serum or plasma concentration of at least about 80 ng/mL of a compound of Formula (I) is measured as the median Cmin of a population of subjects administered the given dose of a compound of Formula (I).
31. The method of claim 1 or 8, wherein the human subject is an adult or a child.
32. The method of claim 1 or 8, wherein the compound of Formula (I) is tafenoquine.
33. The method of claim 1 or 8, wherein the pharmaceutical salt thereof is a salt of tafenoquine or a salt having the following structure, ##STR00015##
34. The method of claim 1 or 8, wherein the compound, or the pharmaceutical composition, is administered orally or sublingually.
35. The method of claim 1 or 8, wherein the species of Plasmodium comprises at least one species selected from P. vivax, P. malariae, P. ovale, P. falciparum, and P. knowlesi.
36. A method of prevention of symptomatic malaria in a human subject, comprising: a) administering to the human subject an initial dose of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), one or more times prior to potential exposure of the subject to at least one species of Plasmodium, wherein each said initial dose is between about 75 and about 299 mg; and b) administering to the human subject an exposure dose of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), one or more times per week during potential exposure of the subject to at least one species of Plasmodium, wherein the total administered amount of the exposure dose is between about 175 and 195 mg per week; wherein the human subject is malaria-naïve and Glucose-6-phosphate dehydrogenase (G6PD) normal, and wherein Formula (I) has the following structure, ##STR00016##
37. The method of claim 36, wherein a serum or plasma concentration of at least about 80 ng/mL of a compound of Formula (I) is attained prior to potential exposure, maintained during potential exposure, and maintained for at least three weeks after potential exposure of the subject to at least one species of Plasmodium.
38. The method of claim 37, wherein the serum or plasma concentration of at least about 80 ng/mL of a compound of Formula (I) is measured in the individual human subject.
39. The method of claim 37, wherein the Cmin serum or plasma concentration of at least about 80 ng/mL of a compound of Formula (I) is measured as the median Cmin of a population of subjects administered the given dose of a compound of Formula (I).
40. The method of claim 36, wherein the initial dose comprises a total amount of about 525-585 mg of the compound of Formula (I).
41. A method of prevention of symptomatic malaria in a human subject, comprising: c) administering to the human subject an initial dose of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), one or more times prior to potential exposure of the subject to at least one species of Plasmodium, wherein the total pre-exposure dose exceeds about 500 mg; and d) administering to the human subject an exposure dose of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), two or more times per week during potential exposure of the subject to at least one species of Plasmodium, wherein the total administered amount of the exposure dose is at least about 175 mg per week; wherein the human subject is malaria-naïve and Glucose-6-phosphate dehydrogenase (G6PD) normal, and wherein Formula (I) has the following structure, ##STR00017##
42. The method of claim 41, wherein a serum or plasma concentration of at least about 80 ng/mL of a compound of Formula (I) is attained prior to potential exposure, maintained during potential exposure, and maintained for at least three weeks after potential exposure of the subject to at least one species of Plasmodium.
43. The method of claim 42, wherein the serum or plasma concentration of at least about 80 ng/mL of a compound of Formula (I) is measured in the individual human subject.
44. The method of claim 42, wherein the Cmin serum or plasma concentration of at least about 80 ng/mL of a compound of Formula (I) is measured as the median Cmin of a population of subjects administered the given dose of a compound of Formula (I).
45. A kit comprising: a) one or more initial dose(s) of about 40 to about 299 mg of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I); b) multiple exposure doses wherein the total administered amount of the exposure dose is about 75 to 299 mg per week of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I); c) one or more post-exposure dose of about 40 to about 299 mg of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I); and d) instructions for taking said initial dose one or more times prior to potential exposure of the subject to at least one species of Plasmodium, taking said exposure dose one or more times per week during potential exposure of the subject to at least one species of Plasmodium, and for taking said post-exposure dose one or more times after potential exposure of the subject to at least one species of Plasmodium, wherein Formula (I) has the following structure, ##STR00018##
46. A kit comprising: a) one or more primary dose(s) of at least three initial dose(s) of about 40 to about 299 mg of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I); b) one or more post-exposure dose of about 40 to about 299 mg of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I); and c) instructions for taking said primary dose one or more times prior to taking said post-exposure dose one or more times after potential exposure of the subject to at least one species of Plasmodium, wherein Formula (I) has the following structure, ##STR00019##
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0048] The foregoing will be apparent from the following more particular description of example embodiments of the invention, as illustrated in the accompanying drawings.
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[0056] Based on these profiles drawn in
[0057] (i) Modification of the invention depicted in
[0058] (ii) Modification of the invention depicted in
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DETAILED DESCRIPTION OF THE INVENTION
[0061] A description of example embodiments of the invention follows.
Definitions
[0062] All definitions of substituents set forth below are further applicable to the use of the term in conjunction with another substituent. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
[0063] As used herein, the singular forms “a,” “and,” and “the” include plural reference unless the context clearly dictates otherwise. Additionally, the term “comprises” is intended to include embodiments where the method, apparatus, composition, etc., consists essentially of and/or consists of the listed steps, components, etc. Similarly, the term “consists essentially of” is intended to include embodiments where the method, apparatus, composition, etc., consists of the listed steps, components, etc.
[0064] As used herein, the term “about” refers to a number that differs from the given number by less than 10%. In other embodiments, the term “about” indicates that the number differs from the given number by less than 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.
[0065] As used herein, “Cmin” refers to the minimum concentration that a drug achieves after the drug has been administered and prior to the administration of a second or additional dose. Further, “Cmax,” as used herein, refers to the maximum concentration.
[0066] As used herein, “exposure dose” refers to the dose(s) which is administered during potential exposure to at least one species of Plasmodium. Further, “maintenance dose” and “exposure dose” have the same meaning and are used interchangeably herein.
[0067] As used herein, “G6PD-normal” refers to human subjects with normal levels of glucose-6-phosphate dehydrogenase. Normal levels of G6PD may be determined by approved laboratory tests using validated methodology known to those skilled in the art.
[0068] As used herein, “initial dose” refers to the dose(s) which is administered prior to potential exposure to at least one species of Plasmodium. Further, “loading dose,” “initial dose,” and “pre-exposure dose” have the same meaning and are used interchangeably herein.
