A Human Microdose Study of the Anti-Malarial GSK3191607 in Healthy Volunteers

Summary

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 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, 6 subjects) FTIH study was conducted in order to assess the human pharmacokinetics of GSK3191607 following IV administration of [14C]-GSK3191607.

Methods

A human microdose study was conducted in order to investigate the clinical pharmacokinetics 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 (PD) parameters, were all used to estimate the potential efficacy of various oral dosing regimens in humans.

Results

The pharmacokinetic profile, based on the microdose data, demonstrated a half-life (~17 hrs) which is similar to other antimalarial compounds currently in clinical development. However, combining the microdose data with the PD 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.

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