Antimalarial pharmacology and therapeutics of atovaquone

Journal of Antimicrobial Chemotherapy

Volumn 68, Issue 5, 2013, Pages 977-985

  Nixon, Gemma L ^a   Moss, Darren M ^a   Shone, Alison E ^a   Lalloo, David G ^a   Fisher, Nicholas ^a   O'neill, Paul M ^b   Ward, Stephen A ^a   Biagini, Giancarlo A ^a  

^a LIVERPOOL SCHOOL OF TROPICAL MEDICINE   (United Kingdom)

^b UNIVERSITY OF LIVERPOOL   (United Kingdom)

Author keywords

Drug development; Drug interactions; Malaria; Mechanism of action; Resistance

Indexed keywords

ATOVAQUONE; ATOVAQUONE PLUS PROGUANIL; EFAVIRENZ; ETRAVIRINE; GENERIC DRUG; INDINAVIR; LOPINAVIR; NAPHTHOQUINONE; PHENYTOIN; RALTEGRAVIR; SAQUINAVIR; ZIDOVUDINE;

ABDOMINAL PAIN; ANTIMALARIAL ACTIVITY; AREA UNDER THE CURVE; CHEMOPROPHYLAXIS; CLINICAL DECISION MAKING; COST CONTROL; DIARRHEA; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG COST; DRUG DISTRIBUTION; DRUG ELIMINATION; DRUG INDUSTRY; DRUG MECHANISM; DRUG METABOLISM; DRUG SAFETY; DRUG SOLUBILITY; DRUG TREATMENT FAILURE; FEVER; HEADACHE; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IC 50; MALARIA; MAXIMUM PLASMA CONCENTRATION; MISSENSE MUTATION; NONHUMAN; PHARMACOPHORE; PRESCRIPTION; RASH; REVIEW; TIME TO MAXIMUM PLASMA CONCENTRATION; TRAVEL; UNITED STATES; VOMITING;

ANTIMALARIALS; ATOVAQUONE; CHEMOPREVENTION; DRUG COMBINATIONS; HUMANS; MALARIA; PROGUANIL; UNITED STATES;

EID: 84877140359     PISSN: 03057453     EISSN: 14602091     Source Type: Journal    
DOI: 10.1093/jac/dks504     Document Type: Review

References (83)

