Volume 93, Issue 6
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



This study aimed to investigate the pharmacokinetic interactions between quinine and lopinavir boosted with ritonavir (LPV/r) in healthy Thai adults (8 males and 12 females). Period 1 (day 1): subjects received a single oral dose of 600 mg quinine sulfate. Period 2: subjects received LPV/r (400/100 mg) twice daily. Period 3: subjects received a single quinine sulfate dose plus LPV/r twice a day. Intensive blood sampling was performed during each phase. Quinine AUC (area under the plasma concentration–time curve from time 0 to 48 hours), AUC (area under the plasma concentration–time curve from time 0 to infinity), and (maximum concentration over the time-span specified), were 56%, 57%, and 47% lower, respectively, in the presence of LPV/r. 3-Hydroxyquinine AUC, AUC, and were significantly lower and the metabolite-to-parent ratio was significantly reduced. Lopinavir and ritonavir exposures were not significantly reduced with quinine coadministration, but of both drugs were significantly lower. The geometric mean ratio (GMR) and 90% CI of AUC, AUC, and for quinine, 3-hydroxyquinine, lopinavir, and ritonavir lay outside the bioequivalent range of 0.8–1.25. Drug treatments during all periods were generally well tolerated. The reduction in systemic exposure of quinine and 3-hydroxyquinine with concomitant LPV/r use raises concerns of suboptimal exposure. Studies in HIV/malaria coinfection patients are needed to determine the clinical impact to decide if any change to the quinine dose is warranted.


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  1. World Health Organization, 2015. The Top 10 Causes of Death. Available at: http://www.who.int/mediacentre/factsheets/fs310/en/. Accessed January 6, 2015.
  2. World Health Organization, 2004. Malaria and HIV Interactions and Their Implications for Public Health Policy. Consultation on Malaria and HIV Interactions and Public Health Policy 2004. Available at: http://www.who.int/hiv/pub/prev_care/malariahiv.pdf. Accessed February 12, 2015.
  3. Laufer MK, van Oosterhout JJG, Thesing PC, Thumba F, Zijlstra EE, Graham SM, Taylor TE, Plowe CV, , 2006. Impact of HIV-associated immunosuppression on malaria infection and disease in Malawi. J Infect Dis 193: 872878.[Crossref]
  4. Hoffman I, Jere C, Taylor T, Munthali P, Dyer JR, Wirima JJ, Rogerson SJ, Kumwenda N, Eron JJ, Fiscus SA, Chakraborty H, Taha TE, Cohen MS, Molyneux ME, , 1999. The effect of Plasmodium falciparum malaria on HIV-1 RNA blood plasma concentration. AIDS 13: 487494.[Crossref]
  5. Orlov M, Vaida F, Williamson K, , 2014. Antigen-presenting phagocytic cells ingest malaria parasites and increase HIV replication in a tumor necrosis factor alpha-dependent manner. J Infect Dis 210: 15621572.[Crossref]
  6. Alemu A, Shiferaw Y, Addis Z, Mathewos B, Birhan W, , 2013. Effect of malaria on HIV/AIDS transmission and progression. Parasit Vectors 6: 1822.[Crossref]
  7. Chalwe V, Mukwamataba D, Menten J, Kamalamba J, Mulenga M, D'Alessandro U, , 2009. Increased risk for severe malaria in HIV-1-infected adults, Zambia. Emerg Infect Dis 15: 749755.[Crossref]
  8. Soyinka JO, Onyeji CO, Omoruyi SI, Owolabi AR, Sarma PV, Cook JM, , 2010. Pharmacokinetic interactions between ritonavir and quinine in healthy volunteers following concurrent administration. Br J Clin Pharmacol 69: 262270.[Crossref]
  9. Byakika-Kibwika P, Lamorde M, Okaba-Kayom V, Mayanja-Kizza H, Katabira E, Hanpithakpong W, Pakker N, Dorlo TP, Tarning J, Lindegardh N, de Vries PJ, Back D, Khoo S, Merry C, , 2012. Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults. J Antimicrob Chemother 67: 12171223.[Crossref]
  10. Morris CA, Lopez-Lazaro L, Jung D, Methaneethorn J, Duparc S, Borghini-Fuhrer I, Pokorny R, Shin CS, Fleckenstein L, , 2012. Drug-drug interaction analysis of pyronaridine/artesunate and ritonavir in healthy volunteers. Am J Trop Med Hyg 86: 489495.[Crossref]
  11. Nyunt MM, Lu Y, El-Gasim M, Parsons TL, Petty BG, Hendrix CW, , 2012. Effects of ritonavir-boosted lopinavir on the pharmacokinetics of quinine. Clin Pharmacol Ther 91: 889895.[Crossref]
  12. World Health Organization, 2015. Guidelines for the Treatment of Malaria, 3rd edition. Available at: http://whqlibdoc.who.int/publications/2010/9789241547925_eng.pdf. Accessed February 12, 2015.
