Atovaquone, sold under the brand name Mepron,
Atovaquone is an analogue of ubiquinone (coenzyme Q10) and exerts its pharmaceutical effects by binding to the ubiquinone binding site on the parasitic mitochondrial cytochrome bc1 complex, thus inhibiting a step of protozoal pyrimidine synthesis.
Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of both ubiquinone and lawsone.
Medical uses
Atovaquone is a medication used to treat and/or prevent:
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For pneumocystis pneumonia (PCP),
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For malaria, it is one of the two components (along with proguanil) in the drug malarone. Malarone has fewer side effects and is more expensive than mefloquine.
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For babesiosis, it is often used in conjunction with oral azithromycin.
Pneumocystis pneumonia
Trimethoprim/sulfamethoxazole (TMP-SMX, Bactrim) is generally considered first-line therapy for PCP (not to be confused with sulfadiazine and pyrimethamine, which is first line for toxoplasmosis). However, atovaquone may be used in patients who cannot tolerate, or are allergic to,
sulfonamide medications such as TMP-SMX. In addition, atovaquone has the advantage of not causing
myelosuppression, which is an important issue in patients who have undergone bone marrow transplantation.
Atovaquone is given prophylactically to kidney transplant patients to prevent PCP in cases where Bactrim is contraindicated for the patient.
Malaria
Atovaquone, as a combination preparation with
proguanil, has been commercially available from
GlaxoSmithKline since 2000 as Malarone for the treatment and prevention of malaria.
Atovaquone/proguanil is highly effective against parasites in the asexual, blood-stage, as well as the primary liver stages of P. falciparum; it is ineffective against the liver-stage hypnozoites of the P. vivax.
Chemoprophylaxis
Atovaquone/proguanil is a standard
chemoprophylaxis for P. falciparum malaria prevention; it is one of three main antimalarial chemoprophylaxis regimens alongside
doxycycline, and
mefloquine (the efficacy of the latter being restricted to regions where microbial resistance has not been established). Its efficacy against liver-stage P. falciparum reduces the required duration of post-exposure prophylaxis. Its safety has been established for up to 20 weeks of continuous use, but it is thought to be safe even in case of years of continuous use.
There is limited evidence regarding efficacy of this chemoprophylactic regiment against other Plasmodium species. P. vivax malaria has been noted following cessation of chemoprophylaxis, suggesting this regiment may fail to exhibit complete efficacy against extra-erythrocytic stages of P. vivax.
Treatment
It is an effective treatment for uncomplicated (mild-to-moderate
) malaria caused by P. falciparum.
In treatment of P. vivax, the initial atovaquone/proguanil course must be followed up with a course of
primaquine.
Resistance
Malarial resistance to atovaquene monotherapy develops rapidly by a single-point mutation in the
cytochrome b gene. Resistance to the atovaquone/proguanil combination is less frequent.
Adverse effects
Atovaquone is associated with gastrointestinal distress, headache, and rash. Adverse effects may necessitate discontinuation of atovaquone therapy. Vomiting and diarrhoea may additionally decrease absorption of atovaquone, causing therapeutic failure (re-administration of a dose after vomiting can be an effective salvage). Atovaqune may cause transient elevations of serum transanimase, and amylase.
Pharmacology
Pharmacodynamics
Atovaquone is a lipophilic analogue of ubiquinone (coenzyme Q10), which serves as electron acceptor of the parasitic inner mitrochondrial membrane cytochrome bc1 complex, which supplies oxidised ubiquinone to the dihydroorotate dehydrogenase, an enzyme that is crucial for parasitic pyrimidine synthesis.
Atovaquone binds to the ubiquinone site of the cytochrome bc1 site, thus inhibiting electron transport and collapsing the mitochondrial membrane potential. This prevents regeneration of ubiquinone and, consequently, pyrimidine synthesis.
The selectivity of atovaquone for the protozoan cytochrome b may be a result of structural differences between the protozoan and the human enzyme.
Synergism
In use for malaria, atovaquone acts
Synergy with the
antifolate proguanil and the two medications are often used in combination; the underlying mechanism of the synergism is unclear as other combinations of electron transport inhibitors and antifolates do not exhibit syngerism.
Proguanil enhances atovaquone's action of collapsing the protozoal mitrochondrial membrane potential.
The atovaquone/proguanil comination significantly reduces the incidence of the development of malarial resistance to atovaquone which arises readily with monotherapy; nevertheless, if resistance develops, the synergy diminishes.
Interactions
Atovaquone may compete for plasma protein binding with some pharmaceuticals.
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Rifampicin - causes a substantial reduction in atovaquone plasma concentration by an unknown mechanism.
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Tetracycline - causes a 40% reduction in atovaquone plasma concentration.
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Zidovudine - atovaquone may increase zidovudine plasma concentrations.
Research
Atovaquone's antiprotozoal effects have been researched in
toxoplasmosis, and visceral leishmaniasis.
COVID-19
Preliminary research found that atovaquone could inhibit the replication of SARS-CoV-2 in vitro.
Clinical trials of atovaquone for the treatment of COVID-19 are planned,
and ongoing in United States in December 2021.
Atovaquone has also been found to inhibit human coronavirus OC43 and feline coronavirus in vitro.
In newer researches, atovaquone did not demonstrate evidence of enhanced SARS-CoV-2 viral clearance compared with placebo.
Veterinary use
Atovaquone is used in livestock veterinary cases of
babesiosis in
cattle, especially if
imidocarb resistance is a concern.
Further reading
External links