[0069] As used herein, a “malaria-naïve” subject is defined operationally as referring to a human child or adult subject, for whom a physician, nurse, or other qualified medical or public health professional may reasonably assume has not previously experienced an episode of symptomatic malaria based on a review of travel and/or medical history.
[0070] As used herein, “non-immune” refers to individuals who have had insufficient prior exposure to malaria to render them immune to the signs and symptoms of malaria when malaria parasites are confirmed by microscopy to be present. A non-immune individual may also be malaria-naïve if they have never been exposed to malaria before.
[0071] “Pharmaceutically acceptable carrier” means non-therapeutic components that are of sufficient purity and quality for use in the formulation of a composition of the invention that, when appropriately administered, typically do not produce an adverse reaction, and that are used as a vehicle for a drug substance (e.g., a compound of Formula (I)).
[0072] As used herein, “post-exposure dose” refers to the dose(s) which is administered after potential exposure to at least one species of Plasmodium.
[0073] As used herein, “post-exposure malaria” refers to malaria which is caused from the latent stages of at least one species of Plasmodium and/or wherein the symptoms of malaria begin after potential exposure or travel.
[0074] As used herein, “potential exposure,” “deployment,” and “travel” refers to the period of time between entry and exit of a human subject into/from a geographical area where they may be exposed to Anopheles mosquitoes harboring human malaria parasites.
[0075] As used herein, “primary dose” refers to the dose(s) which is administered prior to the post-exposure dose and may be administered prior to or during potential exposure to at least one species of Plasmodium, or after potential exposure but prior to becoming symptomatic.
[0076] As used herein, “semi-immune” refers to a resident of a malaria-endemic country who, due to many prior exposures to symptomatic malaria, has developed a partial immunity that usually results in a lack of signs and symptoms of clinical malaria when the presence of malaria parasites in the blood is confirmed by microscopy.
[0077] As used herein, Formula (I) is “tafenoquine” and also includes the following references to tafenoquine: Tafenoquine, Tafenoquine [INN:BAN], Etaquine, UNII-262P8GS9L9, C24H28F3N303, CHEBI:172505, AIDS006901, 106635-81-8 (maleate), AIDS-006901, CID115358, SB-252263, WR 238605, WR-238605, WR238605, LS-172012, 1,4-Pentanediamine, N4-(2,6-dimethoxy-4-methyl-5-(3-(trifuluromethyl)phenoxy)-8-quinolinyl-, 106635-80-7, N(4)-(2,6-Dimethoxy-4-methyl-5-((3-trifluromethyl)phenoxy)-8-quinolinyl)-1,4-pentanediamine, N-[2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl]diamine, (4-Amino-1-methylbutyl) {2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy](8-quinoly)}amine, (R)—N3-(2,6-Dimethoxy-4-methyl-5-(3-trifluoromethyl)phenoxy)quinolin-8-yl)pentane-1,4-diamine, (RS)—N(sup 3)-(2,6-Dimethoxy-4-methyl-5-(3-trifluoro-methylphenoxy)quinolin-8-yl)pentane-1,4-diamine.
Dosing Regimen
[0078] In certain embodiments, dosing is selected to provide a serum or plasma tafenoquine concentration of at least about 80 ng/mL. Doses above 400 mg are often not well tolerated (e.g., the dose may cause gastrointestinal issues or toxicity) by adult subjects regardless of the subjects' G6PD status. In G6PD normal adult subjects, doses of up to 400 mg may be well tolerated, while in G6PD deficient subjects, doses of 300 mg or more may not be well tolerated.
[0079] In one aspect, the method comprises administering to the human subject one or more initial dose(s) of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), for example, at least once per day for three days, once per week for one to three weeks, or at least three times, prior to potential exposure of at least one species of Plasmodium, wherein each said initial dose is about 75 to about 299 mg, followed by administering to the human subject an exposure dose of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), one or more times per week, for example once per day, once every two to six days, or once per week during potential exposure of at least one species of Plasmodium, wherein the total administered amount of the exposure dose is about 75 to about 299 mg per week, followed by administering to the human subject a post-exposure dose of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), for example, at least once per day for three days, once per week for three weeks, or at least three times, after potential exposure of at least one species of Plasmodium; wherein each said post-exposure dose is about 75 to about 299 mg, wherein the human subject is malaria-naïve and Glucose-6-phosphate dehydrogenase (G6PD) normal, and wherein Formula (I) has the following structure,
##STR00011##
Alternative name:-[2,6-Dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl]pentane-1,4-diamine.
[0080] A pharmaceutically acceptable salt thereof, including,
##STR00012##
CAS number for above identified structure of succinate salt 106635-81-8.
[0081] The compounds of the invention useful for practicing the methods described herein may possess one or more chiral centers and so exist in a number of stereoisomeric forms. All stereoisomers and mixtures thereof are included in the scope of the present invention. Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilizing methods known to those skilled in the art. In addition, chiral intermediate compounds may be resolved and used to prepare chiral compounds of the invention.
[0082] The compounds described herein may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included in the scope of the present invention.
[0083] The compounds of the present invention can be administered as the free base or as a pharmaceutically acceptable salt. For example, an acid salt of a compound of the present invention containing an amine or other basic group can be obtained by reacting the compound with a suitable organic or inorganic acid, resulting in pharmaceutically acceptable anionic salt forms. Examples of anionic salts include the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estotate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts. In one embodiment, the compound of Formula (I) is a hydrochloride salt.
[0084] The invention is also directed to methods of the invention using a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. The disclosed compounds of Formula (I), or a pharmaceutically available salt thereof can be administered to the subject in conjunction with an acceptable pharmaceutical carrier or diluent as part of a pharmaceutical composition for prophylaxis of malaria, and according to any of the dosing regimens described herein. Formulation of the compound to be administered will vary according to the route of administration selected (e.g., solution, emulsion, capsule). Suitable pharmaceutical carriers may contain inert ingredients which do not interact with the compound. Standard pharmaceutical formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. Suitable pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg/ml benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer's-lactate and the like. Methods for encapsulating compositions (such as in a coating of hard gelatin or cyclodextran) are known in the art (Baker, et al., “Controlled Release of Biological Active Agents”, John Wiley and Sons, 1986).
[0085] In one embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable carrier or diluent and a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
[0086] The methods of the invention prevent a human subject from having malaria. As used herein “preventing” or “prevention” refers to obtaining desired pharmacological and/or physiological effects. The effect can include achieving, partially or substantially, one or more of the following results: partially or totally avoiding the disease, disorder, or syndrome; or partially or totally avoiding clinical symptom or indicator associated with the disease, disorder, or syndrome.
