title: Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development.
abstract: BACKGROUND
  Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD) model for predicting within-host parasite response was performed.
  
  
  METHODS
  Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50), derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach.
  
  
  RESULTS
  The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours) and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle). The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i.e. the infection became more asynchronous).
  
  
  CONCLUSIONS
  This simulation study demonstrates that the PD effect predicted from in vitro growth inhibition assays does not accord well with the PD effect of the anti-malarials observed within the patient. This simulation-based PK-PD modelling approach should not be considered as a replacement to conducting clinical trials but instead as a decision tool to improve the design of a clinical trial during drug development.
authors.affiliation: Centre for Molecular, Environmental, Genetic & Analytic Epidemiology, Melbourne School of Population Health, University of Melbourne, Level 3, 207 Bouverie St, Carlton, VIC 3053, Australia. sophiez@unimelb.edu.au
authors.forename: Sophie
authors.initials: S
authors.lastname: Zaloumis
authors.forename: Andrew
authors.initials: A
authors.lastname: Humberstone
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Ric N
authors.initials: RN
authors.lastname: Price
authors.forename: Joerg
authors.initials: J
authors.lastname: Moehrle
authors.forename: Javier
authors.initials: J
authors.lastname: Gamo-Benito
authors.forename: James
authors.initials: J
authors.lastname: McCaw
authors.forename: Kris M
authors.initials: KM
authors.lastname: Jamsen
authors.forename: Katherine
authors.initials: K
authors.lastname: Smith
authors.forename: Julie A
authors.initials: JA
authors.lastname: Simpson
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000077332:Artesunate; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D055808:Drug Discovery; D004983:Ethanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D005449:Fluorenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D054884:Host-Pathogen Interactions; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000378:metabolism / Q000469:parasitology; D015767:Mefloquine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D015233:Models, Statistical; D010963:Plasmodium falciparum / Q000187:drug effects; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D010879:Piperazines
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D000077332:Artesunate; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D015767:Mefloquine; D011804:Quinolines; C039060:artenimol; C034759:piperaquine; D010879:Piperazines