Antimalarial pharmacology and therapeutics of atovaquone

Abstract

Atovaquone is used as a fixed-dose combination with proguanil (Malarone) for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travellers. Indeed, in the USA, between 2009 and 2011, Malarone prescriptions accounted for 70% of all antimalarial pre-travel prescriptions. In 2013 the patent for Malarone will expire, potentially resulting in a wave of low-cost generics. Furthermore, the malaria scientific community has a number of antimalarial quinolones with a related pharmacophore to atovaquone at various stages of pre-clinical development. With this in mind, it is timely here to review the current knowledge of atovaquone, with the purpose of aiding the decision making of clinicians and drug developers involved in the future use of atovaquone generics or atovaquone derivatives.

Figure 1.

Historical development of atovaquone and its pharmacokinetic properties. MW, molecular weight; m, measured; p, predicted; PSA, polar surface area; PPB, plasma protein binding.

Figure 2.

Synthetic routes used to synthesize atovaquone. (a) The original synthesis of atovaquone. (b) Williams and Clarke atovaquone synthesis. (c) Improved atovaquone synthesis.

Figure 3.

(a) Cartoon representation of the yeast cytochrome bc₁ complex (3CX5.PDB), with atovaquone modelled at the Q_o site (boxed area). The bc₁ complex is a structural and functional homodimer with a molecular mass of ∼480 kDa, consisting of 10 discrete subunits per monomer in yeast and P. falciparum. The electron-transferring catalytic unit of one monomer is highlighted; cytochrome b is represented in orange, cytochrome c₁ in blue and the Rieske iron-sulphur protein (ISP) in green. Haem groups (cyt b and cyt c₁) are shown in red. The remaining subunits of the complex are rendered in grey. (b) Molecular model of atovaquone (Atv) bound to the Q_o site of the bc₁ complex. Subunits are coloured as in panel (a). Atovaquone was modelled into the Q_o site of cytochrome b as described by Fisher et al. Hydrogen-bonding interactions between the naphthoquinone head group of atovaquone and side chains of Glu-272 (cyt b) and His-181 (ISP) are indicated by yellow lines. The positions of haem b_l (cyt b) and the ISP [2Fe2S] cluster are also shown.

Figure 4.

Atovaquone plasma concentration–time profile after a single dose of Malarone in 13 healthy individuals. Reproduced with permission from the study by Thapar et al.