[0087] The human subject may be an adult or a child. As used herein, a “child” refers to a human subject who is between the ages of 1 day to 17 years, 364 days of age inclusive. The term “adult” refers to a human subject who is 18 years of age or older.
[0088] Example embodiments of initial doses, exposure doses, and post-exposure doses in a human subject are shown in Table 1:
TABLE-US-00001 TABLE 1 Dosing Regimen for a Human Subject Initial dose Embodiment (mg).sup.1 Exposure dose (mg).sup.2 Post-exposure dose (mg) .sup.3 1 40 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 2 50 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 3 75 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 4 100 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 5 125 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 6 150 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 7 175 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 8 190 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 9 200 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 10 210 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 11 225 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 12 250 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 13 275 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 14 300 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 15 325 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 16 350 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 17 375 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 18 399 75, 100, 125, 150, 175, 190, 75, 100, 125, 150, 175, 190, 200, 210, 225, 250, 275, 200, 210, 225, 250, 275, 300, 300, 325, 350, 375, or 399 325, 350, 375, or 399 19 75, 100, 75, 100, 125, or 150 75, 100, 125, 150, 175, 190, 125, 150, 200, 210, 225, 250, 275, 300, 175, 190, 325, 350, 375, or 399 200, 210, 225, 250, 275, 300, 325, 350, 375, or 399 20 75, 100, 175, 190, 200, 210, 225, None 125, 150, 250, 275, 300, 325, 350, 175, 190, 375, or 399 200, 210, 225, 250, 275, 300, 325, 350, 375, or 399 .sup.1Initial dosing prior to potential exposure to at least one species of Plasmodium for a) once per day for up to ten days, b) once per week for three weeks, c) once per week for one week, d) at least three times, or e) divided doses thereof, including once every four days. .sup.2Exposure dosing periodically during potential exposure to at least one species of Plasmodium for a) once per week during period of potential exposure, b) once per day during period of potential exposure, wherein the total administered amount over a week is listed above, c) once every two to six days doses thereof, wherein the total administered amount over a week is listed above, or d) divided doses thereof. .sup.3 Post-exposure dose administered after potential exposure to at least one species of Plasmodium for a) once per day for up to seven days, including once per day for three days b) once per week for three weeks, d) at least three times, or e) divided doses thereof, including once every four days.
[0089] In one embodiment of the invention, the compound of Formula (I) is tafenoquine or a pharmaceutically acceptable salt thereof.
[0090] In certain embodiments of the invention, the malaria-naïve, G6PD-normal human subject is an adult or a child.
[0091] In yet another embodiment, a steady state Cmin serum or plasma concentration of between about 50 ng/mL to about 800 ng/mL of tafenoquine in a malaria naïve, G6PD-normal human subject is attained. In further embodiment, a steady state Cmin serum or plasma concentration of between about 80 ng/mL to about 600 ng/mL of tafenoquine in a malaria naïve, G6PD-normal human subject is attained. In another embodiment, a steady state Cmin serum or plasma concentration of between about 80 ng/mL to about 400 ng/mL of tafenoquine in a malaria naïve, G6PD-normal human subject is attained. In yet another embodiment, a steady state Cmin serum or plasma concentration of between about 80 ng/mL to about 200 ng/mL of tafenoquine in a malaria naïve, G6PD-normal human subject is attained. In another embodiment, a steady state Cmin serum or plasma concentration of about greater than or equal to 80 ng/mL of tafenoquine in a malaria naïve, G6PD-normal human subject is attained. In certain embodiments the 80 ng/mL Cmin concentration will be that of the individual or of the median or 5.sup.th percentile of a population administered the given dosing regimen.
[0092] In one embodiment of the invention, Plasmodium exposure comprises at least one Plasmodium species selected from P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi.
[0093] In yet another embodiment, administering the compound, or the pharmaceutical composition, achieves a steady state Cmin serum or plasma concentration of at least about 80 ng/mL of a compound of Formula (I) or tafenoquine. In other embodiments, administering the compound, or the pharmaceutical composition, achieves a steady state Cmin serum or plasma concentration of at least about 80 ng/mL of a compound of Formula (I) or tafenoquine which is maintained for at least three weeks after potential exposure of at least one species of Plasmodium. In further embodiment, administering the compound, or the pharmaceutical composition, achieves a steady state Cmin serum or plasma concentration of at least about 80 ng/mL of a compound of Formula (I) or tafenoquine in about greater than or equal to 50% of malaria naïve, G6PD-normal individuals.
[0094] The compounds of the present invention can be administered orally or sublingually. Oral and sublingual dosing can be in a single or divided dose.
[0095] The invention also relates to a method of preventing malaria by achieving a steady state Cmin serum or plasma concentration of at least about 80 ng/mL of tafenoquine in a malaria naïve, G6PD-normal human subject. As used herein, “Cmin” refers to the minimum concentration that a drug achieves after the drug has been administered and prior to the administration of a second or additional dose. Steady state Cmin is achieved when the overall intake of a drug Cmin concentration is fairly in dynamic equilibrium with its elimination. In some embodiments, Cmin concentration of a compound of Formula (I) or tafenoquine is determined at one or more points following treatment with techniques known in the art.
EXAMPLES
Example 1: Selection of Tafenoquine Doses for Malaria Prevention Utilizing a Pharmacokinetic-Pharmacodynamic Modeling Approach
[0096] In a Phase III malaria prophylaxis study in non-immune (the vast majority of whom were also likely to have been malaria-naïve) Australian soldiers deployed on peacekeeping duties to Timor-Leste, a weekly regimen of 200 mg following administration of an initial dose of 200 mg daily for three days exhibited a protective efficacy of 100% (95% confidence interval [CI] of 93%-100%) (Nasveld P E et al., Randomized, double-blind study of the safety, tolerability, and efficacy of tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects. Antimicrob Agents Chemother. 2010; 54:792-798; Dow G S, Mc Carthy W F, Reid M, Smith B, Tang D, Shanks D G. A retrospective analysis of the protective efficacy of tafenoquine and mefloquine as prophylactic anti-malarials in non-immune individuals during deployment to a malaria-endemic area. Malaria Journal. 2014, 13:49). The 200 mg dose selected for the Phase III study was the best tolerated of several effective regimens (50, 100, 200 and 400 mg) shown to provide statistically significant reductions in microscopically confirmed parasitemia in Phase II studies in a semi-immune African population (Shanks G D, Oloo A J, Aleman G M, et al. A new primaquine analogue, tafenoquine (WR 238605), for prophylaxis against Plasmodium falciparum malaria. Clin Infect Dis. 2001; 33:1968-1974; Hale B R, Owusu-Agyei S, Fryauff D J, et al. A randomized, double-blind, placebo-controlled, dose-ranging trial of tafenoquine for weekly prophylaxis against Plasmodium falciparum. Clin Infect Dis. 2003; 36:541-549). A dose of 400 mg tafenoquine is generally considered less well tolerated due to a higher frequency of gastrointestinal adverse events and methemoglobinemia.
