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Atovaquone/proguanil is a fixed-dose combination tablet of two antimalarial agents and is highly effective for the prevention of Plasmodium falciparum malaria. In combination with proguanil, the ability of atovaquone to inhibit parasitic mitochondrial electron transport is markedly enhanced. Both atovaquone and proguanil are active against hepatic (pre-erythrocytic) stages of P. falciparum, thereby providing causal prophylaxis and eliminating the need to continue post-travel treatment beyond 7 days. Both agents are also active against erythrocytic stages of P. falciparum, thereby providing suppressive prophylaxis. Atovaquone/proguanil is highly effective against drug-resistant strains of P. falciparum, and cross-resistance has not been observed between atovaquone and other anti-malarial agents.
In comparative, randomised clinical trials, there were no cases of P. falciparum malaria in nonimmune adults, adolescents and children (≥11kg) visiting malaria-endemic regions for ≤28 days and receiving atovaquone/proguanil (250/100mg in adults and dosage based on body weight in children <40kg) once daily. The efficacy for the prevention of P. falciparum malaria was estimated at 100% for atovaquone/proguanil and for mefloquine, and 70% for chloroquine plus proguanil. In individuals (≥11kg) from endemic regions who may carry some immunity to malaria (semi-immune), the prophylactic efficacy rating for atovaquone/proguanil based on placebo-controlled trials was 95–100%.
Atovaquone/proguanil is generally well tolerated by both adults and children. The most common treatment-related adverse events in placebo-controlled trials were headache and abdominal pain, which occurred at a rate similar to that observed with placebo. Atovaquone/proguanil therapy was associated with significantly fewer gastrointestinal adverse events than chloroquine plus proguanil, and significantly fewer neuropsychiatric adverse events than mefloquine in nonimmune individuals. Significantly fewer recipients of atovaquone/proguanil discontinued treatment because of adverse events than individuals receiving chloroquine plus proguanil or mefloquine (p < 0.05).
Conclusion: Atovaquone/proguanil is a fixed-dose combination antimalarial tablet that provides effective prophylaxis of P. falciparum malaria, including drug-resistant strains. Both atovaquone and proguanil are effective against hepatic stages of P. falciparum, which means that treatment need only continue for 7 days after leaving a malaria-endemic region. Atovaquone/proguanil was generally well tolerated and was associated with fewer gastrointestinal adverse events than chloroquine plus proguanil, and fewer neuropsychiatric adverse events than mefloquine. Thus, atovaquone/proguanil provides effective prophylaxis of P. falciparum malaria and compared with other commonly used antimalarial agents has an improved tolerability profile, and, overall, a more convenient dosage regimen, particularly in the post-travel period.
Atovaquone, a hydroxynaphthoquinone, selectively inhibits parasitic mitochondrial electron transport. Although resistance rapidly develops when atovaquone is used as a single agent against Plasmodium falciparum malaria, in combination with proguanil (a biguanide), its activity is enhanced, thereby reducing the likelihood of the emergence of resistance. Cycloguanil, the primary metabolite of proguanil, acts as a parasite dihydrofolate reductase inhibitor. The enhancement of the atovaquone effect, however, is a result of synergy with proguanil, and although this mechanism is not well understood, it is not thought to involve dihydrofolate reductase inhibition.
Both atovaquone and proguanil are active against pre-erythrocytic (hepatic) stages of P. falciparum, thereby providing causal prophylaxis. Both compounds are also active against the erythrocytic parasite stage (suppressive prophylaxis). Atovaquone was more active against various clones and isolates of P. falciparum in the erythrocytic stage than other antimalarial drugs in in vitro studies. The mean 50% inhibitory plasma concentrations (IC50) of atovaquone (0.7–4.3 nmol/L) were lower than those of chloroquine, quinine, mefloquine and artemether against various isolates of P. falciparum. Atovaquone showed similar activity against both chloroquine-sensitive and -resistant isolates of P. falciparum.
Atovaquone/proguanil 250/100mg once daily demonstrated effective causal prophylaxis of P. falciparum malaria in a double-blind, placebo-controlled study in healthy volunteers (n = 16). Parasitaemia was eliminated in all volunteers who received 8 days’ prophylaxis with atovaquone/proguanil and, on day 2, were challenged with bites from mosquitoes infected with P. falciparum malaria; i.e. parasitaemia was eliminated before erythrocytic-stage infection developed. All placebo recipients (n = 4) developed parasitaemia.
Cross-resistance between atovaquone and other antimalarial agents has not been observed in vitro or in malaria rodent models, possibly due to different target sites.
There were no clinically relevant effects on the pharmacokinetic profiles of atovaquone, proguanil or cycloguanil after oral administration of single or multiple doses of a fixed combination tablet of atovaquone/proguanil 250/100mg once daily for 13 days.
Atovaquone is highly lipophilic with low aqueous solubility and shows linear pharmacokinetics, when administered with food, over a dose range of 100–750mg. The drug is poorly absorbed unless taken with fatty food, which increases maximum plasma concentrations (Cmax) by approximately 5-fold. Following a single dose of atovaquone/proguanil 250/100mg, there is a high degree of inter-individual variability in Cmax, although this variability decreased at steady-state. The mean absolute bioavailability of atovaquone when taken with food is 23%. Atovaquone is highly protein bound (>99%) but does not appear to displace other highly protein-bound compounds. There is no apparent accumulation of atovaquone following multiple doses.
