Pharmacotherapeutic Group: Antimalarials. ATC Code: P01B B51.
Pharmacodynamics: Mechanism of Action: The constituents of MALARONE, atovaquone and proguanil hydrochloride, 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.
Pharmacokinetics: There are no pharmacokinetic interactions between atovaquone and proguanil at the recommended dose. In clinical trials, trough levels of atovaquone, proguanil and cycloguanil in children (weighing 11 to 40 kg) are within the effective range observed in adults after adjusting for body-weight.
Absorption: Atovaquone is a highly lipophilic compound with low aqueous solubility.
The pharmacokinetics of atovaquone are comparable between healthy subjects and HIV-infected patients. Although there are no atovaquone biovabilability data in healthy subjects, in HIV-infected patients the absolute bioavailability of a 750 mg single dose of atovaquone tablets taken with food is 21% (90% CI: 17% to 27%).
Dietary fat taken with atovaquone increases the rate and extent of absorption, increasing AUC 2 to 3 times and Cmax 5 times over fasting.
Patients are recommended to take MALARONE tablets with food or a milky drink (see Dosage & Administration).
Proguanil hydrochloride is rapidly and extensively absorbed regardless of food intake.
Distribution: Apparent volume of distribution of atovaquone and proguanil is a function of body-weight.
Atovaquone is highly protein bound (greater than 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 weighing 41 to 80 kg is 42 to 27 L/kg. The volume of distribution is approximately 42 to 20 L/kg in children weighing 11 to 40 kg.
In human plasma the binding of atovaquone and proguanil were unaffected by the presence of the other.
Metabolism: There is no evidence that atovaquone is metabolised and there is negligible excretion of atovaquone in urine with the parent drug being predominantly (greater than 90%) eliminated unchanged in faeces.
Proguanil hydrochloride is partially metabolised 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 MALARONE at recommended doses, proguanil metabolism status appears to have no implications for treatment or prophylaxis of malaria.
Elimination: The elimination half-life of atovaquone is about 2 to 3 days in adults and 1 to 2 days in children.
The elimination half-life of proguanil and cycloguanil is about 12 to 15 hours in both adults and children.
Oral clearance of atovaquone and proguanil is a function of body-weight.
Following oral administration, the clearance of atovaquone in adults and children weighing 41 to 80 kg is approximately 0.16 to 0.05 L/h/kg. The clearance is approximately 0.21 to 0.06 L/h/kg in children weighing 11 to 40 kg.
Following oral administration, the clearance of proguanil in adults weighing 41 to 80 kg is 1.6 to 0.85 L/h/kg. The clearance is approximately 2.2 to 1.0 L/h/kg in children weighing 11 to 40 kg.
Pharmacokinetics in the elderly: 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, but there is no clinically significant change in its elimination half-life (see Dosage & Administration).
Pharmacokinetics in renal impairment: In 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 in patients with severe renal impairment. The elimination half-lives for proguanil and cycloguanil are prolonged in patients with severe renal impairment with corresponding increases in AUC, resulting in the potential of drug accumulation with repeated dosing (see Dosage & Administration and Precautions).
Pharmacokinetics in hepatic impairment: In patients with mild to moderate hepatic impairment there is no clinically significant change in exposure to atovaquone when compared to healthy patients.
In patients with mild to moderate hepatic impairment there is an increase in proguanil AUC with no change in its elimination half-life and there is a decrease in Cmax and AUC for cycloguanil.
No data are available in patients with severe hepatic impairment (see Dosage & Administration).
Toxicology: Pre-clinical Safety Data: Repeat dose toxicity: Findings in repeat dose studies with MALARONE were entirely proguanil related. As proguanil has been used extensively and safely in the treatment and prophylaxis of malaria at doses similar to those used in the fixed dose product MALARONE, these findings are considered of little relevance in the clinical situation.
Mutagenicity: 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.
Carcinogencity: 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.
Microbiology: Atovaquone has potent activity against Plasmodium spp. (in vitro IC50 against P. falciparum 0.23 to 1.43 nanograms/mL).
The antimalarial activity of proguanil is exerted via the primary metabolite cycloguanil (in vitro IC50 against various P. falciparum strains of 4 to 20 nanograms/mL; some activity of proguanil and another metabolite, 4-chlorophenylbiguanide, is seen in vitro at 600-3000 nanograms/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.