[0097] Although the Phase III study in non-immune Australian soldiers demonstrated that a dose of 200 mg once per day for three days, followed by 200 mg once per week, prevented symptomatic malaria during potential exposure, the study did not address whether the treatment regimen would prevent the development of symptomatic malaria following travel due to exposure late in that period of travel and/or from a latent malarial infection. Thus, the present modeling study was undertaken to determine a dosing regimen that will provide adequate protection from post-exposure malarial infection and/or latent malarial infection throughout the three week period following exposure, when most post-exposure malarial infections or latent malarial infections arise.
[0098] Based on the observation in Phase II studies that symptomatic breakthroughs occurred when plasma tafenoquine concentrations were <40 ng/mL, the minimum protective threshold concentration of tafenoquine was set at 80 ng/mL in the present study (see, e.g., Shanks G D, Oloo A J, Aleman G M, et al. A new primaquine analogue, tafenoquine (WR 238605), for prophylaxis against Plasmodium falciparum malaria. Clin Infect Dis. 2001; 33:1968-1974; Hale B R, Owusu-Agyei S, Fryauff D J, et al. A randomized, double-blind, placebo-controlled, dose-ranging trial of tafenoquine for weekly prophylaxis against Plasmodium falciparum. Clin Infect Dis. 2003; 36:541-549; Llanos-Cuentas A, Lacerda M V, Rueangweerayut R, et al. Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study. Lancet. 2014; 383:1049-1058).
[0099] Pharmacokinetic (PK) data from several studies (Phase I/II/III) was modeled to establish a consolidated model of tafenoquine and to determine relevant covariates. More specifically, analysis was performed using data obtained from ten Phase I/II/III clinical studies of tafenoquine (U.S. Army Study Numbers: 1, 2, 3, 4, 5, 14, 15, 33, 44 and 58). Table 2 summarizes the key features of each of the studies included in the pooled dataset such as the study type and design, dose and dosing regimen, population, and sample collection schemes. A total of 866 subjects were included in the population analysis. Ninety-three percent of the subjects were male. A demographic summary pooled across all of the available studies is presented in Table 3.
TABLE-US-00002 TABLE 2 Clinical Studies of Tafenoquine Study No. N Phase Study Type Study Design Doses Population PK Collection 1 45 I Single Dose Randomized, double-blind, TQ 4 to 600 mg or 80 M healthy Before dosing and at 4, 8, 12, Healthy placebo-controlled, placebo volunteers 24, 48, 72, 96 and 168 hr after Volunteer Study single oral dose rising (18-35 y) dosing. For the six higher dose (fasted) groups (250, 300-600 mg), additional samples were collected on Days 16, 23, 30 and 37. 2 18 I Single Dose Randomized, TQ 100, 200 or 18 M healthy N/A Healthy parallel-group, single oral 400 mg volunteers Volunteer Study dose (fasted) (18-32 y) 3 4 I Malaria Challenge Randomized, double-blind, TQ 600 mg (n = 4) or 4 M/2 F Before dosing and at 5, 7, 12, Study in Healthy placebo-controlled, single placebo (n = 2) volunteers 28 and 42 d after dosing on Volunteers dose, fasted, malaria 1 d before (19-30 y) Day 1 challenge sporozoite inoculation 4 25 I Single and Repeat Randomized, double-blind, TQ 200, 400 or 30 M/6 F On Day 1 (Dose 1) and at Dose Healthy placebo-controlled, multiple 600 mg or placebo (23-46 y) Week 10 (Dose 10) before Volunteer Study dose (fasted for ≧ 2 hr) weekly for 10 weeks dosing and at 2, 4, 6, 8, 12, 16 and 24 hr after dosing. Additional trough blood samples were drawn pre-dose (weekly) prior to Doses 2 through 9 at Weeks 12, 14, 16, 18 and 20. 5 10 I Malaria Challenge Randomized, double-blind, TQ 600 mg or placebo on 12 M Before dosing on Day 17, Study in Healthy placebo-controlled, multiple Days −3 and −2 before volunteers before dosing on Day 24 and Volunteers oral dose (fed) sporozoite (19-36 y) on Days 26, 31, 38, 45 and 59. inoculation (Day 0), then 300 mg on Days 3, 10, 17 and 24 14 58 I Relative Randomized, relative TQ 400 mg OD for 3 d 43 M/15 F Relative to the first dose, blood Bioavailability in bioavailability of 3 oral (fed) (21-60 y) samples were collected from Healthy Volunteers formulations each subject before dosing and up to 96 hr after dosing. Additional blood samples were collected on an ambulatory basis on Days 6, 7 and 8 and in Weeks 4, 6, 8, 10, 12, 14, 16 and 18. 15 34 I Drug-Drug Single sequence, TQ 400 mg OD for 3 d 20 M/14 F Blood samples for Interaction Studies desipramine interaction (fed); (25-60 y) determination of SB-252263 in Healthy desipramine 100 mg on (TQ) plasma concentrations Volunteers morning of Day 1 and were collected up to 96 hr after Day 11 (fasted) the second dose of desipramine (Day 11) and thereafter at 2-week intervals until 9 weeks after the last (third) dose of SB-252263. 33 491 III Malaria Prophylaxis Double-blind, randomized, TQ 200 mg for 3 d, then Non-immune During the prophylactic phase Study mefloquine 200 mg weekly Australian (Day 2 and Weeks 4, 8, 16 and positive control MQ 250 mg for 3 d, then army troops 26) 250 mg weekly 632 M/22 F (18-51 y) 44 135 II Malaria Prophylaxis Double-blind, randomized, TQ 400 mg for 3 d, then Non-immune For the 104 soldiers on Study placebo-controlled 400 mg monthly Royal Thai monthly TQ prophylaxis, blood Army samples were collected after 104 M commencing the loading dose randomized to at approximately 8, 24, 48 and receive TQ and 56 hr and then in intervals of 101 M 3 ± 4 d until the first monthly randomized to dose. After each monthly dose, receive placebo samples were collected at approximately 8 hr after dosing, mid-month and at the end of the monthly dose (trough plasma drug concentration). Following the last monthly dose, samples were collected at approximately 4, 8, 12 and 24 hr and then in intervals of 3 ± 4 d for 2 months. At each blood collection, samples were obtained from 2 to 28 volunteers (mean ± SD, 12.6 ± 7.1 volunteers). For the 31 soldiers on weekly prophylaxis, blood samples were collected after 2 ± 22 weeks of medication (mean ± SD, 11.8 ± 6.8 weeks). Samples from this group were collected at approximately 12 hr and 168 hr after weekly medication and at 14, 21 and 28 d after the last dose. 58 46 II P. vivax Treatment Randomized, TQ 400 mg OD for 3 d in 120 M/F Daily for Days 0-7, Days 12-20 Study active-control, Cohort 1 and TQ 600 mg (60 in each and Days 28-30 double-blind, OD for 1 d in Cohort 2 cohort) double-dummy (20-60 y) d: days; F: female; hr: hours; M: male; MQ: mefloquine; N: number of subjects; N/A: not available; No.: number; OD: once daily; PK: pharmacokinetic; SD: standard deviation; TQ: tafenoquine; y: years.
