Background and ObjectivesFexinidazole 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.MethodsFexinidazole 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.ResultsFexinidazole 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 (tmax) 2–5 h] and sulfone (tmax 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.ConclusionsThese studies show that fexinidazole can be safely assessed in patients as a potential oral cure for both stages of HAT.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-014-0136-3) contains supplementary material, which is available to authorized users.

Rat hepatocytes were used to study the toxicity of a new semisynthetic macrolide, roxithromycin, in comparison with erythromycin base and erythromycin estolate. Roxithromycin caused lactate dehydrogenase leakage close to that of erythromycin estolate and higher than erythromycin base after 21 h of exposure to the drugs. This effect was, at least in part, explained by the higher uptake: roxithromycin was two to three times more concentrated by liver cells than erythromycin base. For both roxithromycin and erythromycin base, the uptake depended on time, temperature, and extracellular antibiotic concentration. The accumulated macrolides egressed rapidly when cells were incubated in antibiotic-free medium. No uptake and no loss of accumulated drugs were observed at 4C. After accumulation by hepatocytes, roxithromycin and erythromycin base underwent similar subcellular distribution, mostly concentrating in cytosol and lysosomes. The small amount accumulated in the other particulate fractions followed the order mitochondria >> nuclei > microsomes. Roxithromycin, however, was less concentrated than erythromycin base in the microsomes.Erythromycin base and its derivatives are macrolide antibiotics widely used for the treatment of respiratory tract infections and are a useful alternative to penicillin in allergic patients (18). However, they have two major limitations: erythromycin base is inactivated by gastric juice and erythromycin estolate, though more gastro-resistant, may produce hepatic injury in patients (10) and in experimental models (7,8,27,28). A new semisynthetic macrolide, roxithromycin (formerly RU 28965), recently synthesized by Roussel Uclaf (Paris, France) and which is an ether oxime derivative of erythromycin (14) (Fig. 1), was reported to have similar antibacterial activity (1, 14, 24) but more favorable pharmacokinetic properties than erythromycin base (20,26).Cultured rat hepatocytes, which are known to show a good correlation between the in vitro and in vivo toxicities of macrolides (7,8,27,28), were used to evaluate the hepatotoxicity of the new antibiotic in comparison with the two analogs inducing mild (erythromycin base) and severe (erythromycin estolate) hepatic damage. The results presented in this study show that roxithromycin causes lactate dehydrogenase leakage higher than erythromycin base and close to that of erythromycin estolate, although it does not possess a surface-active component like lauryl sulfate, which seems to be the main cause of erythromycin estolate hepatotoxicity (8).Erythromycin and its derivatives have been described to be concentrated intracellularly by eucaryotic cells to different degrees (13), so different uptake of roxithromycin and erythromycin base by hepatocytes might explain their different toxicities for liver cells. To gain an insight into the mechanism of the different hepatotoxicities of the two macrolides, the uptake and subcellular distribution of roxi-* Corresponding author.

1. The pharmacokinetics of the antimycobacterial agent rifabutin were studied in healthy volunteers, following single (450 mg) and repeated (450 mg once daily for 10 days) oral administration. 2. After repeated administration, induction of metabolism was indicated by lower AUC and Cmin values, compared to the corresponding theoretical values. The elimination half-life was unchanged after repeated administration. 3. Induction of presystemic extrahepatic metabolism, which seems to be important in the availability of rifabutin, should be mainly responsible for the decrease in the AUC observed, while induced systemic clearance (if any) should be of minor importance. 4. Induction of presystemic extrahepatic metabolism after repeated administration has also been reported for rifampicin, an antibiotic agent with hepatic enzyme-inducing properties, which has a structure similar to rifabutin but a different pharmacokinetic profile.

No abstract