The AAPS Journal

, Volume 16, Issue 5, pp 962–974 | Cite as

Making the Most of Clinical Data: Reviewing the Role of Pharmacokinetic-Pharmacodynamic Models of Anti-malarial Drugs

  • Julie A. SimpsonEmail author
  • Sophie Zaloumis
  • Alysha M. DeLivera
  • Ric N. Price
  • James M McCaw
Review Article


Mechanistic within-host models integrating blood anti-malarial drug concentrations with the parasite-time profile provide a valuable decision tool for determining dosing regimens for anti-malarial treatments, as well as a formative component of population-level drug resistance models. We reviewed published anti-malarial pharmacokinetic-pharmacodynamic models to identify the challenges for these complex models where parameter estimation from clinical field data is limited. The inclusion of key pharmacodynamic processes in the mechanistic structure adopted varies considerably. These include the life cycle of the parasite within the red blood cell, the action of the anti-malarial on a specific stage of the life cycle, and the reduction in parasite growth associated with immunity. With regard to estimation of the pharmacodynamic parameters, the majority of studies simply compared descriptive summaries of the simulated outputs to published observations of host and parasite responses from clinical studies. Few studies formally estimated the pharmacodynamic parameters within a rigorous statistical framework using observed individual patient data. We recommend three steps in the development and evaluation of these models. Firstly, exploration through simulation to assess how the different parameters influence the parasite dynamics. Secondly, application of a simulation-estimation approach to determine whether the model parameters can be estimated with reasonable precision based on sampling designs that mimic clinical efficacy studies. Thirdly, fitting the mechanistic model to the clinical data within a Bayesian framework. We propose that authors present the model both schematically and in equation form and give a detailed description of each parameter, including a biological interpretation of the parameter estimates.


anti-malarial treatment Bayesian methods parameter estimation pharmacokinetic-pharmacodynamic model Plasmodium falciparum 



The work was supported by the Victorian Centre for Biostatistics (ViCBiostat), which is funded by the National Health and Medical Research Centre of Australia (NHMRC) Centre of Research Excellence 1035261, and by NHMRC Project Grant 1025319. JMcC is supported by an Australian Research Council Future Fellowship 1101002580. RNP is a Wellcome Trust Senior Fellow in Clinical Science (091625).