TABLE-US-00003 TABLE 3 Demographic Summary of Subjects in the Tafenoquine Population PK Analysis Baseline Characteristic Statistic All Subjects Male Female Number of subjects n (%) 866 808 (93.3) 58 (6.7) Age (years) Mean 27.8 27.1 37.2 SE 0.28 0.25 1.68 Median 25.0 25.0 35.0 Min, Max 18.0, 60.0 18.0, 60.0 19.0, 60.0 Race Asian n (%) 181 (20.9) 172 (19.9) 9 (1.0) Black or African n (%) 26 (3.0) 21 (2.4) 5 (0.6) Caucasian/White n (%) 626 (72.3) 582 (67.2) 44 (5.1) Hispanic n (%) 31 (3.6) 31 (3.6) — Other n (%) 2 (0.2) 2 (0.2) — Food No n (%) 92 (10.6) 86 (9.9) 6 (0.7) Yes n (%) 774 (89.4) 722 (83.4) 52 (6.0) Weight (kg) Mean 75.0 75.9 62.4 SE 0.47 0.48 1.37 Median 75.0 76.0 62.3 Min, Max 43.0, 135.0 43.0, 135.0 43.0, 88.0 n: number of subjects; Min: minimum; Max: maximum; PK: pharmacokinetic; SE: standard error.
[0100] To summarize the conclusions of this analysis, this analysis demonstrated that a dosing regimen involving an initial dose of 200 mg once per day for three days followed by exposure doses of 200 mg week throughout the period of exposure would result in trough plasma tafenoquine concentrations >80 ng/mL in >95% of individuals. Several alternative dosing regimens that incorporated removal of the initial dose, lowering of the dose given, and monthly administration were also modeled to determine whether they would achieve trough concentrations >80 ng/mL in >50% of individuals. We also modeled two post-exposure prophylaxis regimens to assess the duration of time in which protective plasma tafenoquine concentrations could be maintained. Our results show that an initial dose of 200 mg daily for three days followed by weekly 200 mg exposure doses continued as post-exposure doses until three weeks after potential exposure (e.g., deployment to a malaria area) should offer protection against malaria both throughout the period of exposure and for the period after exposure when latent malarial infections can arise (e.g., three weeks post-exposure).
Methods:
[0101] The tafenoquine concentrations of plasma samples across the ten studies were analyzed using a validated high-performance liquid chromatography-mass spectrometry method (HPLC-MS) or HPLC with fluorescence detection as previously described (see, Kocisko D A, Walsh D S, Eamsila C, Edstein M D. Measurement of tafenoquine (WR 238605) in human plasma, and venous and capillary blood by high-pressure liquid chromatography. Ther Drug Monit. 2000; 22:184-189; Charles B G, Miller A K, Nasveld P E, Reid M G, Harris I E, Edstein M D. Population pharmacokinetics of tafenoquine during malaria prophylaxis in healthy subjects. Antimicrob Agents Chemother. 2007; 51:2709-2715.
[0102] Population PK analyses were carried out using NONMEM version 7.1.2, PDx-Pop version 4.2 (Icon Development Solutions, Hanover, Md.) and Intel Visual Fortran Compiler version 12 on a Microsoft Windows XP platform. Plasma tafenoquine concentrations, demographic information and clinical laboratory results from ten studies were used to build a pooled NONMEM input data file for the current population PK analysis. The data were prepared for analysis using SAS software version 9.1.3 (SAS Institute Inc., Cary, N.C.). Actual dosing and actual blood sampling times, when available, were used for the analysis. Plasma tafenoquine concentrations that were below or equal to the limit of quantification were excluded from the analysis.
[0103] Based on the PK profile of tafenoquine from previous modeling efforts (Shanks G D, Oloo A J, Aleman G M, et al. A new primaquine analogue, tafenoquine (WR 238605), for prophylaxis against Plasmodium falciparum malaria. Clin Infect Dis. 2001; 33:1968-1974; Obaldia N 3rd, Rossan R N, Cooper R D, et al. WR 238605, chloroquine, and their combinations as blood schizonticides against a chloroquine-resistant strain of Plasmodium vivax in Aotus monkeys. Am J Trop Med Hyg. 1997; 56:508-10), a one-compartment PK model with first-order absorption and elimination processes was selected to describe best the pharmacokinetics of tafenoquine. As part of the modeling process, a two-compartment PK model with first-order absorption and elimination process was also explored and discarded. The one-compartment PK model was specified in the NONMEM control file and was parameterized in terms of apparent clearance (CL/F), apparent volume of distribution (V/F) and absorption rate constant (Ka) using the PREDPP ADVAN2 with TRANS2 subroutine in NONMEM. First-order conditional estimation (FOCE) with interaction between variance of inter-individual variability and the variance of residual error was used as the estimation method. Inter-individual variability was best described by an exponential error model, as shown below:
Pi={circumflex over (P)}exp(η.sub.i) [0104] where: [0105] Pi is the estimated parameter for the i.sup.th individual. [0106] {circumflex over (P)} is the population value for the parameter. [0107] η.sub.i are inter-individual random effects for the i.sup.th individual for parameter P and were assumed to be independent and symmetrically distributed with a zero mean and a variance ω.sup.2.
