Atovaquone and proguanil interfere with two different pathways involved in the biosynthesis of pyrimidines required for nucleic acid replication. The mechanism of action of atovaquone against P. falciparum is via inhibition of mitochondrial electron transport, at the level of the cytochrome bc1 complex, and collapse of mitochondrial membrane potential. One mechanism of action of proguanil, via its metabolite cycloguanil, is inhibition of dihydrofolate reductase, which disrupts deoxythymidylate synthesis. Proguanil also has antimalarial activity independent of its metabolism to cycloguanil, and proguanil, but not cycloguanil, is able to potentiate the ability of atovaquone to collapse mitochondrial membrane potential in malaria parasites. This latter mechanism may explain the synergy seen when atovaquone and proguanil are used in combination.
Atovaquone has potent activity against Plasmodium spp (in vitro IC50 against P. falciparum 0.23-1.43 ng/mL).
Atovaquone is not cross-resistant with any other antimalarial drugs in current use. Among more than 30 P. falciparum isolates, in vitro resistance was detected against chloroquine (41% of isolates), quinine (32% of isolates), mefloquine (29% of isolates), and halofantrine (48% of isolates) but not atovaquone (0% of isolates).
The antimalarial activity of proguanil is exerted via the primary metabolite cycloguanil (in vitro IC50 against various P. falciparum strains of 4-20 ng/mL; some activity of proguanil and another metabolite, 4-chlorophenylbiguanide, is seen in vitro at 600-3000 ng/mL).
In in vitro studies of P. falciparum the combination of atovaquone and proguanil was shown to be synergistic. This enhanced efficacy was also demonstrated in clinical studies in both immune and non-immune patients.
There are no pharmacokinetic interactions between atovaquone and proguanil at the recommended doses.
In prophylaxis clinical trials where children have received atovaquone/proguanil dosed by bodyweight, trough levels of atovaquone, proguanil and cycloguanil in children are generally within the range observed in adults (see following table).
Trough Plasma Concentrations [Mean ± SD, (range)] of Atovaquone, Proguanil and Cycloguanil during Prophylaxis with atovaquone/proguanil in Children* and Adults:
| Atovaquone:Proguanil HCl Daily Dose | 62.5 mg:25 mg | 125 mg:50 mg | 187.5 mg:75 mg | 250mg:100 mg |
|---|---|---|---|---|
| [Weight Category] | [11-20 kg] | [21-30 kg] | [31-40 kg] | Adult (>40 kg) |
| Atovaquone (μg/mL) No. Subjects | 2.2 ± 1.1 (0.2-5.8) n=87 | 3.2 ± 1.8 (0.2-10.9) n=88 | 4.1 ± 1.8 (0.7-8.8) n=76 | 2.1 + 1.2 (0.1-5.7) n=100 |
| Proguanil (ng/mL) No. Subjects | 12.3 ± 14.4 (<5.0-14.3) n=72 | 18.8 ± 11.2 (<5.0-87.0) n=83 | 26.8 ± 17.1 (5.1-55.9) n=75 | 26.8 + 14.0 (5.2-73.2) n=95 |
| Cycloguanil (ng/mL) No. Subjects | 7.7 ± 7.2 (<5.0-43.5) n=58 | 8.1 ± 6.3 (<5.0-44.1) n=69 | 8.7 ± 7.3 (6.4-17.0) n=66 | 10.9 + 5.6 (5.0-37.8) n=95 |
* Pooled data from two studies
Atovaquone is a highly lipophilic compound with low aqueous solubility. In HIV-infected patients, the absolute bioavailability of a 750 mg single dose of atovaquone tablets taken with food is 23% with an inter-subject variability of about 45%.
Dietary fat taken with atovaquone increases the rate and extent of absorption, increasing AUC 2-3 times and Cmax 5 times over fasting. Patients are recommended to take atovaquone/proguanil tablets with food or a milky drink.
Proguanil hydrochloride is rapidly and extensively absorbed regardless of food intake.
Apparent volume of distribution of atovaquone and proguanil is a function of bodyweight.
Atovaquone is highly protein bound (>99%) but does not displace other highly protein bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely.
Following oral administration, the volume of distribution of atovaquone in adults and children is approximately 8.8 L/kg.