1. Hudson AT. Atovaquone-a novel broad-spectrum antiinfective drug. Parasitol Today 1993; 9: 66-8.
2. McKeage K, Scott LJ. Atovaquone/proguanil-a review of its use for the prophylaxis of Plasmodium falciparum malaria. Drugs 2003; 63: 597-623.
3. Nakato H, Vivancos R, Hunter PR. A systematic review and meta-analysis of the effectiveness and safety of atovaquone-proguanil (Malarone) for chemoprophylaxis against malaria. J Antimicrob Chemother 2007; 60: 929-36.
4. Looareesuwan S, Chulay JD, Canfield CJ et al. Malaronew (atovaquone and proguanil hydrochloride): a review of its clinical development for treatment of malaria. Am J Trop Med Hyg 1999; 60: 533-41.
5. Spencer CM, Goa KL. Atovaquone-a review of its pharmacological properties and therapeutic efficacy in opportunistic infections. Drugs 1995; 50: 176-96.
6. Haile LG, Flaherty JF. Atovaquone-a review. Ann Pharmacother 1993; 27: 1488-94.
7. Osei-Akoto A, Orton LC, Owusu-Ofori S. Atovaquone-proguanil for treating uncomplicated malaria. Cochrane Database Syst Rev 2005; Issue 4: CD004529.
8. Lalloo DG, Hill DR. Preventing malaria in travellers. BMJ 2008; 336: 1362-6.
9. LaRocque RC, Rao SR, Lee J et al. Global TravEpiNet: a national consortium of clinics providing care to international travelers-analysis of demographic characteristics, travel destinations, and pretravel healthcare of high-risk US international travelers, 2009-2011. Clin Infect Dis 2012; 54: 455-62.
10. Fieser LF, Richardson AP. Naphthoquinone antimalarials. II. Correlation of structure and activity against P. lophurae in ducks. J Am Chem Soc 1948; 70: 3156-65.
11. Fieser LF, Heymann H, Seligman AM. Naphthoquinone antimalarials. XX. Metabolic degradation. J Pharmacol Exp Ther 1948; 94: 112-24.
12. Fieser LF, Chang FC, Dauben WG et al. Naphthoquinone antimalarials. XVIII. Metabolic oxidation products. J Pharmacol Exp Ther 1948; 94: 85-96.
13. Fieser LF, Schirmer JP, Archer S et al. Naphthoquinone antimalarials. XXIX. 2-Hydroxy-3-(omega-cyclohexylalkyl)-1,4-naphthoquinones. J Med Chem 1967; 10: 513-7.
14. Fawaz G, Haddad FS. The effect of lapinone (M-2350) on P. vivax infection in man. Am J Trop Med 1951; 31: 569-71.
15. Hudson AT, Randall AW, Fry M et al. Novel anti-malarial hydroxynaphthoquinones with potent broad-spectrum anti-protozoal activity. Parasitology 1985; 90: 45-55.
16. Hudson AT, Pether MJ, Randall AW et al. In vitro activity of 2-cycloalkyl-3-hydroxy-1,4-naphthoquinones against Theileria, Eimeria and Plasmodia species. Eur J Med Chem 1986; 21: 271-5.
17. Hudson AT, Dickins M, Ginger CD et al. 566C80: a potent broad spectrum anti-infective agent with activity against malaria and opportunistic infections in AIDS patients. Drugs Exp Clin Res 1991; 17: 427-35.
18. Patent WO9320044. 1,4 Naphthoquinone derivatives with antiprotozoal and anti-parasitic activity. http://www.freepatentsonline.com/EP0634996.html (8 November 2012, date last accessed).
19. Patent 4981874. Medicaments. http://www.google.com/patents/US4981874 (8 November 2012, date last accessed).
20. Williams DR, Clark MP. Synthesis of atovaquone. Tetrahedron Lett 1998; 39: 7629-32.
21. Patent WO/2010/001379. A process for preparing atovaquone and associate intermediates. http://patentscope.wipo.int/search/en/WO2010001379 (8 November 2012, date last accessed).
22. Patent WO/2010/001378. Process for the epimerization of atovaquone isomer, atovaquone intermediates and mixtures thereof. http://patentscope.wipo.int/search/en/WO2010001378 (8 November 2012, date last accessed).
23. Patent WO/2008/122988. Process for preparation of atovaquone and the conversion of cis-isomer to trans-isomer. http://www.freepatentsonline.com/WO2008122988.html (8 November 2012, date last accessed).
24. Baggish AL, Hill DR. Antiparasitic agent atovaquone. Antimicrob Agents Chemother 2002; 46: 1163-73.
25. Biagini GA, Fisher N, Shone AE et al. Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria. Proc Natl Acad Sci USA 2012; 109: 8298-303.
26. Zhang Y, Clark JA, Connelly MC et al. Lead optimization of 3-carboxyl-4(1H)-quinolones to deliver orally bioavailable antimalarials. J Med Chem 2012; 55: 4205-19.
27. Cross RM, Namelikonda NK, Mutka TS et al. Synthesis, antimalarial activity, and structure-activity relationship of 7-(2-phenoxyethoxy)-4(1H)-quinolones. J Med Chem 2011; 54: 8321-7.
28. Barton V, Fisher N, Biagini GA et al. Inhibiting Plasmodium cytochrome bc1: a complex issue. Curr Opin Chem Biol 2010; 14: 440-6.
29. Winter RW, Kelly JX, Smilkstein MJ et al. Optimization of endochin-like quinolones for antimalarial activity. Exp Parasitol 2011; 127: 545-51.
30. Winter RW, Kelly JX, Smilkstein MJ et al. Antimalarial quinolones: synthesis, potency, and mechanistic studies. Exp Parasitol 2008; 118: 487-97.