  13. Achan J, Talisuna AO, Erhart A, Tibenderana JK, Baliraine FN, Rosenthal PJ, D'Alessandro U, , 2011. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J 10: 1475.[Crossref]
  14. Bamford A, Turkova A, Lyall H, Foster C, Klein N, Bastiaans D, Burger D, Bernadi S, Butler K, Chiappini E, Clayden P, Della Negra M, Giacomet V, Giaquinto C, Gibb D, Galli L, Hainaut M, Koros M, Marques L, Nastouli E, Niehues T, Noguera-Julian A, Rojo P, Rudin C, , 2015. Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV-1 infection 2015: optimizing health in preparation for adult life. HIV Med 3: 12217.
  15. Ahmed BS, Phelps BR, Reuben EB, Ferris RE, , 2014. Does a significant reduction in malaria risk make lopinavir/ritonavir-based ART cost-effective for children with HIV in co-endemic, low-resource settings? Trans R Soc Trop Med Hyg 108: 4954.[Crossref]
  16. Eagling VA, Back DJ, Barry MG, , 1997. Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol 14: 190194.
  17. Sevrioukova IF, Poulos TL, , 2010. Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir. Proc Natl Acad Sci USA 107: 1842218427.[Crossref]
  18. Zhao XJ, Yokoyama H, Chiba K, Chiba K, Wanwimolruk S, Ishizaki T, , 1996. Identification of human cytochrome P450 isoforms involved in the 3-hydroxylation of quinine by human live microsomes and nine recombinant human cytochromes P450. J Pharmacol Exp Ther 279: 13271334.
  19. Lakhman SS, Ma Q, Morse GD, , 2009. Pharmacogenomics of CYP3A: considerations for HIV treatment. Pharmacog 10: 13231339.[Crossref]
  20. Zhang H, Coville PF, Walker RJ, Miners JO, Birkett DJ, Wanwimolruk S, , 1997. Evidence for involvement of human CYP3A in the 3-hydroxylation of quinine. Br J Clin Pharmacol 43: 245252.[Crossref]
  21. Wyen C, Fuhr U, Frank D, Aarnoutse RE, Klaassen T, Lazar A, Seeringer A, Doroshyenko O, Kirchheiner JC, Abdulrazik F, Schmeisser N, Lehmann C, Hein W, Schömig E, Burger DM, Fätkenheuer G, Jetter A, , 2008. Effect of an antiretroviral regimen containing ritonavir boosted lopinavir on intestinal and hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected patients. Clin Pharmacol Ther 84: 7582.[Crossref]
  22. Kumar GN, Jayanti VK, Johnson MK, Uchic J, Thomas S, Lee RD, Grabowski BA, Sham HL, Kempf DJ, Denissen JF, Marsh KC, Sun E, Roberts SA, , 2004. Metabolism and disposition of the HIV-1 protease inhibitor lopinavir (ABT-378) given in combination with ritonavir in rats, dogs, and humans. Pharm Res 21: 16221630.[Crossref]
  23. Schon A, del Mar Ingaramo M, Freire E, , 2003. The binding of HIV-1 protease inhibitors to human serum proteins. Biophys Chem 105: 221230.[Crossref]
  24. Fukushima K, Kobuchi S, Mizuhara K, Aoyama H, Takada K, Sugioka N, , 2013. Time-dependent interaction of ritonavir in chronic use: the power balance between inhibition and induction of P-glycoprotein and cytochrome P450 3A. J Pharm Sci 102: 20442055.[Crossref]
  25. Greman P, Parikh S, Lawrence J, Dorsey G, Rosenthat PJ, Havlir D, Charlebois E, Hanpitakpong W, Lindergardh N, Aweeka FT, , 2009. Lopinavir/ritonavir affects pharmacokinetic exposure of artemether/lumefantrine in HIV-uninfected healthy volunteers. J Acquir Immune Defic Syndr 51: 424429.[Crossref]