Proguanil is 75% protein bound. Following oral administration, the volume of distribution of proguanil in adults and children ranged from 20 to 42 L/kg.
In human plasma the binding of atovaquone and proguanil was unaffected by the presence of the other.
There is no evidence that atovaquone is metabolised and there is negligible excretion of atovaquone in urine with the parent drug being predominantly (>90%) eliminated unchanged in faeces.
Proguanil hydrochloride is partially metabolised, primarily by the polymorphic cytochrome P450 isoenzyme 2C19, with less than 40% being excreted unchanged in the urine. Its metabolites, cycloguanil and 4-chlorophenylbiguanide, are also excreted in the urine.
During administration of atovaquone/proguanil at recommended doses proguanil metabolism status appears to have no implications for treatment or prophylaxis of malaria.
The elimination half life of atovaquone is about 2-3 days in adults and 1-2 days in children.
The elimination half lives of proguanil and cycloguanil are about 12-15 hours in both adults and children.
Oral clearance for atovaquone and proguanil increases with increased bodyweight and is about 70% higher in an 80 kg subject relative to a 40 kg subject. The mean oral clearance in paediatric and adult patients weighing 10 to 80 kg ranged from 0.8 to 10.8 L/h for atovaquone and from 15 to 106 L/h for proguanil. The mean oral clearance in paediatric and adult patients weighing 5 to 40 kg ranged from 0.5 to 6.3 L/h for atovaquone and from 8.7 to 64 L/h for proguanil.
There is no clinically significant change in the average rate or extent of absorption of atovaquone or proguanil between elderly and young patients. Systemic availability of cycloguanil is higher in the elderly compared to the young patients (AUC is increased by 140% and Cmax is increased by 80%), but there is no clinically significant change in its elimination half life.
There are no studies in children with renal impairment.
In adult patients with mild to moderate renal impairment, oral clearance and/or AUC data for atovaquone, proguanil and cycloguanil are within the range of values observed in patients with normal renal function.
Atovaquone Cmax and AUC are reduced by 64% and 54%, respectively, in patients with severe renal impairment.
In adult patients with severe renal impairment, the elimination half lives for proguanil (t½ 39 h) and cycloguanil (t½ 37 h) are prolonged, resulting in the potential for drug accumulation with repeated dosing.
There are no studies in children with hepatic impairment.
In adult patients with mild to moderate hepatic impairment there is no clinically significant change in exposure to atovaquone when compared to healthy patients.
In adult patients with mild to moderate hepatic impairment there is an 85% increase in proguanil AUC with no change in elimination half life and there is a 65-68% decrease in Cmax and AUC for cycloguanil.
No data are available in patients with severe hepatic impairment.
Findings in repeat dose toxicity studies with atovaquone-proguanil hydrochloride combination were entirely proguanil related and were observed at doses providing no significant margin of exposure in comparison with the expected clinical exposure. As proguanil has been used extensively and safely in the treatment and prophylaxis of malaria at doses similar to those used in the combination, these findings are considered of little relevance to the clinical situation.
In rats and rabbits there was no evidence of teratogenicity for the combination. No data are available regarding the effects of the combination on fertility or pre- and post-natal development, but studies on the individual components of atovaquone/proguanil have shown no effects on these parameters. In a rabbit teratogenicity study using the combination, unexplained maternal toxicity was found at a systemic exposure similar to that observed in humans following clinical use.
A wide range of mutagenicity tests have shown no evidence that atovaquone or proguanil have mutagenic activity as single agents.
Mutagenicity studies have not been performed with atovaquone in combination with proguanil.
Cycloguanil, the active metabolite of proguanil, was also negative in the Ames test, but was positive in the Mouse Lymphoma assay and the Mouse Micronucleus assay. These positive effects with cycloguanil (a dihydrofolate antagonist) were significantly reduced or abolished with folinic acid supplementation.
Oncogenicity studies of atovaquone alone in mice showed an increased incidence of hepatocellular adenomas and carcinomas. No such findings were observed in rats and mutagenicity tests were negative. These findings appear to be due to the inherent susceptibility of mice to atovaquone and are considered of no relevance in the clinical situation.
Oncogenicity studies on proguanil alone showed no evidence of carcinogenicity in rats and mice.
Oncogenicity studies on proguanil in combination with atovaquone have not been performed.
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