31. Fry M, Pudney M. Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4'-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80). Biochem Pharmacol 1992; 43: 1545-3.
32. Srivastava IK, Rottenberg H, Vaidya AB. Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite. J Biol Chem 1997; 272: 3961-6.
33. Biagini GA, Viriyavejakul P, O'Neill PM et al. Functional characterization and target validation of alternative complex I of Plasmodium falciparum mitochondria. Antimicrob Agents Chemother 2006; 50: 1841-51.
34. Seymour KK, Yeo AE, Rieckmann KH et al. dCTP levels are maintained in Plasmodium falciparum subjected to pyrimidine deficiency or excess. Ann Trop Med Parasitol 1997; 91: 603-9.
35. Hammond DJ, Burchell JR, Pudney M. Inhibition of pyrimidine biosynthesis de novo in Plasmodium falciparum by 2-(4-tbutylcyclohexyl)-3-hydroxy-1,4-naphthoquinone in vitro. Mol Biochem Parasitol 1985; 14: 97-109.
36. Painter HJ, Morrisey JM, Mather MW et al. Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum. Nature 2007; 446: 88-91.
37. Bulusu V, Jayaraman V, Balaram H. Metabolic fate of fumarate, a side product of the purine salvage pathway in the intraerythrocytic stages of Plasmodium falciparum. J Biol Chem 2011; 286: 9236-45.
38. White NJ. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob Agents Chemother 1997; 41: 1413-22.
39. Dembele L, Gego A, Zeeman AM et al. Towards an in vitro model of Plasmodium hypnozoites suitable for drug discovery. PLoS One 2011; 6: e18162.
40. Kessl JJ, Meshnick SR, Trumpower BL. Modeling the molecular basis of atovaquone resistance in parasites and pathogenic fungi. Trends Parasitol 2007; 23: 494-501.
41. Korsinczky M, Chen N, Kotecka B et al. Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site. Antimicrob Agents Chemother 2000; 44: 2100-8.
42. Musset L, Bouchaud O, Matheron S et al. Clinical atovaquoneproguanil resistance of Plasmodium falciparum associated with cytochrome b codon 268 mutations. Microbes Infect 2006; 8: 2599-604.
43. Berry A, Senescau A, Lelievre J et al. Prevalence of Plasmodium falciparum cytochrome b gene mutations in isolates imported from Africa, and implications for atovaquone resistance. Trans R Soc Trop Med Hyg 2006; 100: 986-8.
44. Fivelman QL, Butcher GA, Adagu IS et al. Malarone treatment failure and in vitro confirmation of resistance of Plasmodium falciparum isolate from Lagos, Nigeria. Malar J 2002; 1: 1.
45. Schwartz E, Bujanover S, Kain KC. Genetic confirmation of atovaquone-proguanil-resistant Plasmodium falciparum malaria acquired by a nonimmune traveler to East Africa. Clin Infect Dis 2003; 37: 450-1.
46. Fisher N, Majid RA, Antoine T et al. Cytochrome b mutation Y268S conferring atovaquone resistance phenotype in malaria parasite results in reduced parasite bc1 catalytic turnover and protein expression. J Biol Chem 2012; 287: 9731-41.
47. Chiodini PL, Conlon CP, Hutchinson DB et al. Evaluation of atovaquone in the treatment of patients with uncomplicated Plasmodium falciparum malaria. J Antimicrob Chemother 1995; 36: 1073-8.
48. Looareesuwan S, Viravan C, Webster HK et al. Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. Am J Trop Med Hyg 1996; 54: 62-6.
49. Pesole G, Gissi C, De Chirico A et al. Nucleotide substitution rate of mammalian mitochondrial genomes. J Mol Evol 1999; 48: 427-34.
50. Smilkstein MJ, Forquer I, Kanazawa A et al. A drug-selected Plasmodium falciparum lacking the need for conventional electron transport. Mol Biochem Parasitol 2008; 159: 64-8.
51. Ding XC, Ubben D, Wells TN. A framework for assessing the risk of resistance for anti-malarials in development. Malar J 2012; 11: 292.
52. Thapar MM, Ashton M, Lindegardh N et al. Time-dependent pharmacokinetics and drug metabolism of atovaquone plus proguanil (Malarone) when taken as chemoprophylaxis. Eur J Clin Pharmacol 2002; 58: 19-27.
53. Khositnithikul R, Tan-Ariya P, Mungthin M. In vitro atovaquone/proguanil susceptibility and characterization of the cytochrome b gene of Plasmodium falciparum from different endemic regions of Thailand. Malar J 2008; 7: 23.
54. Biagini GA, Fisher N, Berry N et al. Acridinediones: selective and potent inhibitors of the malaria parasite mitochondrial bc1 complex. Mol Pharmacol 2008; 73: 1347-55.
55. Zsila F, Fitos I. Combination of chiroptical, absorption and fluorescence spectroscopic methods reveals multiple, hydrophobicitydriven human serum albumin binding of the antimalarial atovaquone and related hydroxynaphthoquinone compounds. Org Biomol Chem 2010; 8: 4905-14.
56. Hughes W, Leoung G, Kramer F et al. Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med 1993; 328: 1521-7.