The metabolism of atovaquone in humans appears to be negligible. The main route of elimination is hepatic and negligible amounts are excreted in the urine (<1%). The elimination half-life (t1/2) of atovaquone was similar after single or multiple doses (87.2 and 55.9 hours, respectively). Atovaquone clearance increases by almost 2-fold in children compared with adults.
Proguanil shows linear pharmacokinetics and is rapidly and extensively absorbed regardless of food intake. The absolute bioavailability of proguanil is thought to be as high as 60%, and 75% of the drug is bound to plasma protein. Proguanil primarily localises in erythrocytes with concentrations in whole blood approximately 5-fold higher than those in plasma.
Proguanil is metabolised to cycloguanil and to a lesser extent to 4-chlorophenyl biguanide. Metabolism to cycloguanil is mediated primarily via the cytochrome P450 (CYP)2C19 pathway but differences in absorption parameters and t1/2 for proguanil and cycloguanil between extensive and poor CYP2C19 metabolisers were not clinically relevant (13.1 vs 14.5 hours at steady-state). The main route of elimination of proguanil is via renal excretion.
In children, the pharmacokinetic parameters of proguanil and cycloguanil are similar to adults. In patients with severe renal impairment (creatinine clearance <1.8 L/h [<30 ml/min]) there is an increased risk of accumulation of proguanil and more markedly of cycloguanil. The systemic availability of cycloguanil was raised in the elderly compared with younger individuals but this did not appear to be clinically relevant.
Plasma concentrations of atovaquone are decreased when coadministered with rifampicin (rifampin), rifabutin, metoclopramide or tetracycline. Drug interactions between proguanil or cycloguanil and other agents metabolised by the CYP2C19 pathway have not been demonstrated.
In three, large (n > 185) randomised trials in nonimmune adults and children (weighing 11–40kg) visiting malaria-endemic regions for up to 28 days, there were no cases of P. falciparum malaria in individuals receiving oral atovaquone/proguanil (250/100mg in adults and dosage based on bodyweight in children <40kg) once daily. In nonimmune travellers, the efficacy rating for the prevention of P. falciparum malaria was estimated at 100% for atovaquone/proguanil and for mefloquine, and 70% for chloroquine plus proguanil. In a placebo-controlled trial in nonimmune migrants receiving atovaquone/proguanil for the prevention of P. falciparum malaria for 20 weeks, the prophylactic efficacy was 96%.
In three randomised, double-blind, placebo-controlled trials in semi-immune adults and children (i.e. those living in malaria-endemic regions), atovaquone/proguanil was significantly more effective in the prevention of P. falciparum malaria than placebo (p < 0.001), and the overall prophylactic efficacy rating was 95–100%.
The prophylactic regimen of atovaquone/proguanil once daily, for periods of up to 5 months in nonimmune and up to 3 months in semi-immune individuals, was generally well tolerated in clinical trials including more than 3000 adults and children. Overall, the most common adverse events in recipients of atovaquone/proguanil were headache (approximately 4% of adults) and abdominal pain (approximately 4% of adults), which occurred at a rate similar to that observed with placebo.
Atovaquone/proguanil 250/100mg (dosage reduced in children) once daily was at least as well tolerated as comparator agents. In nonimmune travellers atovaquone/proguanil was associated with significantly fewer gastrointestinal adverse events (p = 0.001) than chloroquine plus proguanil (participants aged ≥14 years), and significantly fewer neuropsychiatric adverse events (p = 0.001) and less nausea (p = 0.001) than mefloquine (participants aged ≥3 years). Compared with chloroquine plus proguanil, or mefloquine, atovaquone/proguanil was associated with a significantly lower incidence of treatment-related adverse events (i.e. events that started while the individual was taking the study drug) that lead to withdrawal of prophylaxis (p < 0.05). Eight weeks’ treatment with atovaquone/proguanil 250/100mg daily appeared to be better tolerated than doxycycline in nonimmune adult volunteers.
In nonimmune children (11–40kg), atovaquone/proguanil (dosage based on bodyweight) once daily was associated with fewer treatment-related gastrointestinal adverse events than chloroquine plus proguanil. In a study of semi-immune children, atovaquone/proguanil and placebo were associated with a higher incidence of abdominal pain, vomiting and headache than that reported by adults, but all events were considered mild. Atovaquone/proguanil was at least as well tolerated in the elderly (>65 years) [n = 47] as it was in the entire study population (≥3 years) [n = 1998].
Dosage and Administration
For prophylaxis of P. falciparum malaria in adults, the fixed-dose combination tablet of atovaquone/proguanil 250/100mg should be administered once daily. Dosage in children is based on bodyweight, with a paediatric tablet containing atovaquone/proguanil 62.5/25mg available for children weighing 11–40kg.
Atovaquone/proguanil should be taken at the same time each day with food or a milky drink to maximise absorption. Treatment should be started 1 or 2 days before entering a malaria-endemic area, continued during the stay and for 7 days after leaving the region. If vomiting occurs within 1 hour of administration, a repeat dose should be taken.
Atovaquone/proguanil is contraindicated in patients with severe renal impairment (creatinine clearance 1.8 L/h [<30 ml/min]). Dosage adjustment is not required in the elderly. Concomitant administration of atovaquone/proguanil is not recommended with rifampicin or rifabutin. P. falciparum malaria carries an increased risk in pregnancy both to the mother and the fetus and, if possible, pregnant women should not travel to malaria-endemic regions. Breast feeding is not recommended while receiving atovaquone/proguanil therapy.
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