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SUMMARY:Mechanistic model development to characterise drug effects on plat
 elets over time in pharmaceutical research. - Shaun Flint\, GSK
DTSTART:20180206T130000Z
DTEND:20180206T140000Z
UID:TALK100759@talks.cam.ac.uk
CONTACT:Dr Vivien Gruar
DESCRIPTION:Pharmacokinetic pharmacodynamic (PKPD) modelling is a powerful
  approach used extensively in pre-clinical and clinical drug development t
 o quantitatively characterise drug candidates\, aid go/no-go decisions\, i
 nform future clinical study design and determine optimal dosing regimens t
 hat maximise treatment benefits and minimise side effects. Mechanistic mod
 els such as Physiologically-Based Pharmacokinetic (PBPK) models are increa
 singly utilised to allow a more detailed description of the relevant physi
 ological processes [1]. \n\nThe aim of this project is to use mechanistic 
 models to fully characterise the time-course of platelet count changes aft
 er drug administration and\, in particular\, to predict the onset and degr
 ee of thrombocytopenia (low platelet count). These are important questions
  for drug development because significant haematologic side effects\, incl
 uding thrombocytopaenia\, may result in serious clinical consequences\, su
 ch as bleeding or reduced efficacy as a result of delayed or missed doses.
  A key component of designing a dosing regimen that minimises these concer
 ns is the ability to accurately model drug effects on platelet counts (and
  other haematologic parameters) over time. Semi-mechanistic models able to
  mimic maturation and circulation of platelets and other haematologic cell
  lineages incorporating drug effects are available in the literature (e.g.
  [2-3]). These models use empiric approaches to describe relevant processe
 s and might be not be suitable to extrapolate drug effects to new dosing r
 egimens (e.g. extrapolation of a model based on single-dose data to a repe
 at-dose regimen). \n\nThis project would explore the fundamental propertie
 s of\, and differences between\, semi-mechanistic models and mechanistic m
 odels such as the one proposed in [4]. It will include a theoretical explo
 ration of model performance using simulations and access to a human clinic
 al study dataset to allow the model to be assessed against real-life data.
 \n\nReferences:\n# Zhao P\, Zhang L\, Grillo JA\, et al. Applications of p
 hysiologically based pharmacokinetic (PBPK) modeling and simulation during
  regulatory review. Clinical Pharmacology & Therapeutics. 2011\;89(2):259-
 67.\n# Wang Y.M.\, Krzyzanski W.\, Doshi S.\, et al. Pharmacodynamics-medi
 ated drug disposition (PDMDD) and precursor pool lifespan model for single
  dose of romiplostim in healthy subjects. The AAPS journal 2010\; 12(4): 7
 29-740.\n# Bender B.C.\, Schaedeli-Stark F.\, Koch R.\, et al. A populatio
 n pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing
  the effect of trastuzumab emtansine (T-DM1) on platelet counts in patient
 s with HER2-positive metastatic breast cancer. Cancer chemoth pharm 2012\;
  70(4): 591-601.\n# Harker L.A.\, Roskos L.K.\, Marzec U.M.\, et al. Effec
 ts of megakaryocyte growth and development factor on platelet production\,
  platelet life span\, and platelet function in healthy human volunteers. B
 lood. 2000\;95(8):2514-22.\n\n
LOCATION:MR3 Centre for Mathematical Sciences
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