[0108] Different structural models (additive, proportional, exponential and combined additive and proportional) were investigated for residual unexplained variability (RUV). RUV was best described by a proportional error model, as shown below:
C.sub.ij=Ĉ.sub.ij(1+ε.sub.pij) [0109] where: [0110] C.sub.ij is the j.sup.th observation for the i.sup.th individual. [0111] Ĉ.sub.ij is the j.sup.th predicted value for the i.sup.th individual. [0112] ε.sub.pij is the proportional residual random error for the i.sup.th individual and the j.sup.th measurement and was assumed to be independent and symmetrically distributed with a zero mean and a variance σ.sup.2.
[0113] For optimal model selection, diagnostic plots were generated by PDx-Pop version 4.2 in conjunction with Microsoft Excel and S+ version 8. The standard criteria of change in the minimum objective function value (ΔOFV) equal to minus twice the log-likelihood of the data as well as diagnostics were used to assess goodness of fit. Successful model runs were determined by each of the following criteria: successful model convergence; a minimum of three significant figures reported for any parameter; a non-singular covariance matrix; completion of the covariance step without warnings; CIs for the structural parameters that did not include zero; absence of trends in the distribution of weighted residuals versus model predictions and in the weighted residuals versus the independent variable; and insensitivity of model convergence and covariance to initial parameter estimates.
[0114] Covariate analysis was performed to the base PK model to identify and to evaluate the extent to which the covariates accounted for the variability in the PK parameters. Prior to including covariates in the population model, visual inspection of the relationship between each η and covariate was performed using scatter plots. The scatter plots were also used to provide visual identification of collinearity between the covariates of interest. Covariates that were identified to demonstrate collinearity based on exploratory plots were not allowed to enter the covariate model at the same time. The decision to include covariates in the final model was also based on whether it was sensible physiologically to include them.
[0115] Sex, age, race and body weight (WT) were selected for evaluation as potential covariates of CL/F, V/F and Ka. Starting with the base PK model, a process was initiated in which covariates were selected one at a time and included in the model if inclusion resulted in a reduction in the OFV of at least 3.84 (p 0.05, df=1). This process was followed by a multivariate analysis, in which all selected covariates were added together and the model was fit to the data, resulting in the full PK model. Backward deletion was applied by dropping one covariate at a time until no covariate could be removed without significantly increasing the OFV (p≦0.001), resulting in the final PK model. However, if a CI of any of the covariate effects included the null value, the effect was considered not significant and the model was further simplified until all structural parameters were well estimated. Continuous covariates in the model were centered on the population median value of the subjects included in the analysis and are described in more detail in the results section.
[0116] The final PK model was evaluated using bootstrapping and a visual predictive check. Using the bootstrap approach, the bootstrap parameter values were obtained by repeatedly fitting the final population model to 1000 bootstrap samples. The mean and CI values of the bootstrap parameters were then compared to the final population model parameter estimates and associated CIs from NONMEM. The 95% bootstrap percentile CIs were determined for the PK parameters derived from 1000 bootstrap datasets and compared to the original parameters obtained from the final model.
[0117] A visual predictive check was performed by simulating the plasma tafenoquine concentrations from the original subjects in the NONMEM dataset using the parameter estimates from the final PK model. One thousand predicted profiles were simulated for each original subject. Random effects were included in the simulation. The median, 5.sup.th percentile and 95.sup.th percentile PK concentration-versus-time profiles from the simulations were compared with those from observed plasma tafenoquine concentrations.
[0118] Simulations of PK data for various doses and dose regimens were performed using the final PK model parameters. The simulation step included creation of NONMEM data files with virtual subjects with desired sampling times and dosing regimens and running of the simulations with 2000 replicates using the final PK model parameters in NONMEM. The outputs from the simulations were summarized using SAS software version 9.1.3 and presented graphically using Phoenix WinNonlin version 6.2 (Pharsight, St. Louis, Mo.).
[0119] A one-compartment PK model with first-order absorption and elimination rate constants was selected as the structural model. Different error models for inter-individual and residual unexplained variability were also tested. The exponential error model was chosen to describe inter-individual variability of each PK parameter (CL/F, V/F and Ka) and the proportional error model was chosen to describe residual error. A two-compartment PK model was also tested but was not pursued further because of unreliable estimates from bootstrap results during model evaluation (data not shown).
[0120] Because age, WT, race, sex and meal condition (fed versus fasted) were the only common covariates present for all ten studies, these covariates were selected for covariate model exploration. Each of these covariates was included in the base PK model to test for its significance. Because diversity in race was restricted due to a majority of the subjects being Asian or Caucasian, the effect of race was explored only for Asian subjects versus Caucasian/other subjects as the reference. Sex and race were confounded with WT and were not explored further in the full covariate model.
[0121] The full covariate model included the effect of WT on CL/F and V/F; age on CL/F, V/F and Ka; and meal condition on V/F and Ka. The effect of meal condition on bioavailability alone could not be explored and the effect of meal condition on CL/F was not significant. The full covariate PK model was further reduced by backward elimination and resulted in WT and age as significant covariates of CL/F, and WT and meal condition as significant covariates of V/F. Goodness-of-fit plots are presented in
[0122] Base structural parameters and the relationship of covariates to CL/F and V/F are summarized in Table 4. For oral tafenoquine, the population CL/F and V/F were determined to be 4.17 L/h and 2470 L, respectively. The first-order Ka of oral tafenoquine was 0.359 The inter-individual variability of CL/F, V/F and Ka was 23.6%, 24.1% and 54.1%, respectively. The final PK model revealed that CL/F of tafenoquine is a function of WT and age. These covariates decreased inter-individual variability associated with CL/F from 26.5% to 23.6%. The relationship between CL/F and both covariates was as follows:
CL/F (L/h)=4.17×(WT/75).sup.0.552×(AGE/25).sup.−0.2
TABLE-US-00004 TABLE 4 Tafenoquine Population PK Parameters of the Final PK Model Parameters Bootstrap 95% CI Inter-individual (Units) Final Estimate Lower Upper Variability a CL/F (L/h) = θ.sub.CL × (WT/75).sup.θ.sup.
