Efficacy and pharmacokinetics of atovaquone and proguanil in children with multidrug-resistant Plasmodium falciparum malaria

Abstract

A trial was conducted in 32 Thai children with uncomplicated multidrug-resistant falciparum malaria to assess the efficacy, safety and pharmacokinetics of atovaquone and proguanil; plasma concentrations of atovaquone, proguanil and its metabolite, cycloguanil, were measured in a subset of 9 children. The children received atovaquone (17 mg/kg/d for 3 d) plus proguanil (7 mg/kg/d for 3 d). Twenty-six children who had only Plasmodium falciparum infection and remained in hospital for 28 d were assessed for drug efficacy. The combination regimen produced a cure rate of 100%. Parasite and fever clearance times were 47 h (range 8-75) and 50 h (range 7-111), respectively. Atovaquone and proguanil were rapidly absorbed, with median time to peak concentrations of 6 h (range 6-24) and 6 h (range 6-12), respectively. Peak concentrations of cycloguanil were achieved between 6 and 12 h (median 6) after administration of proguanil. Mean peak plasma concentration of atovaquone on day 3 was 5.1 micrograms/mL (SD = 2.1). The day 3 mean peak plasma concentration of proguanil was 306 ng/mL (SD = 108) compared with 44.3 ng/mL (SD = 27.3) for cycloguanil. Mean values for the AUC (area under plasma concentration-time curve) were 161.8 micrograms/mL.h (SD = 126.9) for atovaquone, 4646 ng/mL.h (SD = 1226) for proguanil, and 787 ng/mL.h (SD = 397) for cycloguanil. Terminal elimination half-lives of atovaquone, proguanil and cycloguanil were estimated as 31.8 h (SD = 8.9), 14.9 h (SD = 3.3) and 14.6 h (SD = 2.6), respectively. No major adverse effect was attributable to the study drugs. Atovaquone/proguanil combination is safe and highly effective, and should be especially valuable for treatment of multidrug-resistant falciparum malaria.

Malarone (atovaquone and proguanil hydrochloride): a review of its clinical development for treatment of malaria. Malarone Clinical Trials Study Group.

“…[1][2][3][4][5][6][7][8][9][10] These studies enrolled 1,395 patients with Plasmodium falciparum malaria and 32 patients with non-falciparum malaria, including 278 females and 200 children Յ 12 years of age. Four uncontrolled studies evaluated 397 patients.…”

“…2 One uncontrolled study in Thailand (115-123) evaluated the optimal regimen of atovaquone and proguanil hydrochloride for treatment of malaria in 32 children. 7 Eight randomized, controlled studies (Table 1) compared the optimal regimen of atovaquone and proguanil hydrochloride versus standard antimalarial treatment in 1,030 patients living in endemic countries (seven studies) or returning to France (one study). Seven of these studies were in adults and one (115-131) was in children.…”

“…22 During treatment with atovaquone and proguanil hydrochloride, maximum plasma concentrations of atovaquone are approximately 5 g/ml after the third dose and approximately 1 g/ ml seven days after starting treatment. 7 The enhanced clinical efficacy of atovaquone in combination with proguanil hydrochloride may be due to synergy between these two drugs 15 or to a reduction in the rate at which parasites resistant to both drugs develop. 22 The studies summarized above provide substantial evidence that atovaquone and proguanil hydrochloride is safe and effective for treatment of malaria caused by P. falciparum, and limited data indicate that this combination is also active against the blood stages of P. vivax, P. ovale, and P. malariae.…”

New liquid chromatographic method for simultaneous quantification of Atovaquone and Proguanil with its active metabolite Cycloguanil in human plasma

“…The above cited fact is the primary reason for emergence of many fixed dose combinations in the treatment of malaria, Atovaquone (ATV) and Proguanil (PGN) being one of them. [2][3][4][5][6] ATV is a hydroxyl-1,4-naphthoquinone[CAS: 95233-18-4], an analog of ubiquone with anti-pneumocystic activity. It acts by selectively affecting mitochondrial electron transport and pyridine biosynthesis in plasmodium species.…”

“…Thirdly, simple administration with single daily dose increases the patient compliance. 3,5,7 The Therapeutic Drug Monitoring (TDM) of ATV plus PGN requires a fast, reliable and validated analytical method for estimation in human plasma. The complexity of dosage forms including the presence of multiple drug entities pose challenge during the development of assay procedure.…”