  26. Achan J, Kakuru A, Ikilezi G, Ruel T, Clark TD, Nsanabana C, Charlebois E, Aweeka F, Dorsey G, Rosenthal PJ, Havlir D, Kamya MR, , 2012. Antiretroviral agents and prevention of malaria in HIV-infected Ugandan children. N Engl J Med 367: 21102118.[Crossref]
  27. Karbwang J, Na Bangchang K, Molunto P, Bunnag D, , 1989. Determination of quinine and quinidine in biological fluids by high performance liquid chromatography. Southeast Asian J Trop Med Public Health 20: 6569.
  28. National Cancer Institute, 2003. The NCI Common Terminology Criteria for Adverse Events v3.0 (CTCAE). U.S. Department of Health and Human Service, 171. Available at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed April 2, 2012.
  29. Droste JA, Verweij-Van Wissen CP, Burger DM, , 2008. Simultaneous determination of the HIV drugs indinavir, amprenavir, saquinavir, ritonavir, lopinavir, nelfinavir, the nelfinavir hydroxymetabolite M8, and nevirapine in human plasma by reversed-phase high-performance liquid chromatography. Ther Drug Monit 25: 393399.[Crossref]
  30. DiFrancesco R, Tooley K, Rosenkranz SL, Siminski S, Taylor CR, Pande P, Morse GD, , 2013. Clinical pharmacology quality assurance for HIV and related infectious diseases research. Clin Pharmacol Ther 93: 479482.[Crossref]
  31. Gibaldi M, Perrier D, , 1982. Non-compartmental analysis based on statistical moment theory. Pharmacokinetics 2: 409417.
  32. US FDA, 2012. Guidance for Industry: Drug Interaction Studies—Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations. Rockville, MD: Food and Drug Administration, 3954.
  33. Bongiovanni M, Cicconi P, Landonio S, , 2005. Predictive factors of lopinavir/ritonavir discontinuation for drug-related toxicity: results from a cohort of 416 multi-experienced HIV-infected individuals. Int J Antimicrob Agents 26: 8891.[Crossref]
  34. Banhegyi D, Katlama C, da Cunha CA, Schneider S, Rachlis A, Workman C, De Meyer S, Vandevoorde A, Van De Casteele T, Tomaka F, , 2012. Week 96 efficacy, virology and safety of darunavir/r versus lopinavir/r in treatment-experienced patients in TITAN. Curr HIV Res 10: 171181.[Crossref]
  35. Hermes A, Squires K, Fredrick L, Martinez M, Pasley M, Trinh R, Norton M, , 2012. Meta-analysis of the safety, tolerability, and efficacy of lopinavir/ritonavir-containing antiretroviral therapy in HIV-1-infected women. HIV Clin Trials 13: 308323.[Crossref]
  36. AlKadi HO, , 2007. Antimalarial drug toxicity: a review. Chemother 53: 385391.[Crossref]
  37. Flexner C, Tierney C, Gross R, , 2010. Comparison of once-daily versus twice-daily combination antiretroviral therapy in treatment-naive patients: results of AIDS clinical trials group (ACTG) A5073, a 48-week randomized controlled trial. Clin Infect Dis 50: 10411052.[Crossref]
  38. Mirghani RA, Hellgren U, Bertilsson L, Gustafsson LL, Ericsson O, , 2003. Metabolism and elimination of quinine in healthy volunteers. Eur J Clin Pharmacol 59: 423427.[Crossref]
  39. Hull MW, Montaner JSG, , 2011. Ritonavir-boosted protease inhibitors in HIV therapy. Ann Med 43: 375388.[Crossref]
  40. Hesse LM, von Moltke LL, Shader RI, Greenblatt DJ, , 2001. Ritonavir, efavirenz, and nelfinavir inhibit CYP2B6 activity in vitro: potential drug interactions with bupropion. Drug Metab Dispos 29: 100102.
