Chemistry:Atovaquone

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Atovaquone, sold under the brand name Mepron,[1] is an naphthoquinone antiprotozoal[2] medication used in the prevention and treatment Pneumocystis jirovecii pneumonia (PCP),[1] and malaria (in combination with proguanil), as well as for treatment of babesiosis (in combination with azithromycin).[3]

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.[4]

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:

Pneumocystis pneumonia

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.[4]

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.[4]

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.[4]

Treatment

It is an effective treatment for uncomplicated (mild-to-moderate[4]) malaria caused by P. falciparum.[2] In treatment of P. vivax, the initial atovaquone/proguanil course must be followed up with a course of primaquine.[4]

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.[2][4]

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.[4]

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.[4]

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.[4]

The selectivity of atovaquone for the protozoan cytochrome b may be a result of structural differences between the protozoan and the human enzyme.[4]

Synergism

In use for malaria, atovaquone acts synergistically 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.[2] Proguanil enhances atovaquone's action of collapsing the protozoal mitrochondrial membrane potential.[4]

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.[4]

Interactions

Atovaquone may compete for plasma protein binding with some pharmaceuticals.[4]

  • Rifampicin - causes a substantial reduction in atovaquone plasma concentration by an unknown mechanism.[4]
  • Tetracycline - causes a 40% reduction in atovaquone plasma concentration.[4]
  • Zidovudine - atovaquone may increase zidovudine plasma concentrations.[4]

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.[10] Clinical trials of atovaquone for the treatment of COVID-19 are planned,[11][12] and ongoing in United States in December 2021.[13][needs update]

Atovaquone has also been found to inhibit human coronavirus OC43 and feline coronavirus in vitro.[14]

In newer researches, atovaquone did not demonstrate evidence of enhanced SARS-CoV-2 viral clearance compared with placebo.[15]

Veterinary use

Atovaquone is used in livestock veterinary cases of babesiosis in cattle, especially if imidocarb resistance is a concern.[16]

References

  1. ↑ 1.0 1.1 "Atovaquone Oral SUSPENSION- atovaquone suspension". 10 December 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b31ff20a-c363-4be0-9bc0-3081c163b63c. 
  2. ↑ 2.0 2.1 2.2 2.3 Rang & Dale's Pharmacology (9th ed.). Edinburgh London New York: Elsevier. 2020. pp. 704–705. ISBN 978-0-7020-7448-6. 
  3. ↑ "Antiparasitic agent atovaquone". Antimicrobial Agents and Chemotherapy 46 (5): 1163–1173. May 2002. doi:10.1128/AAC.46.5.1163-1173.2002. ISSN 0066-4804. PMID 11959541. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 Goodman & Gilman's The Pharmacological Basis of Therapeutics. Pharmacology (14th ed.). McGraw Hill. 2023. pp. 1248, 1290, 1294–1295, 1302. ISBN 978-1-264-25808-6. 
  5. ↑ "Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS". The New England Journal of Medicine 328 (21): 1521–1527. May 1993. doi:10.1056/NEJM199305273282103. PMID 8479489. 
  6. ↑ "Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Atovaquone Study Group". Annals of Internal Medicine 121 (3): 174–180. August 1994. doi:10.7326/0003-4819-121-3-199408010-00003. PMID 7880228. 
  7. ↑ "Malarone: New Malaria Medication With Fewer Side-effects". Medical College of Wisconsin. 11 January 2001. http://healthlink.mcw.edu/article/979237802.html. 
  8. ↑ "Evidence of Plasmodium falciparum malaria resistant to atovaquone and proguanil hydrochloride: case reports". BMJ (Clinical Research Ed.) 326 (7390): 628–629. March 2003. doi:10.1136/bmj.326.7390.628. PMID 12649236. 
  9. ↑ "Atovaquone and azithromycin for the treatment of babesiosis". The New England Journal of Medicine 343 (20): 1454–1458. November 2000. doi:10.1056/NEJM200011163432004. PMID 11078770. 
  10. ↑ "Identification of Atovaquone, Ouabain and Mebendazole as FDA-Approved Drugs Targeting SARS-CoV-2". Chemrxiv. May 2020. doi:10.26434/chemrxiv.12003930.v4. https://chemrxiv.org/articles/Identification_of_FDA_Approved_Drugs_Targeting_COVID-19_Virus_by_Structure-Based_Drug_Repositioning/12003930/4. Retrieved 20 June 2020. 
  11. ↑ Clinical trial number NCT04339426 for "Atovaquone and Azithromycin Combination for Confirmed COVID-19 Infection" at ClinicalTrials.gov
  12. ↑ Clinical trial number NCT04456153 for "Atovaquone for Treatment of COVID-19" at ClinicalTrials.gov
  13. ↑ "Ny forskning finder lægemiddel mod corona: 'Kan redde menneskeliv'" (in da). B.T.. 10 December 2021. https://www.bt.dk/samfund/ny-forskning-finder-laegemiddel-mod-corona-kan-redde-menneskeliv. 
  14. ↑ "Repurposing old drugs as antiviral agents for coronaviruses". Biomedical Journal 43 (4): 368–374. August 2020. doi:10.1016/j.bj.2020.05.003. PMID 32563698. 
  15. ↑ "Atovaquone for treatment of COVID-19: A prospective randomized, double-blind, placebo-controlled clinical trial". Frontiers in Pharmacology 13. 2022. doi:10.3389/fphar.2022.1020123. PMID 36249792. 
  16. ↑ "Chemotherapy against babesiosis". Veterinary Parasitology 138 (1–2): 147–160. May 2006. doi:10.1016/j.vetpar.2006.01.048. PMID 16504402. 

Further reading

  • "Molecular basis for atovaquone resistance in Pneumocystis jirovecii modeled in the cytochrome bc(1) complex of Saccharomyces cerevisiae". The Journal of Biological Chemistry 279 (4): 2817–2824. January 2004. doi:10.1074/jbc.M309984200. PMID 14576156. 

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