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Br J Clin Pharmacol. 2018 Mar;84(3):482-489. doi: 10.1111/bcp.13476. Epub 2017 Dec 29.

A human microdose study of the antimalarial drug GSK3191607 in healthy volunteers.

Author information

1
Clinical Pharmacology Modeling and Simulation (CPMS), GlaxoSmithKline, King of Prussia, PA, USA.
2
Discovery Medicine, Diseases of the Developing World, GlaxoSmithKline, Collegeville, PA, USA.
3
Drug Product Design and Development (DPDD), GlaxoSmithKline, Ware, Herts, UK.
4
Malaria DPU, Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
5
Mechanistic Safety and Disposition, GlaxoSmithKline, Ware, UK.
6
Diseases of the Developing World, GlaxoSmithKline, Stockley Park, Uxbridge, UK.
7
Bioanalysis, Immunogenicity and Biomarkers (BIB), GlaxoSmithKline, Ware, UK.
8
Statistics, Programming and Data Strategy (SPDS), GlaxoSmithKline, Stockley Park, Uxbridge, UK.
9
Clinical Pharmacology Science & Study Operations (CPSSO), GlaxoSmithKline, Stevenage, Hertfordshire, UK.

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.

KEYWORDS:

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

PMID:
29168205
PMCID:
PMC5809343
DOI:
10.1111/bcp.13476
[Indexed for MEDLINE]
Free PMC Article

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