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.

Intravenous (i.v.) paracetamol is used as 1-g infusions with a maximal daily dose of 4 g/day. However, a higher initial analgesic dose could be of interest in the immediate postoperative period when the pain is maximal. The purpose of the present study was to determine in healthy subjects the safety and the pharmacokinetics of i.v. paracetamol, starting with a 2-g dose, followed by 1-g doses every 6 h, leading to a total of 5 g the first 24 h. This was an open-label, single-sequence study. The paracetamol pharmacokinetic profile was assessed in 26 subjects after both the 2-g starting dose and the 1-g doses. Safety, especially hepatotoxicity, was evaluated up to 72 h after the initial 2-g dose. Following the first 15-min i.v. administration of paracetamol 2 g, plasma concentrations ranged from 67.9+/-21.8 mug/ml (peak plasma concentration (C(max)) at the end of infusion) to 6.2+/-2.3 mug/ml (trough plasma concentration (C(min)) measured just before the next infusion) without any C(max) in the toxic range for any subject. After the repeated 1-g infusions, the plasma concentrations were approximately 35% lower than that measured after 2 g, showing the absence of accumulation. No clinical adverse events related to the drug administration nor clinically relevant changes in laboratory parameters, including biochemical signs of hepatotoxicity, were reported. After i.v. administration of paracetamol 2-g starting dose and 5 g during the first 24 h, the pharmacokinetics of paracetamol remain unchanged, with concentrations far below the toxic threshold. Overall, these results demonstrate that the i.v. administration of a 2-g starting dose of paracetamol, followed by three i.v. administrations of 1 g during the first 24 h is safe in healthy subjects.

The objective of the present study was to evaluate the pharmacokinetic parameters for both S- and R-ibuprofen enantiomers in very premature neonates (gestational age strictly inferior to 28 weeks) and possible relationships between the pharmacokinetic parameters and various covariates. Newborns were randomized to receive ibuprofen or placebo for the prophylactic treatment of patent ductus arteriosus (PDA) at an initial dose of 10 mg/kg ibuprofen within 6 hours after birth, followed by two 5-mg/kg doses at 24-hour intervals (n = 52). If a PDA was still present afterwards, a curative course of ibuprofen using the same dosage regimen was administered (n = 10). A sparse sampling strategy was used because only 2 samples were collected after the third prophylactic injection and 1 after the third curative injection. A model including the chiral transformation of R- to S-ibuprofen was fitted to the concentration-time data using a population approach (NONMEM). R- and S-ibuprofen t(1/2) were about 10 hours and 25.5 hours, respectively. After prophylactic treatment, the mean clearance of R-ibuprofen (CLR = 12.7 mL/h) was about 2.5-fold higher than for S-ibuprofen (CLS = 5.0 mL/h). In addition, clearance of R- and S-ibuprofen increased significantly with gestational age. The mean estimation of R-ibuprofen clearance was found to be higher than for S-ibuprofen, and the clearance of both enantiomers increased with gestational age. This should be considered to assess pharmacokinetic-pharmacodynamic relationships of ibuprofen in premature neonates and subsequently to understand and refine the use of ibuprofen in managing PDA either as a prophylactic or curative treatment.

The purpose of this study was to determine whether administration of doxorubicin (DOX) as a continuous infusion or a bolus injection resulted in similar leukemic cell drug concentration in patients with refractory chronic lymphocytic leukemia (CLL). This study was carried out on five patients with refractory CLL, with DOX administered either as a bolus injection (35 mg/m2; CHOP protocol) or as a constant-rate infusion for a period of 96 h (9 mg/m2 per day; VAD protocol). The two types of drug administration were used alternatively with the same patient. Plasma and cellular DOX concentration were determined using high-performance liquid chromatography. Peak plasma DOX levels were higher after the bolus injection than after continuous administration (1509 +/- 80 ng/ml vs 11.6 +/- 1.8 ng/ml, respectively), whereas the plasma area under the curve (AUC) levels were similar. Maximum DOX cellular concentrations were 8629 +/- 2902 ng/10(9) cells (bolus injection) and 2745 +/- 673 ng/10(9) cells (96 h infusion). The cellular AUC after the bolus injection was 2.85 times greater than that observed after continuous administration. This difference was due to a higher cellular peak level followed by a relatively prolonged retention of the drug, with a loss of only 25% in the first 24 h following. These findings demonstrated that in CLL the cellular DOX exposure can be notably modified by the method of drug administration, with higher drug intracellular concentrations being achieved after bolus administration than with the infusion schedule.

The pharmacokinetic properties and tolerability of three different strengths of prulifloxacin (CAS 123447-62-1), a new antibacterial agent prodrug of AF3013 (CAS 112984-60-8), have been investigated in a randomized, cross-over study performed in 12 Caucasian male subjects (age range 19-34 years). Prulifloxacin was administered as a single oral dose at the dosages of 300, 450 and 600 mg. Plasma concentrations of the active metabolite AF3013 were determined in blood samples collected before the administration (pre-dose) and at 15, 30, 45 min, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 h after dosing. Urine samples were also collected. Determination in biological samples was performed using validated and specific HPLC methods. The following parameters were calculated: Cmax, tmax, AUC0-t, AUC0--infinity, t1/2, V/F, Aeut, CLren and fe. The analysis of variance performed on dose-normalized data after logarithmic transformation evidenced no statistically significant differences between the three doses concerning Cmax and AUC. Friedman's test applied to tmax and t1/2 did not show any statistically significant difference between doses. A significant linear relationship between doses and AUC0-infinity was detected (p < 0.05). Very high urinary concentrations and the relatively long terminal half-life (10-12 h) suggest that a once-daily application would show adequate clinical efficacy, especially in urinary infections. The safety profile of the three doses was very good.