[0123] Thus, tafenoquine CL/F was found to increase as WT increased (expressed in kilograms) and to decrease with age (expressed in years).
[0124] The final PK model revealed that V/F of tafenoquine is a function of WT and meal condition. These covariates decreased the inter-individual variability of V/F from 29.6% to 24.1%. The relationship between V/F and both covariates was as follows:
V/F (L)=2470×(WT/75).sup.0.781×(0.822).sup.FOOD
where FOOD=0 for fasted and 1 for fed.
[0125] Tafenoquine V/F was found to increase as WT increased and to decrease in the fed condition compared with the fasting condition.
[0126] The bootstrapping technique was used to evaluate the final PK model. The comparison between the parameter estimates derived from the bootstrap and the estimates derived from NONMEM and between the estimates of the variability of the random effects derived from the bootstrap and the corresponding NONMEM estimates are presented in Table 5. In this modeling effort, the differences of mean bootstrap estimates from the NONMEM estimates of those parameters were less than 15%. Overall, the mean population PK parameter estimates and 95% CI obtained from the bootstrap procedure were comparable to the estimates and 95% CI from the final PK model. The success rate of bootstrap runs was 100% for the PK model.
TABLE-US-00005 TABLE 5 Comparison of Bootstrap and NONMEM Parameter Estimates for Tafenoquine Parameters NONMEM Estimate Bootstrap Estimate Difference .sup.a θ.sub.CL 4.17 4.15 −0.37% θ.sub.CL-WT 0.552 0.554 0.35% θ.sub.CL-AGE −0.200 −0.200 0.08% θ.sub.V 2470 2482 0.47% θ.sub.V-WT 0.781 0.774 −0.96% θ.sub.V-FOOD 0.822 0.810 −1.52% θ.sub.KA 0.359 0.351 −2.29% ω.sup.2.sub.CL 0.0555 0.0536 −3.44% COV.sub.CL, V 0.0289 0.0250 −13.40% ω.sup.2.sub.V 0.0583 0.0521 −10.55% ω.sup.2.sub.Ka 0.293 0.283 −3.49% σ.sup.2 0.0488 0.0486 −0.50% CL or CL/F: apparent clearance; COV: covariance; Ka: absorption rate constant; PK: pharmacokinetic; V or V/F: apparent volume of distribution; WT: weight; ω.sup.2: variance of the inter-individual random effect; σ.sup.2: variance of the proportional residual random effect. .sup.a Expressed as percent of difference between bootstrap and NONMEM estimates from the final model ([Bootstrap/NONMEM − 1] × 100%).
[0127] The visual predictive check was performed using the NONMEM parameter estimates estimated from the final PK model. Median, 5.sup.th percentile and 95.sup.th percentile plots of model-predicted versus observed plasma tafenoquine concentrations are presented in
Results:
[0128] The simulated reference regimen (200 mg daily for three days then 200 mg weekly) resulted in the achievement of plasma tafenoquine concentrations >80 ng/mL immediately after the loading dose in 95% of individuals (
[0129] Variations of the Reference Regimen are simulated in
[0130] Upon return from a malaria endemic area, it is usual practice to administer a regimen for post-exposure prophylaxis to reduce the risk of contracting P. falciparum malaria in the final three weeks of deployment and to prevent P. vivax relapses. Simulation of the administration of a post-exposure prophylaxis regimen of 200 mg once daily for three days (Regimen 3,
[0131] A total of 866 subjects were included in this population PK modeling of tafenoquine. Results showed that a one-compartment PK model with first-order absorption and elimination was an appropriate base PK model for describing the pharmacokinetics of tafenoquine administered orally. Inter-individual variability was described by an exponential model and residual variability was described by a proportional model. Model evaluation using bootstrapping and the visual predictive check confirmed the reliability of the final PK model and its reproduction of plasma tafenoquine concentrations.
[0132] Variability in the final PK model was explained by the effect of changes in WT and age on CL/F, and WT and meal status on V/F although assessment of the effect of meal status on V/F was limited by the relatively small percentage of subjects dosed under fasted conditions. The explained variability is not sufficient to suggest that the intended regimen should be modified based on either age or meal status in order to achieve the desired steady-state plasma tafenoquine concentration, because the reference regimen is predicted to result in the attainment of the intended steady-state trough plasma tafenoquine concentrations in >95% of individuals. The effect of WT, age and meal status are evident, but even in these sub-populations, protective plasma tafenoquine concentrations are achieved in the vast majority of individuals.
[0133] The data shows that removal of the loading dose and/or lowering the dose to 100 or 150 mg would result in the attainment of protective plasma tafenoquine concentrations over the entirety of the simulated deployment of six months. Protective concentrations would be reached with all these regimens after the second or third dose. A monthly dosing schedule is predicted not to result in the attainment of protective plasma tafenoquine concentrations over the entirety of the simulated deployment of six months, confirming clinical experience with this regimen in Thai marines (Edstein M D, Kocisko D A, Walsh D S, Eamsila C, Charles B G, Rieckmann K H. Plasma concentrations of tafenoquine, a new long-acting antimalarial agent, in Thai soldiers receiving monthly prophylaxis. Clin Infect Dis. 2003; 37:1654-1658).