  1. 1.
    WHO. World Malaria Report. Geneva: Available: 2008.
  2. 2.
    WHO. Guidelines for the treatment of malaria. Geneva. Available from 2010.
  3. 3.
    Barnes KI, Watkins WM, White NJ. Antimalarial dosing regimens and drug resistance. Trends Parasitol. 2008;24(3):127–34.Google Scholar
  4. 4.
    Czock D, Keller F. Mechanism-based pharmacokinetic-pharmacodynamic modeling of antimicrobial drug effects. J Pharmacokinet Pharmacodyn. 2007;34(6):727–51.PubMedCrossRefGoogle Scholar
  5. 5.
    Winter K, Hastings IM. Development, evaluation, and application of an in silico model for antimalarial drug treatment and failure. Antimicrob Agents Chemother. 2011;55(7):3380–92.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Zaloumis S, Humberstone A, Charman SA, Price RN, Moehrle J, Gamo-Benito J, et al. Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development. Malar J. 2012;11:303.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Kay K, Hastings IM. Improving pharmacokinetic-pharmacodynamic modeling to investigate anti-infective chemotherapy with application to the current generation of antimalarial drugs. PLoS Comput Biol. 2013;9(7):e1003151.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Pongtavornpinyo W, Hastings IM, Dondorp A, White LJ, Maude RJ, Saralamba S, et al. Probability of emergence of antimalarial resistance in different stages of the parasite life cycle. Evol Appl. 2009;2(1):52–61.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Austin DJ, White NJ, Anderson RM. The dynamics of drug action on the within-host population growth of infectious agents: melding pharmacokinetics with pathogen population dynamics. J Theor Biol. 1998;194(3):313–39.PubMedCrossRefGoogle Scholar
  10. 10.
    Gordi T, Xie R, Jusko WJ. Semi-mechanistic pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of artemisinin. Br J Clin Pharmacol. 2005;60(6):594–604.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Gravenor MB, van Hensbroek MB, Kwiatkowski D. Estimating sequestered parasite population dynamics in cerebral malaria. Proc Natl Acad Sci U S A. 1998;95(13):7620–4.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Hoshen MB, Na-Bangchang K, Stein WD, Ginsburg H. Mathematical modelling of the chemotherapy of Plasmodium falciparum malaria with artesunate: postulation of ‘dormancy’, a partial cytostatic effect of the drug, and its implication for treatment regimens. Parasitology. 2000;121(Pt 3):237–46.PubMedCrossRefGoogle Scholar
  13. 13.
    Hoshen MB, Stein WD, Ginsburg HD. Pharmacokinetic-pharmacodynamic modelling of the antimalarial activity of mefloquine. Parasitology. 2001;123(Pt 4):337–46.PubMedGoogle Scholar
  14. 14.
    Saralamba S, Pan-Ngum W, Maude RJ, Lee SJ, Tarning J, Lindegardh N, et al. Intrahost modeling of artemisinin resistance in Plasmodium falciparum. Proc Natl Acad Sci U S A. 2011;108(1):397–402.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Simpson JA, Watkins ER, Price RN, Aarons L, Kyle DE, White NJ. Mefloquine pharmacokinetic-pharmacodynamic models: implications for dosing and resistance. Antimicrob Agents Chemother. 2000;44(12):3414–24.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Smith T, Dietz K, Vounatsou P, Muller I, English M, Marsh K. Bayesian age-stage modelling of Plasmodium falciparum sequestered parasite loads in severe malaria patients. Parasitology. 2004;129(Pt 3):289–99.PubMedCrossRefGoogle Scholar
  17. 17.
    Svensson US, Alin H, Karlsson MO, Bergqvist Y, Ashton M. Population pharmacokinetic and pharmacodynamic modelling of artemisinin and mefloquine enantiomers in patients with falciparum malaria. Eur J Clin Pharmacol. 2002;58(5):339–51.PubMedCrossRefGoogle Scholar
  18. 18.
    Hoshen MB, Stein WD, Ginsburg H. Modelling the chloroquine chemotherapy of falciparum malaria: the value of spacing a split dose. Parasitology. 1998;116(Pt 5):407–16.PubMedCrossRefGoogle Scholar
  19. 19.
    Hoshen MB, Stein WD, Ginsburg H. Mathematical modelling of malaria chemotherapy: combining artesunate and mefloquine. Parasitology. 2002;124(Pt 1):9–15.PubMedGoogle Scholar
  20. 20.
    Hodel EM, Kay K, Hayes DJ, Terlouw DJ, Hastings IM. Optimizing the programmatic deployment of the anti-malarials artemether-lumefantrine and dihydroartemisinin-piperaquine using pharmacological modelling. Malar J. 2014;13:138.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Hietala SF, Martensson A, Ngasala B, Dahlstrom S, Lindegardh N, Annerberg A, et al. Population pharmacokinetics and pharmacodynamics of artemether and lumefantrine during combination treatment in children with uncomplicated falciparum malaria in Tanzania. Antimicrob Agents Chemother. 2010;54(11):4780–8.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Gravenor MB, Lloyd AL, Kremsner PG, Missinou MA, English M, Marsh K, et al. A model for estimating total parasite load in falciparum malaria patients. J Theor Biol. 2002;217(2):137–48.PubMedCrossRefGoogle Scholar