57. Wichmann O, Muehlen M, Gruss H et al. Malarone treatment failure not associated with previously described mutations in the cytochrome b gene. Malar J 2004; 3: 14.
58. Durand R, Prendki V, Cailhol J et al. Plasmodium falciparum malaria and atovaquone-proguanil treatment failure. Emerg Infect Dis 2008; 14: 320-2.
59. Hughes WT, Kennedy W, Shenep JL et al. Safety and pharmacokinetics of 566C80, a hydroxynaphthoquinone with anti-Pneumocystis carinii activity: a phase I study in human immunodeficiency virus (HIV)-infected men. J Infect Dis 1991; 163: 843-8.
60. Rosenberg DM, McCarthy W, Slavinsky J et al. Atovaquone suspension for treatment of Pneumocystis carinii pneumonia in HIV-infected patients. AIDS 2001; 15: 211-4.
61. Hussein Z, Eaves J, Hutchinson DB et al. Population pharmacokinetics of atovaquone in patients with acute malaria caused by Plasmodium falciparum. Clin Pharmacol Ther 1997; 61: 518-30.
62. Nicolaides E, Galia E, Efthymiopoulos C et al. Forecasting the in vivo performance of four low solubility drugs from their in vitro dissolution data. Pharm Res 1999; 16: 1876-2.
63. Rolan PE, Mercer AJ, Weatherley BC et al. Examination of some factors responsible for a food-induced increase in absorption of atovaquone. Brit J Clin Pharmacol 1994; 37: 13-20.
64. Chotivanich K, Mungthin M, Ruengweerayuth R et al. The effects of serum lipids on the in vitro activity of lumefantrine and atovaquone against Plasmodium falciparum. Malar J 2012; 11: 177.
65. Dixon R, Pozniak AL, Watt HM et al. Single-dose and steady-state pharmacokinetics of a novel microfluidized suspension of atovaquone in human immunodeficiency virus-seropositive patients. Antimicrob Agents Chemother 1996; 40: 556-60.
66. Rolan PE, Mercer AJ, Tate E et al. Disposition of atovaquone in humans. Antimicrob Agents Chemother 1997; 41: 1319-21.
67. van Luin M, Van der Ende ME, Richter C et al. Lower atovaquone/proguanil concentrations in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. AIDS 2010; 24: 1223-6.
68. Hidalgo K, Lyles A, Dean SR. A potential interaction between warfarin and atovaquone. Ann Pharmacother 2011; 45: e3.
69. Davis JD, Dixon R, Khan AZ et al. Atovaquone has no effect on the pharmacokinetics of phenytoin in healthy male volunteers. Br J Clin Pharmacol 1996; 42: 246-8.
70. Sousa M, Pozniak A, Boffito M. Pharmacokinetics and pharmacodynamics of drug interactions involving rifampicin, rifabutin and antimalarial drugs. J Antimicrob Chemother 2008; 62: 872-8.
71. Miller JL, Trepanier LA. Inhibition by atovaquone of CYP2C9-mediated sulphamethoxazole hydroxylamine formation. Eur J Clin Pharmacol 2002; 58: 69-72.
72. Tommasi C, Bellagamba R, Tempestilli M et al. Marked increase in etravirine and saquinavir plasma concentrations during atovaquone/proguanil prophylaxis. Malar J 2011; 10: 141.
73. Scholler-Gyure M, Kakuda TN, Raoof A et al. Clinical pharmacokinetics and pharmacodynamics of etravirine. Clin Pharmacokine 2009; 48: 561-74.
74. Eagling VA, Wiltshire H, Whitcombe IW et al. CYP3A4-mediated hepatic metabolism of the HIV-1 protease inhibitor saquinavir in vitro. Xenobiotica 2002; 32: 1-17.
75. Kassahun K, McIntosh I, Cui D et al. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dis 2007; 35: 1657-3.
76. Lee BL, Tauber MG, Sadler B et al. Atovaquone inhibits the glucuronidation and increases the plasma concentrations of zidovudine. Clin Pharmacol Ther 1996; 59: 14-21.
77. Cretton EM, Xie MY, Bevan RJ et al. Catabolism of 3'-azido-3'-deoxythymidine in hepatocytes and liver microsomes, with evidence of formation of 3'-amino-3'-deoxythymidine, a highly toxic catabolite for human bone marrow cells. Mol Pharmacol 1991; 39: 258-66.
78. Belanger AS, Caron P, Harvey M et al. Glucuronidation of the antiretroviral drug efavirenz by UGT2B7 and an in vitro investigation of drug-drug interaction with zidovudine. Drug Metab Dis 2009; 37: 1793-6.
79. Emmanuel A, Gillotin C, Farinotti R. Atovaquone suspension and indinavir have minimal pharmacokinetic interactions. In: Abstracts of the Twelfth International Conference on AIDS, Geneva, Switzerland, 1998. Abstract 12384.
80. Hochman JH, Chiba M, Nishime J et al. Influence of P-glycoprotein on the transport and metabolism of indinavir in Caco-2 cells expressing cytochrome P-450 3A4. J Pharmacol Exp Ther 2000; 292: 310-8.
81. Cheung TW. Overdose of atovaquone in a patient with AIDS. AIDS 1999; 13: 1984-5.
82. Marroquin LD, Hynes J, Dykens JA et al. Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants. Toxicol Sci 2007; 97: 539-47.
83. Solmaz SR, Hunte C. Structure of complex III with bound cytochrome c in reduced state and definition of a minimal core interface for electron transfer. J Biol Chem 2008; 283: 17542-9.