Pharmacokinetics of secnidazole in healthy volunteers after single oral dose

Introduction: Secnidazole is an anti infective agent which belongs to the 5-nitroimidazole class. Method: The objective of the trial was to characterize the pharmacokinetics of secnidazole after oral administration of a 2g dose, as microgranules formulation in healthy subjects. Blood samples were collected before, 1, 2, 3, 6, 9, 12, 24, 36, 48, 72, 96, 120, 168 and 240 h after dosing. Urines were collected in 24-h-fractions for the first five days and in 48 h-fraction for the last sample. The cumulative urinary excretion was captured for each subject from urine concentration (lg/L). Pharmacokinetic parameters were obtained by a non-compartmental approach (WinNonlin Pharsight). The assay was performed by ultra-performance liquid chromatography coupled with mass spectrometry detection (UPLC-MS/MS, Quattro Premier, Waters) after simple protein precipitation of 50 lL plasma sample. Chromatographic separation was done on a C18 Acquity column (50 mm · 2.1 mm, id 1.7 lm, Waters), in isocratic mode (80% water/0.1% formic acid and 20% acetonitrile). Ornidazole was used as internal standard. The detection was operated in positive mode and multiple reaction monitoring was used for quantification (186 > 128 ion transition for secnidazole). The lower limit of quantification was 10 and 100 lg/L for plasma and urine samples respectively. Results: Sixteen subjects (8 female, 8 male) were included. Population characteristics such as: age ranged from 23 to 50 years (mean ± SD: 38 ± 9.2 years), weight ranged from 51 to 90 Kg (mean ± SD = 64.6 ± 10.1 Kg) and body mass index (BMI) ranged from 19.9 to 24.2 Kg/m 2 (mean ± SD = 21.9 ± 1.5 Kg/m 2 ;). Secnidazole exposure achieved a maximal concentration (Cmax) with a mean of 37.9 ± 8.5 mg/L (range 20–56 mg/L) and at a median time associated with the Cmax (Tmax) of 6 h (range 3–6 h). The area under the curve to the last measurable time (AUC0_t) and the total area under the curve (AUC0_¥) were 1281.9 ± 416.4 mg h/L and 1304.2 ± 444.1 mg h/L (mean ± SD) respectively. The Cl/F and V/F were 1.7 ± 0.5 L/h and 40.2 ± 9.2 L respectively and the elimination half-life (t1/2) was 17.5 ± 4.3 h (mean ± SD). The mean amount of secnidazole excreted in the 168-h urine collection was 310.47 mg (15.5% of the administered dose). For example, for the subject number 5, the observed parameters are: Cmax 37.3 mg/L, Tmax 3 h, AUC0_¥ 1029.5 mg h/L and t1/2 15.6 h. Conclusion: After a 2 g single oral dose, secnidazole presents a good absorption profile and relatively long elimination half life ensuring probable sufficient exposure with once a day administration

Use of triazole antifungal drugs in setting up an animal model of cerebral scedosporiosis

Scedosporium apiospermum is a soil fungus which may cause severe and often fatal cerebral mycosis in immunocompetent patients in the case of near drowning and in immunosuppressed patients such as lung transplant recipients. Due to the low susceptibility of the fungus to antifungal drugs and to the low permeability of the blood-brain barrier, it might be difficult to reach a therapeutic tissue concentration. Indeed, the diffusion of the drug in the brain depends on several parameters such as integrity of the blood-brain barrier. To evaluate the drug diffusion, two experimental models were developed in immunocompetent and immunosuppressed rats. Inocula of S.apiospermum (strain IHEM 3817): 106 spores in immunocompetent and 105 spores in immunosuppressed rats were administered in the penile vein and a scale (graded from 0 to 9) was established based on weight, clinical and neurological signs evaluated by the tail suspension test. Cerebral involvement was confirmed among others by magnetic resonance imaging of brain, which  highlighted differences in localisation of fungal abscesses in brain depending on the immune status. As voriconazole or posaconazole exhibit an in vitro activity against the tested strain (E-test), they were given to the rats at doses ranging from 10 to 50 mg/kg/d by i.v. or oral route, respectively (6 rats per dose and controls). The efficacy criteria was defined as time doubling the survival time and  absence of  neurological sequelae. Whatever the immune status, the effective doses were 30 mg/kg/d for voriconazole and 50 mg/kg/d for posaconazole. The chosen doses of voriconazole and posaconazole were higher than the doses calculated on the basis of data published for mice, rabbits and guinea pigs.This might be explained by the chosen animal species and  criteria of efficacy. So, this infectious model appears to be a valuable tool to evaluate the cerebral diffusion of two antifungal drugs in rats. The data enable to perform pharmacokinetic (PK) and pharmacodynamic (PD) studies for PK-PD modelling

Cytotoxics compounded sterile preparation control by HPLC during a 16-month assessment in a French university hospital: importance of the mixing bags step