  23. 23.
    Amaratunga C, Sreng S, Suon S, Phelps ES, Stepniewska K, Lim P, et al. Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study. Lancet Infect Dis. 2012;12(11):851–8.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;361(5):455–67.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Noedl H, Se Y, Sriwichai S, Schaecher K, Teja-Isavadharm P, Smith B, et al. Artemisinin resistance in Cambodia: a clinical trial designed to address an emerging problem in Southeast Asia. Clin Infect Dis. 2010;51(11):e82–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Phyo AP, Nkhoma S, Stepniewska K, Ashley EA, Nair S, McGready R, et al. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet. 2012;379(9830):1960–6.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Dietz K, Raddatz G, Molineaux L. Mathematical model of the first wave of Plasmodium falciparum asexual parasitemia in non-immune and vaccinated individuals. AmJTrop Med Hyg. 2006;75(2 Suppl):46–55.Google Scholar
  28. 28.
    Klonis N, Xie SC, McCaw JM, Crespo-Ortiz MP, Zaloumis SG, Simpson JA, et al. Altered temporal response of malaria parasites determines differential sensitivity to artemisinin. Proc Natl Acad Sci U S A. 2013;110(13):5157–62.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Geary TG, Divo AA, Jensen JB. Stage specific actions of antimalarial drugs on Plasmodium falciparum in culture. AmJTrop Med Hyg. 1989;40(3):240–4.Google Scholar
  30. 30.
    Simpson JA, Price R, ter Kuile F, Teja-Isavatharm P, Nosten F, Chongsuphajaisiddhi T, et al. Population pharmacokinetics of mefloquine in patients with acute falciparum malaria. Clin Pharmacol Ther. 1999;66(5):472–84.PubMedCrossRefGoogle Scholar
  31. 31.
    Price RN, Simpson JA, Davis TME. Artemisinins. Kucers’ the use of antibiotics. 6th ed: Hodder Arnold; 2010. pp. 2090–104.Google Scholar
  32. 32.
    Evans M, Hastings N, Peacock B. “von Mises distribution”. Statistical distributions. 3rd ed. Wiley: New York; 2000. p. 189–91.Google Scholar
  33. 33.
    Jamsen KM, Duffull SB, Tarning J, Lindegardh N, White NJ, Simpson JA. Optimal designs for population pharmacokinetic studies of oral artesunate in patients with uncomplicated falciparum malaria. Malar J. 2011;10:181.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Jamsen KM, Duffull SB, Tarning J, Lindegardh N, White NJ, Simpson JA. Optimal designs for population pharmacokinetic studies of the partner drugs co-administered with artemisinin derivatives in patients with uncomplicated falciparum malaria. Malar J. 2012;11:143.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    White NJ. The parasite clearance curve. Malar J. 2011;10:278.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Price R, Nosten F, Simpson JA, Luxemburger C, Phaipun L, ter Kuile F, et al. Risk factors for gametocyte carriage in uncomplicated falciparum malaria. AmJTrop Med Hyg. 1999;60(6):1019–23.Google Scholar
  37. 37.
    Price RN, Simpson JA, Nosten F, Luxemburger C, Hkirjaroen L, ter Kuile F, et al. Factors contributing to anemia after uncomplicated falciparum malaria. AmJTrop Med Hyg. 2001;65(5):614–22.Google Scholar
  38. 38.
    Dondorp AM, Desakorn V, Pongtavornpinyo W, Sahassananda D, Silamut K, Chotivanich K, et al. Estimation of the total parasite biomass in acute falciparum malaria from plasma PfHRP2. PLoS Med. 2005;2(8):e204.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, Piera K, et al. Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria. Proc Natl Acad Sci U S A. 2008;105(44):17097–102.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Kamau E, Tolbert LS, Kortepeter L, Pratt M, Nyakoe N, Muringo L, et al. Development of a highly sensitive genus-specific quantitative reverse transcriptase real-time PCR assay for detection and quantitation of plasmodium by amplifying RNA and DNA of the 18S rRNA genes. J Clin Microbiol. 2011;49(8):2946–53.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    McCarthy JS, Sekuloski S, Griffin PM, Elliott S, Douglas N, Peatey C, et al. A pilot randomised trial of induced blood-stage Plasmodium falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs. PLoS One. 2011;6(8):e21914.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    White NJ. Pharmacokinetic and pharmacodynamic considerations in antimalarial dose optimization. Antimicrob Agents Chemother. 