Atovaquone

Atovaquone is a selective and potent inhibitor of the eukaryotic mitochondrial electron transport chain in a number of parasitic protozoa and the parasitic fungus P. jiroveci. The site of action appears to be the cytochrome bc1 complex (complex III). The ultimate metabolic effect of such blockade is likely to be inhibition of nucleic acid and ATP synthesis.

Microbiology

Atovaquone has potent activity against Pneumocystic sp, both in vitro and in animal models, (IC₅₀ 0.5-8 μg/mL).

Absorption

Atovaquone is a highly lipophilic compound with a low aqueous solubility. It is 99.9% bound to plasma proteins. The bioavailability of the drug demonstrates a relative decrease with single doses above 750 mg, and shows considerable inter-individual variability. Average absolute bioavailablility of a 750 mg single dose of atovaquone suspension administered with food to adult HIV positive males is 47% (compared to 23% for atovaquone tablets). Following the intravenous administration, the volume of distribution and clearance were calculated to be 0.62±0.19 l/kg and 0.15±0.09 ml/min/kg, respectively.

The bioavailability of atovaquone is greater when administered with food than in the fasting state. In healthy volunteers, a standardized breakfast (23 g fat; 610 kCal) increased bioavailability two to three-fold following a single 750 mg dose. The mean area under the atovaquone plasma concentration-time curve (AUC) was increased 2.5 fold and the mean C_max was increased 3.4 fold. The mean (±SD) AUC values for suspension were 324.3 (±115.0) µg/ml.h fasted and 800.6 (±319.8) µg/ml.h with food.

In a safety and pharmacokinetic study in patients with PCP, the following results were obtained:

In a small safety and pharmacokinetic study of two higher dosing regimens [750 mg three times daily (n=8) and 1500 mg twice daily (n=8)] in HIV infected volunteers with severity criteria comparable to patients with PCP, similar C_avg were reached with the two doses [for the 750 mg tid and 1500 mg bid doses: 24.8 (7-40) and 23.4 µg/ml (7-35) respectively]. Moreover, for both doses a C_avg,ss >15 µg/ml was reached in 87.5% of patients.

Average steady state concentrations above 15 µg/ml are predictive of a high (>90%) success rate.

Biotransformation/Elimination

In healthy volunteers and patients with AIDS, atovaquone has a half-life of 2 to 3 days.

In healthy volunteers there is no evidence that the drug is metabolised and there is negligible excretion of atovaquone in the urine, with parent drug being predominantly (>90%) excreted unchanged in faeces.

Carcinogenicity

Oncogenicity studies in mice showed an increased incidence of hepatocellular adenomas and carcinomas without determination of the no observed adverse effect level. 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 not predictive of a risk in the clinical situation.

Reproductive toxicity

In the dosage range of 600 to 1200 mg/kg studies in rabbits gave indications of maternal and embryotoxic effects.