The Centralized Chemotherapy Reconstitution Unit (CCRU) of Paul Brousse Hospital Pharmacy Department assessed the reliability of its Cytotoxics Compounded Sterile Products (CCSP) preparation method in order to improve its CCSP quality assurance system. Five cytotoxic drugs — gemcitabine, 5-fluorouracil, docetaxel, paclitaxel, and oxaliplatin — were assayed by high performance liquid chromatography (HPLC) to determine CCSP concentration. During the observation period, 23,892 CCSP were prepared. Overall, 12,964 preparations contained one of the five analyzed drugs; 7382 (56.9%) out of 12,964 CCSP were analyzed by HPLC; 646 (8.8%) out of 7382 concentrations were outside ± 20% of the prescribed dose; 544 (84.2%) out of 646 were post-administration results and could not be verified. Out of 102 (15.8%) pre-administration results that were re-tested after re-shaking, 94 (92.2%) were found to be acceptable upon re-testing, and 8 (7.8%) were confirmed to be unacceptable and needed to be re-compounded. The 8.8% of tested CCSP were outside ± 20% of the prescribed dose, but extrapolating the results on re-tested CCSP, we can say that our CCSP preparation is reliable with an estimation of only 0.7% of 7382 CCSP analyzed, confirmed as being ± 20% outside the prescribed dose. Nevertheless, this ± 20% magnitude of error should be reduced. Based on pre-administration results, the primary cause of concentration errors appeared to be insufficient mixing of the finished product. Most CCSP dosages occurred after it had been administered, the organization should, therefore, be improved to include testing all CCSP prior to administration. Pharmaceutical companies should endeavor to manufacture compounded injectible drugs in a ‘ready to use’ form and provide vehicles in accurate volumes in order to improve compounding precision

Pharmacokinetics of voriconazole and posaconazole administered in experimental models of disseminated scedosporiosis with cerebral involvement

International audienc

Investigating the KNDy hypothesis in humans by co-administration of kisspeptin, neurokinin B and naltrexone in men

Context: A subpopulation of hypothalamic neurons co-localise three neuropeptides namely kisspeptin, neurokinin B (NKB) and dynorphin collectively termed KNDy neurons. Animal studies suggest they interact to affect pulsatile GnRH release (KNDy hypothesis); kisspeptin stimulates, NKB modulates and dynorphin (an opioid) inhibits. Objective: To investigate the KNDy hypothesis in humans, we assessed for the first time the effects of co-administration of kisspeptin-54, NKB and an opioid receptor antagonist, naltrexone on LH pulsatility (surrogate marker for GnRH pulsatility) and gonadotropin release. Design, setting and participants: Ethically approved prospective, single-blinded placebo-controlled study. Healthy male volunteers (n=5/group) attended our research facility for 8 study visits. Intervention and main outcome measure: After 1h baseline blood sampling, participants received a different intervention at each visit: oral 50mg naltrexone (NAL), 8h intravenous infusions of vehicle, 2.56nmol/kg/h NKB (NKB), 0.1nmol/kg/h kissspeptin-54 (KP) alone and in combination. Frequent blood sampling to measure plasma gonadotropins and sex steroids was conducted and LH pulsatility was determined using blinded deconvolution analysis. Results: All kisspeptin and naltrexone containing groups potently increased LH and LH pulsatility (p<0.001 vs vehicle). NKB alone did not affect gonadotropins. NKB+KP had significantly lower increases in gonadotropins compared with kisspeptin alone (p<0.01). NAL+KP was the only group to significantly increase LH pulse amplitude (p<0.001 vs vehicle). Conclusions: Our results suggest significant interactions between the KNDy neuropeptides on LH pulsatility and gonadotropin release in humans. This has important implications for improving our understanding of GnRH pulse generation in humans

Impact of cyclosporine dosing regimen and infection on voriconazole pharmacodynamics in an experimental model of cerebral scedosporiosis

International audienc

Ovarian Hyperstimulation Syndrome (OHSS) requiring Intensive Care Unit (ICU) admission between 1996-2020 in England, Wales, and Northern Ireland

Introduction: Ovarian Hyperstimulation Syndrome (OHSS) is a life-threatening iatrogenic complication of In vitro fertilisation (IVF). This study aimed to quantify rates of Ovarian Hyperstimulation Syndrome (OHSS) requiring intensive care unit (ICU) admission and assess whether trends have changed between 1996-2020 commensurate with the introduction of safer IVF practices. Methods: Data regarding Intensive Care Unit (ICU) admission across England, Wales and Northern Ireland was gathered retrospectively from the Intensive Care National Audit and Research Centre (ICNARC) database. 38,957 female patients aged between 18-55 years were admitted to ICU for OHSS or related conditions between 1996-2020. The primary outcome was the rate of OHSS requiring ICU admission expressed as a proportion of the number of fresh IVF cycles conducted in that year according to Human Fertility and Embryology Authority (HFEA) records. Baseline characteristics (for example, age, ethnicity, BMI), biochemical parameters (such as renal function, serum electrolytes), length of ICU stay and duration and need for organ support, were also compared between ICU patients with ‘confirmed OHSS’ and those ‘without OHSS’. Results: There were 238 cases of ‘confirmed OHSS’ requiring ICU admission recorded between 1996-2020. Rates of OHSS requiring ICU admission declined over the study period (P=0.006); the annual rate of severe OHSS requiring intensive care admission halved when comparing those occurring between 1996-2007 and 2008-2020 (OR=0.37, 95% CI 0.37-0.45; P<0.0001). Patients spent a mean of 3.5 days in the ICU, with 86.3% of patients with ‘confirmed OHSS’ requiring at least 2 days of higher level (i.e., level 2 or 3) care. Patients with ‘confirmed OHSS’ required a shorter duration of renal, advanced cardiovascular, and advanced respiratory support than patients ‘without OHSS’ (P<0.0001 for all comparisons). There was no significant difference in BMI or ethnicity between those with ‘confirmed OHSS’ and those ‘without OHSS’, however women with ‘confirmed OHSS’ were younger (34 versus 41 years old, p<0.0001). Discussion: Although absolute rates of OHSS requiring ICU admission recorded in this study are likely to represent a significant underestimate of all clinically significant OHSS, rates of OHSS requiring ICU admission have decreased since 1996 in concordance with the introduction of modern IVF practices

Pharmacokinetics of secnidazole after single oral dose in healthy volunteers

National audienc

Pharmacokinetic analysis of diazepam liberation from avizafone in healthy volunteers : Non-compartmental approach and compartmental modeling

Date du colloque&nbsp;: 04/2009</p