Table 1. Pharmacokinetic Parameters [Mean (CV)] in Healthy Volunteers Treated with Atovaquone and Proguanil Hydrochloride*
|
|
Cmax (µg/mL) |
AUC0-¥ (h·µg/mL) |
t½ (h) |
Clearance/F (L/h/kg) |
Vz/F (L/kg) |
|
|
Atovaquone |
11.8 (20) |
541 (35) |
60 (23) |
0.03 (46) |
2.8 (37) |
|
|
Proguanil |
0.52 (22) |
6.16 (23) |
14.7 (17) |
68.8 (32) |
23.2 (30) |
|
|
Cycloguanil |
0.09 (53) |
1.34 (44) |
12.6 (43) |
- |
- |
|
* 18 healthy adults given 1000 mg atovaquone and 400 mg proguanil hydrochloride. Cmax = maximum concentration, AUC = area under the concentration-time curve, t½ = elimination half-life, CL/F = apparent oral clearance; Vz/F = apparent volume of distribution. Table from Beerahee 1999 (6) with permission of the author.
Table 2. Summary of Studies of Malarone for Malaria Prophylaxis
|
Reference |
Country / Population |
Treatment regimen |
Number of subjects enrolled |
Number of evaluable subjects |
Number of cases of falciparum malaria |
|
Residents of Endemic Areas |
|||||
|
Shanks 1998 (106) |
Kenya Adults |
Malarone x 1a
Malarone x 2b |
70
67 |
54 54 54 |
0
0 |
|
Lell 1998 (76) |
Gabon Pediatrics |
Malarone |
125 |
115 137 |
0 |
|
Sukwa 1999 (113) |
Zambia Adults |
Malarone |
136 |
102 111 |
2 |
|
Faucher 2002 (40) |
Gabon Pediatrics |
Malarone |
165 165 |
150 144 |
1 31 |
|
Non-immunes |
|||||
|
Ling 2002 (77) |
Indonesia Transmigrants |
Malarone |
150 149 |
148c 149c |
1d 23d |
|
Camus 2001 (17) |
European Pediatric travellers |
Malarone |
110c 111c |
110e 111e |
0 |
|
Høgh 2000 (52) |
European, S. African and Canadian adult travellers |
Malarone |
540 543 |
501e 507e |
0 |
|
Overbosch 2001 (92) |
European, S. African and Canadian adult and pediatric travellers |
Malarone |
508 505 |
489e 477e |
0 |
|
van der Berg 1999 (118)
|
South Africa, South African military personnel |
Malarone |
175 |
113 |
1 |
|
Nasveld 2000 (90)
|
Papua New Guinea, Australian military personnel |
Malarone |
75 75 |
73 73 |
0 |
|
Challenge Studies |
|||||
|
Shapiro 1999 (108) |
United States Non-immunes |
Atovaquone 250mg Atovaquone
750mg |
6
6
|
6
6
4 |
0 0
4 |
|
Berman 2001 (9)
|
United States Non-immunes |
Malarone |
12 |
12 4 |
0 |
a Malarone x 1 = Atovaquone 250mg / Proguanil 100mg
b Malarone x 2 = Atovaquone 500mg / Proguanil 200mg
c Received prophylaxis
d Three subjects in the Malarone arm developed P. vivax during prophylaxis (one of the three was co-infected with P. vivax and P. falciparum). Sixteen subjects in the placebo arm developed P. vivax during prophylaxis (two of the sixteen were co-infected with P. vivax and P.falciparum).
e Completed the study
Table 3. Adverse Events in Active–Controlled Clinical Trials of Malarone for Prophylaxis of Malaria in Non-immune Travelers
|
|
Percent of Subjects With Adverse Events* (Percent of Subjects With Adverse Events Attributable to Therapy) |
|||||||
|
|
Study 1 |
Study 2 |
||||||
|
Adverse Event |
Malarone (n = 493) |
Mefloquine (n = 483) |
Malarone (n = 511) |
Chloroquine plus Proguanil (n = 511) |
||||
|
Diarrhea |
38 |
(8) |
36 |
(7) |
34 |
(5) |
39 |
(7) |
|
Nausea |
14 |
(3) |
20 |
(8) |
11 |
(2) |
18 |
(7) |
|
Abdominal pain |
17 |
(5) |
16 |
(5) |
14 |
(3) |
22 |
(6) |
|
Headache |
12 |
(4) |
17 |
(7) |
12 |
(4) |
14 |
(4) |
|
Dreams |
7 |
(7) |
16 |
(14) |
6 |
(4) |
7 |
(3) |
|
Insomnia |
5 |
(3) |
16 |
(13) |
4 |
(2) |
5 |
(2) |
|
Fever |
9 |
(<1) |
11 |
(1) |
8 |
(<1) |
8 |
(<1) |
|
Dizziness |
5 |
(2) |
14 |
(9) |
7 |
(3) |
8 |
(4) |
|
Vomiting |
8 |
(1) |
10 |
(2) |
8 |
(0) |
14 |
(2) |
|
Oral ulcers |
9 |
(6) |
6 |
(4) |
5 |
(4) |
7 |
(5) |
|
Pruritus |
4 |
(2) |
5 |
(2) |
3 |
(1) |
2 |
(<1) |
|
Visual difficulties |
2 |
(2) |
5 |
(3) |
3 |
(2) |
3 |
(2) |
|
Depression |
<1 |
(<1) |
5 |
(4) |
<1 |
(<1) |
1 |
(<1) |
|
Anxiety |
1 |
(<1) |
5 |
(4) |
<1 |
(<1) |
1 |
(<1) |
|
Any adverse event |
64 |
(30) |
69 |
(42) |
58 |
(22) |
66 |
(28) |
|
Any neuropsychiatric event |
20 |
(14) |
37 |
(29) |
16 |
(10) |
20 |
(10) |
|
Any gastrointestinal event |
49 |
(16) |
50 |
(19) |
43 |
(12) |
54 |
(20) |
*Adverse events that started while receiving active study drug.
Figure 1. Structure of Atovaquone
Figure 2. Structures of Proguanil Hydrochloride and its Metabolites, Cycloguanil and 4-Chlorophenyl Biguanide
Figure 3. Synergistic activity of atovaquone and proguanil against Plasmodium falciparum in vitro. (from Canfield 1995)
