Vol.61 No.4 July 2013
Pharmacokinetics of atovaquone suspension and atovaquone/proguanil combination tablet in healthy Japanese subjects
1)Medicines Department, GlaxoSmithKline K.K., 4-6-15 Sendagaya, Shibuya-ku, Tokyo
2)Biomedical Data Sciences Department, GlaxoSmithKline K.K.
Abstract
The pharmacokinetic profiles of atovaquone and proguanil were assessed in healthy Japanese volunteers when administered as atovaquone oral suspension or atovaquone/proguanil HCl combination tablets. The combination tablet of atovaquone 1,000 mg and proguanil HCl 400 mg or oral suspensions of atovaquone 750 or 1,500 mg were administered to one of three groups (10 volunteers per group) after a meal. The time courses of plasma concentrations of atovaquone, proguanil and cycloguanil (metabolite of proguanil) were determined.
In the atovaquone/proguanil combination tablet group, the pharmacokinetic profiles according to subject CYP2C19 genotype were also investigated.
The postprandial Cmax of atovaquone reached 14.0 and 15.7 μg/mL for 750 and 1,500 mg single oral administration respectively, at 4 hours after administration. The AUCt of atovaquone in the 750 mg and 1,500 mg groups were 901.4 and 1,076.9 μg・hr/mL, respectively. Dose proportional exposure between atovaquone 750 mg and 1,500 mg was not observed. The T1/2 of atovaquone was approximately 60-70 hours, indicating relatively slow excretion. When a single oral dose of the combination tablet containing atovaquone 1,000 mg and proguanil 400 mg was administered postprandially, the plasma concentration of atovaquone and proguanil reached Cmax of 7.3 μg/mL and 364.5 ng/mL at 3 hours after administration and its T1/2 were approximately 70 and 18 hours, respectively. Cycloguanil was quantifiable in plasma at 1 hour after administration, and was excreted with the T1/2 of 18.6 hours after reaching a Cmax of 86.0 ng/mL. In subjects with the PM type of CYP2C19, the AUCt of proguanil tended to be higher and the AUCt of cycloguanil tended to be lower than in subjects with other types of CYP2C19. Elevated ALT/AST in 4 subjects and drug eruption in 1 subject were reported during the study, all of which all events were mild in intensity.
This is the first report of the pharmacokinetics of atovaquone oral suspension and atovaquone/proguanil HCl combination tablets in a Japanese population, although the two medicines have been used in some patients in Japan. Confirmed pharmacokinetics of ATQ/PRG in a Japanese population will be valuable when administering ATQ/PRG to Japanese patients.
Key word
atovaquone, proguanil HCl, pharmacokinetics
Received
February 19, 2013
Accepted
May 17, 2013
Jpn. J. Chemother. 61 (4): 335-342, 2013