  41. Kharasch ED, Mitchell D, Coles R, Blanco R, , 2008. Rapid clinical induction of hepatic cytochrome P4502B6 activity by ritonavir. Antimicrob Agents Chemother 52: 16631669.[Crossref]
  42. Yeh RF, Gaver VE, Patterson KB, Rezk NL, Baxter-Meheux F, Blake MJ, Eron JJ, Jr Klein CE, Rublein JC, Kashuba AD, , 2006. Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J Acquir Immune Defic Syndr 42: 5260.
  43. Foisy MM, Yakiwchuk EM, Hughes CA, , 2008. Induction effects of ritonavir: implications for drug interactions. Ann Pharmacother 42: 10481059.[Crossref]
  44. Annaert P, Ye ZW, Stieger B, Augustijn S, , 2010. Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1. Xenobiotica 40: 163176.[Crossref]
  45. Lubomirov R, di Iulio J, Fayet A, Colombo S, Martinez R, Marzolini C, Furrer H, Vernazza P, Calmy A, Cavassini M, Ledergerber B, Rentsch K, Descombes P, Buclin T, Decosterd LA, Csajka C, Telenti A, Swiss HIV Cohort Study, , 2010. ADME pharmacogenetics: investigation of the pharmacokinetics of the antiretroviral agent lopinavir coformulated with ritonavir. Pharmacogenet Genomics 20: 217230.
  46. Hartkoorn RC, Kwan WS, Shallcross V, Chaikan A, Liptrott N, Egan D, Sora ES, James CE, Gibbons S, Bray PG, Back DJ, Khoo SH, Owen A, , 2010. HIV protease inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3 and lopinavir plasma concentrations are influenced by SLCO1B1 polymorphisms. Pharmacogenet Genomics 20: 112120.[Crossref]
  47. Bierman WF, Scheffer GL, Schoonderwoerd A, Jansen G, van Agtmael MA, Danner SA, Scheper RJ, , 2010. Protease inhibitors atazanavir, lopinavir and ritonavir are potent blockers, but poor substrates, of ABC transporters in a broad panel of ABC transporter-overexpressing cell lines. J Antimicrob Chemother 65: 16721680.[Crossref]
  48. Silamut K, Molunto P, Ho M, Davis TM, White NJ, , 1991. Alpha 1-acid glycoprotein (orosomucoid) and plasma protein binding of quinine in falciparum malaria. Br J Clin Pharmacol 32: 311315.[Crossref]
  49. Pussard E, Merzouk M, Barennes H, , 2007. Increased uptake of quinine into the brain by inhibition of P-glycoprotein. Eur J Pharm Sci 32: 123127.[Crossref]
  50. Silamut K, White N, Looareesuwan S, Warrell DA, , 1985. Binding of quinine to plasma proteins in falciparum malaria. Am J Trop Med Hyg 34: 681686.
  51. Nsanzabana C, Rosenthal P, , 2011. In vitro activity of antiretroviral drugs against Plasmodium falciparum . Antimicrob Agents Chemother 55: 50735077.[Crossref]
  52. Martin R, Butterworth A, Gardiner D, Kirk K, McCarthy JS, Skinner-Adams TS, , 2012. Saquinavir inhibits the malaria parasite's chloroquine resistance transporter. Antimicrob Agents Chemother 56: 22832289.[Crossref]

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  • Received : 19 Jun 2015
  • Accepted : 16 Aug 2015

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