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INTRODUCTION: There is an urgent need to develop new drugs to treat malaria due to increasing resistance to first-line therapeutics targeting the causative organism, Plasmodium falciparum (P. falciparum). One drug candidate is DM1157, a small molecule that inhibits the formation of hemozoin, which protects P. falciparum from heme toxicity. We describe a first-in-human, phase 1 trial of DM1157 in healthy adult volunteers that was halted early because of significant toxicity. METHODS: Adverse events were summarized using descriptive statistics. We used pharmacokinetic modeling to quantitatively assess whether the DM1157 exposure needed for P. falciparum inhibition was achievable at safe doses. RESULTS: We found that there was no dose where both the safety and efficacy target were simultaneously achieved; conversely, the model predicted that 27 mg was the highest dosage at which patients would consistently maintain safe exposure with multiple dosing. By pre-defining dose escalation stopping rules and conducting an interim pharmacokinetic/pharmacodynamic analysis, we determined that the study would be unable to safely achieve a dosage needed to observe an anti-malarial effect, thereby providing strong rationale to halt the study. CONCLUSION: This study provides an important example of the risks and challenges of conducting early phase research as well as the role of modeling and simulation to optimize participant safety (ClinicalTrials.gov, NCT03490162).
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The synthesis, optical properties, and solid-state structures of a series of o-(aryleneethynylene) oligomers containing three to seven aryl units is described. The main chain in all examples is composed of between one and five 4,5-dimethoxybenzene rings which are capped on each end by 2-pyridyl rings. These oligomers demonstrate pH-dependent emission and absorption spectra. Single crystals were obtained from the aryleneethynylenes containing three to five arene rings. These single crystals were investigated by X-ray diffraction.