[0134] As highlighted in a recent retrospective analysis of the efficacy of tafenoquine in non-immune subjects (Dow G S, Mc Carthy W F, Reid M, Smith B, Tang D, Shanks D G. A retrospective analysis of the protective efficacy of tafenoquine and mefloquine as prophylactic anti-malarials in non-immune individuals during deployment to a malaria-endemic area. Malaria Journal. 2014, 13:49), a post-dosing regimen may be needed to manage the residual risk of malaria from later exposure during travel. We explored two post-exposure prophylaxis regimens of tafenoquine: administration of a reverse load of 200 mg once daily for three days (Regimen 3) versus extension of the reference regimen for an additional three weeks. The extended reference regimen maintained trough plasma tafenoquine concentrations >80 ng/mL for approximately three to four days longer in 95% of individuals than did the reverse load, but tafenoquine concentrations of both regimens remained in excess of the threshold in a majority of individuals for at least one month. The Cmax of tafenoquine achieved after administration of the reverse load was lower than that attained after administration of 400 mg once daily for three days. A loading dose of 400 mg once daily for three days has been shown to be safe in G6PD-normal individuals in several clinical studies but exhibits gastrointestinal intolerability (Shanks G D, Oloo A J, Aleman G M, et al. A new primaquine analogue, tafenoquine (WR 238605), for prophylaxis against Plasmodium falciparum malaria. Clin Infect Dis. 2001; 33:1968-1974; Walsh D S, Eamsila C, Sasiprapha T, et al. Efficacy of monthly tafenoquine for prophylaxis of Plasmodium vivax and multidrug-resistant P. falciparum malaria. J Infect Dis. 2004; 190:1456-1463; Elmes N J, Nasveld P E, Kitchener S J, Kocisko D A, Edstein M D. The efficacy and tolerability of three different regimens of tafenoquine versus primaquine for post-exposure prophylaxis of Plasmodium vivax malaria in the Southwest Pacific. Trans R Soc Trop Med Hyg. 2008; 102:1095-1101). The incidence of gastrointestinal adverse events after the administration of 200 mg tafenoquine once daily for three days (total dose 600 mg) is approximately half of that after administration of 400 mg once daily or BID for three days (total dose 1200 mg) and similar to the standard of care (Elmes N J, Nasveld P E, Kitchener S J, Kocisko D A, Edstein M D. The efficacy and tolerability of three different regimens of tafenoquine versus primaquine for post-exposure prophylaxis of Plasmodium vivax malaria in the Southwest Pacific. Trans R Soc Trop Med Hyg. 2008; 102:1095-1101). It is therefore conceivable that gastrointestinal intolerability might be no worse than the standard of care for those who receive the reverse load (200 mg once daily for three days). However, additional clinical data are required to demonstrate this directly.
[0135] Recent reports have associated P. vivax relapses/primaquine failures with polymorphisms in cytochrome P450 (CYP) 2D6 (Bennett J W, Pybus B S, Yadava A, et al. Primaquine failure and cytochrome P-450 2D6 in Plasmodium vivax malaria. N Engl J Med. 2013; 369:1381-1382). Presumably, this is because the production of an unknown primaquine metabolite that is important for P. vivax anti-hypnozoite activity is inhibited in individuals with CYP2D6 mutations. Conceivably, the same might also be true for tafenoquine. If so, it likely has no clinical relevance in the context of prophylactic use. This is because at the reference regimen described here, no malaria breakthroughs were observed in a large cohort of non-immune and primarily Caucasian Australian soldiers (Bennett J W, Pybus B S, Yadava A, et al. Primaquine failure and cytochrome P-450 2D6 in Plasmodium vivax malaria. N Engl J Med. 2013; 369:1381-1382). Although CPY2D6 polymorphisms were not determined in the 491 Australian soldiers who received tafenoquine, a good number would have been poor metabolizers, because the prevalence of CYP2D6 poor metabolizers in Caucasian populations ranges from 6% to 10% (Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook Pty Ltd; 2004).
[0136] The Australian and U.S. Armed Forces routinely use daily doxycycline or atovaquone/proguanil for malaria prophylaxis (DOD Health Memo: http://www.health.mil/˜/media/MHS/Policy %20Files/Import/13-002.ashx; Shanks G D, Elmes N J. Malaria in the military and Melanesia. ADF Health, 2008; 9:54-59). Weekly mefloquine is used where the risk-benefit is appropriate (DOD Health Memo: http://www.health.mil/˜/media/MHS/Policy %20Files/Import/13-002.ashx). Post-exposure prophylaxis usually involves administration of a blood-schizonticidal anti-malarial for one month (doxycycline or mefloquine), a causal prophylactic drug for seven days (atovaquone/proguanil) and/or a combination of a blood-schizonticidal drug (doxycycline) and primaquine for two weeks to reduce the risk of P. vivax relapse or the contraction of P. falciparum malaria from late-deployment exposure (DOD Health Memo: http://www.health.mil/˜/media/MHS/Policy %20Files/Import/13-002.ashx; Shanks G D, Elmes N J. Malaria in the military and Melanesia. ADF Health. 2008; 9:54-59). Weekly tafenoquine extended for three weeks following deployment is predicted to maintain the same level of protection as the standard of care and provide a more convenient prophylaxis and post-exposure prophylaxis regimen. Compression of the post-exposure prophylactic regimen to a three-day reverse load (200 mg/day or lower daily dose for 3 days) could further economize the dosing schedule, and thus improve compliance, but additional clinical data are required to assess GI tolerability. There will remain a small risk of P. vivax relapses, but this risk is not anticipated to be greater than that of the standard of care (blood schizontocide plus primaquine 30 mg/day for 14 days) (Elmes N J, Nasveld P E, Kitchener S J, Kocisko D A, Edstein M D. The efficacy and tolerability of three different regimens of tafenoquine versus primaquine for post-exposure prophylaxis of Plasmodium vivax malaria in the Southwest Pacific. Trans R Soc Trop Med Hyg. 2008; 102:1095-1101).
[0137] In Example 1, the population pharmacokinetics of tafenoquine were assessed using data from ten Phase I/II/III clinical studies, resulting in a stable, predictive model used to confirm the efficacy of the intended reference tafenoquine regimen (200 mg/day for 3 days, then 200 mg weekly) and to explore additional regimens. Elimination of the loading dose and/or reduction of the dose to 100 and 150 mg maintained protective levels of drug in the majority of individuals. Two additional post-exposure prophylaxis regimens (Regimen 3 reverse load of 200 mg/day for 3 days and the extended reference regimen) showed promise for being well tolerated and effective. Tafenoquine administered weekly for three weeks following deployment is predicted to maintain the same level of protection as the standard of care and provide a more convenient prophylaxis and post-exposure prophylaxis regimen. Compression of the post-exposure prophylactic regimen to a three-day reverse load (Regimen 3) could further economize the dosing schedule. A small risk of P. vivax relapse will remain but is not anticipated to be greater than that of the standard of care.
REFERENCES
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[0144] The teachings of all patents, published applications, and references cited herein are incorporated by reference in their entirety.
[0145] While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.