Fexinidazole (FEX) is a nitroimidazole being developed as a new trypanocide treatment for human African trypanosomiasis/sleeping sickness. Its main metabolites, fexinidazole sulfoxide (M1) and fexinidazole sulfone (M2), show the same in vitro pharmacological activity as FEX.An LC-MS/MS assay was developed for quantitation of FEX in DBS, collected via finger-prick from healthy subjects. The DBS assay was specific, accurate and reproducible for FEX, M1 and M2 when validated against the current plasma assay. DBS samples were stable for 24 h at 37°C with 95% relative humidity, and 58 weeks desiccated at room temperature.DBS finger-prick sampling offers a simple, practical method for determining FEX, M1 and M2 concentrations in clinical studies in Africa.
Acoziborole is a novel boron-containing candidate developed as an oral drug for the treatment of human African trypanosomiasis (HAT). Results from preclinical studies allowed progression to Phase 1 trials. We aimed to determine the best dose regimen for all stages of HAT. Acoziborole was assessed in 128 healthy adult males of sub-Saharan African origin living in France. The study included a single oral administration of a 20- to 1200-mg dose in a randomised double-blind study in cohorts of 8 (6 active, 2 placebo) to assess safety, tolerability, and pharmacokinetics. In three additional open cohorts of 6 participants, the effect of activated charcoal was evaluated, bioequivalence of capsules versus tablets was assessed, and safety in the 960-mg tablet cohorts was monitored. Acoziborole was well tolerated at all doses tested; no dose-related adverse events were observed. The drug appeared rapidly in plasma (at 1 h), reached tmax between 24 and 72 h, and remained stable for up to 96 h, after which a slow decrease was quantifiable until 14 weeks after dosing. Charcoal had little impact on the enterohepatic recirculation effect, except for the 20-mg dose. Bioequivalence between capsule and tablet formulations was demonstrated. The therapeutic single dose for administration under fasted conditions was fixed to 960 mg. The maximum administered dose was 1200 mg. This study showed that acoziborole could be safely assessed in patients as a potential single-dose oral cure for both stages of gambiense HAT. The study was registered with ClinicalTrials.gov: NCT01533961.
BackgroundVisceral leishmaniasis (VL) treatment in HIV patients very often fails and is followed by high relapse and case-fatality rates. Hence, treatment efficacy assessment is imperative but based on invasive organ aspiration for parasite detection. In the search of a less-invasive alternative and because the host immune response is pivotal for treatment outcome in immunocompromised VL patients, we studied changes in the whole blood transcriptional profile of VL-HIV patients during treatment.MethodsEmbedded in a clinical trial in Northwest Ethiopia, RNA-Seq was performed on whole blood samples of 28 VL-HIV patients before and after completion of a 29-day treatment regimen of AmBisome or AmBisome/miltefosine. Pathway analyses were combined with a machine learning approach to establish a clinically-useful 4-gene set.FindingsDistinct signatures of differentially expressed genes between D0 and D29 were identified for patients who failed treatment and were successfully treated. Pathway analyses in the latter highlighted a downregulation of genes associated with host cellular activity and immunity, and upregulation of antimicrobial peptide activity in phagolysosomes. No signs of disease remission nor pathway enrichment were observed in treatment failure patients. Next, we identified a 4-gene pre-post signature (PRSS33, IL10, SLFN14, HRH4) that could accurately discriminate treatment outcome at end of treatment (D29), displaying an average area-under-the-ROC-curve of 0.95 (CI: 0.75–1.00).InterpretationA simple blood-based signature thus holds significant promise to facilitate treatment efficacy monitoring and provide an alternative test-of-cure to guide patient management in VL-HIV patients.FundingProject funding was provided by the AfricoLeish project, supported by the European Union Seventh Framework Programme (EU FP7).
Fexinidazole is a 5-nitroimidazole recently included in a clinical efficacy trial as an oral drug for the treatment of human African trypanosomiasis (HAT). Preclinical studies showed it acts as a pharmacologically active pro-drug with two key active metabolites: sulfoxide and sulfone (the most active metabolite). The present studies aimed to determine the best dose regimen for the treatment of stage 2 sleeping sickness patients, which could eventually also treat stage 1 patients.Fexinidazole was assessed in 154 healthy adult male subjects of sub-Saharan African origin. Three initial first-in-human studies and two additional studies assessed a single ascending dose and multiple ascending doses (both under fasted conditions), tablet versus suspension formulation and food effect (fasted vs. high-fat meal and field-adapted food), and multiple ascending doses with a loading dose regimen under fed conditions.Fexinidazole was well-tolerated in a single dose from 100 to 3,600 mg, with quick absorption of the parent drug and rapid metabolism into sulfoxide [time to maximum concentration (t max) 2-5 h] and sulfone (t max 18-24 h). The tablet formulation was approximately 25 % less bioavailable than the suspension, and food intake increased drug absorption and plasma concentrations of fexinidazole and its two metabolites by approximately 200 %. Fourteen-day multiple ascending dosing administered up to 3,600 mg/day in fasted conditions showed that fexinidazole was generally well-tolerated (mild to moderate, spontaneously reversible drug-related adverse events). Following the high-fat food effect finding, another study was conducted to evaluate the impact of a low-fat regimen closer to that of the target population, showing that the type of meal does not influence fexinidazole absorption. The last study showed that a loading dose of 1,800 mg/day for 4 days followed by a 1,200 mg/day regimen for 6 days with a normal meal provided the desired exposure of fexinidazole and its metabolites, particularly sulfone, with good tolerability. Based on preclinical evidence from a chronic infection mouse model, systemic drug concentrations obtained are expected to be clinically effective in stage 2 HAT.These studies show that fexinidazole can be safely assessed in patients as a potential oral cure for both stages of HAT.
This abstract corresponds with the following slides: https://f1000research.com/slides/7-632 presented at Medecins Sans Frontieres UK Scientific Days: Medical Research 2018. To watch the presentation click here: https://f1000research.com/videos/7-832 This abstract is part of an F1000Research gateway that includes posters, slides and videos from the MSF Scientific Day: Medical Research 2018. To see more please visit: https://f1000research.com/gateways/MSF/scidays
