A human microdose study of the antimalarial drug GSK3191607 in healthy volunteers Articles uri icon

authors

  • Okour, Malek
  • Derimanov, Geo
  • Barnett, Rodger
  • Fernandez, Esther
  • FERRER BAZAGA, SANTIAGO
  • Gresham, Stephanie
  • Hossain, Mohammad
  • Gamo, Francisco Javier
  • Koh, Gavin
  • Pereira, Adrian
  • Rolfe, Katie
  • Wong, Deborah
  • Young, Graeme
  • Rami, Harshad
  • Haselden, John

publication date

  • March 2018

start page

  • 482

end page

  • 489

issue

  • 3

volume

  • 84

International Standard Serial Number (ISSN)

  • 0306-5251

Electronic International Standard Serial Number (EISSN)

  • 1365-2125

abstract

  • Aims
    GSK3191607, a novel inhibitor of the Plasmodium falciparum ATP4 (PfATP4) pathway, is being considered for development in humans. However, a key problem encountered during the preclinical evaluation of the compound was its inconsistent pharmacokinetic (PK) profile across preclinical species (mouse, rat and dog), which prevented reliable prediction of PK parameters in humans and precluded a well-founded assessment of the potential for clinical development of the compound. Therefore, an open-label microdose (100 μg, six subjects) first time in humans study was conducted to assess the human PK of GSK3191607 following intravenous administration of [14C]-GSK3191607.

    Methods
    A human microdose study was conducted to investigate the clinical PK of GSK3191607 and enable a Go/No Go decision on further progression of the compound. The PK disposition parameters estimated from the microdose study, combined with preclinical in vitro and in vivo pharmacodynamic parameters, were all used to estimate the potential efficacy of various oral dosing regimens in humans.

    Results
    The PK profile, based on the microdose data, demonstrated a half-life (~17 h) similar to other antimalarial compounds currently in clinical development. However, combining the microdose data with the pharmacodynamic data provided results that do not support further clinical development of the compound for a single dose cure.

    Conclusions
    The information generated by this study provides a basis for predicting the expected oral PK profiles of GSK3191607 in man and supports decisions on the future clinical development of the compound.

subjects

  • Biology and Biomedicine

keywords

  • clinical research; drug development; malaria; microdose; pharmacokinetic; phase 0