MEPRON - atovaquone suspension 
GlaxoSmithKline LLC
MEPRON
(atovaquone)
Suspension
DESCRIPTION
MEPRON (atovaquone) is an antiprotozoal agent. The chemical name of atovaquone is trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione. Atovaquone is a yellow crystalline solid that is practically insoluble in water. It has a molecular weight of 366.84 and the molecular formula C22H19ClO3. The compound has the following structural formula:
atovaquone chemical structure
MEPRON Suspension is a formulation of micro-fine particles of atovaquone. The atovaquone particles, reduced in size to facilitate absorption, are significantly smaller than those in the previously marketed tablet formulation. MEPRON Suspension is for oral administration and is bright yellow with a citrus flavor. Each teaspoonful (5 mL) contains 750 mg of atovaquone and the inactive ingredients benzyl alcohol, flavor, poloxamer 188, purified water, saccharin sodium, and xanthan gum.
MICROBIOLOGY
Mechanism of Action
Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystis activity. The mechanism of action against Pneumocystis carinii has not been fully elucidated. In Plasmodium species, the site of action appears to be the cytochrome bc1 complex (Complex III). Several metabolic enzymes are linked to the mitochondrial electron transport chain via ubiquinone. Inhibition of electron transport by atovaquone will result in indirect inhibition of these enzymes. The ultimate metabolic effects of such blockade may include inhibition of nucleic acid and ATP synthesis.
Activity In Vitro
Several laboratories, using different in vitro methodologies, have shown the IC50 (50% inhibitory concentration) of atovaquone against rat P. carinii to be in the range of 0.1 to 3.0 mcg/mL.
Drug Resistance
Phenotypic resistance to atovaquone in vitro has not been demonstrated for P. carinii. However, in 2 patients who developed P. carinii pneumonia (PCP) after prophylaxis with atovaquone, DNA sequence analysis identified mutations in the predicted amino acid sequence of P. carinii cytochrome b (a likely target site for atovaquone). The clinical significance of this is unknown.
CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption
Atovaquone is a highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone is highly dependent on formulation and diet. The suspension formulation provides an approximately 2-fold increase in atovaquone bioavailability in the fasting or fed state compared to the previously marketed tablet formulation. The absolute bioavailability of a 750-mg dose of MEPRON Suspension administered under fed conditions in 9 HIV-infected (CD4 >100 cells/mm3) volunteers was 47% ± 15%. In the same study, the bioavailability of a 750-mg dose of the previously marketed tablet formulation was 23% ± 11%.
Administering atovaquone with food enhances its absorption by approximately 2 fold. In one study, 16 healthy volunteers received a single dose of 750 mg MEPRON Suspension after an overnight fast and following a standard breakfast (23 g fat: 610 kCal). The mean (±SD) area under the concentration-time curve (AUC) values were 324 ± 115 and 801 ± 320 hr●mcg/mL under fasting and fed conditions, respectively, representing a 2.6 ± 1.0-fold increase. The effect of food (23 g fat: 400 kCal) on plasma atovaqu