2013;57(12):5792–807.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Ding XC, Ubben D, Wells TN. A framework for assessing the risk of resistance for anti-malarials in development. Malar J. 2012;11:292.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Sanz LM, Crespo B, De-Cozar C, Ding XC, Llergo JL, Burrows JN, et al. P. falciparum in vitro killing rates allow to discriminate between different antimalarial mode-of-action. PLoS One. 2012;7(2):e30949.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Beauchemin CA, Handel A. A review of mathematical models of influenza A infections within a host or cell culture: lessons learned and challenges ahead. BMC Public Health. 11;11 Suppl 1:S7.CrossRefGoogle Scholar
  46. 46.
    Gunawardena J. Models in biology: ‘accurate descriptions of our pathetic thinking’. BMC Biol. 2014;12:29.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Siekmann I, Sneyd J, Crampin EJ. MCMC can detect nonidentifiable models. Biophys J. 2012;103(11):2275–86.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Steimer JL, Mallet A, Golmard JL, Boisvieux JF. Alternative approaches to estimation of population pharmacokinetic parameters: comparison with the nonlinear mixed-effect model. Drug Metab Rev. 1984;15(1–2):265–92.PubMedCrossRefGoogle Scholar
  49. 49.
    Simpson JA, Aarons L, Collins WE, Jeffery GM, White NJ. Population dynamics of untreated Plasmodium falciparum malaria within the adult human host during the expansion phase of the infection. Parasitology. 2002;124(Pt 3):247–63.PubMedGoogle Scholar
  50. 50.
    Earl DJ, Deem MW. Parallel tempering: theory, applications, and new perspectives. Phys Chem Chem Phys. 2005;7(23):3910–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Ezzet F, van Vugt M, Nosten F, Looareesuwan S, White NJ. Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria. Antimicrob Agents Chemother. 2000;44(3):697–704.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Tarning J, Zongo I, Some FA, Rouamba N, Parikh S, Rosenthal PJ, et al. Population pharmacokinetics and pharmacodynamics of piperaquine in children with uncomplicated falciparum malaria. Clin Pharmacol Ther. 2012;91(3):497–505.PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Hendriksen IC, Mtove G, Kent A, Gesase S, Reyburn H, Lemnge MM, et al. Population pharmacokinetics of intramuscular artesunate in African children with severe malaria: implications for a practical dosing regimen. Clin Pharmacol Ther. 2013;93(5):443–50.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Das D, Tripura R, Phyo AP, Lwin KM, Tarning J, Lee SJ, et al. Effect of high-dose or split-dose artesunate on parasite clearance in artemisinin-resistant falciparum malaria. Clin Infect Dis. 2013;56(5):e48–58.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Khoury DS, Cromer D, Best SE, James KR, Kim PS, Engwerda CR, et al. Effect of mature blood-stage Plasmodium parasite sequestration on pathogen biomass in mathematical and in vivo models of malaria. Infect Immun. 2014;82(1):212–20.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Murray CJ, Rosenfeld LC, Lim SS, Andrews KG, Foreman KJ, Haring D, et al. Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet. 2012;379(9814):413–31.PubMedCrossRefGoogle Scholar
  57. 57.
    Patel K, Batty KT, Moore BR, Gibbons PL, Bulitta JB, Kirkpatrick CM. Mechanism-based model of parasite growth and dihydroartemisinin pharmacodynamics in murine malaria. Antimicrob Agents Chemother. 2013;57(1):508–16.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    ter Kuile F, White NJ, Holloway P, Pasvol G, Krishna S. Plasmodium falciparum: in vitro studies of the pharmacodynamic properties of drugs used for the treatment of severe malaria. Exp Parasitol. 1993;76(1):85–95.PubMedCrossRefGoogle Scholar
  59. 59.
    Jamsen KM, Duffull SB, Tarning J, Price RN, Simpson JA. A robust design for identification of the parasite clearance estimator. Malar J. 2013;12:410.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  • Julie A. Simpson
    • 1
    Email author
  • Sophie Zaloumis
    • 1
  • Alysha M. DeLivera
    • 1
  • Ric N. Price
    • 2
    • 3
  • James M McCaw
    • 1
    • 4
  1. 1.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneMelbourneAustralia
  2. 2.Centre for Tropical Medicine, Nuffield Department of Clinical MedicineUniversity of OxfordOxfordUK
  3. 3.Global Health and Tropical Medicine Division, Menzies School of Health ResearchCharles Darwin UniversityDarwinAustralia
  4. 4.Murdoch Childrens Research InstituteThe Royal Children’s HospitalParkvilleAustralia

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