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EP42675 is a first‐in‐class, synthetic, parenteral, anticoagulant combining in a single molecule a direct thrombin inhibitor and an indirect factor Xa(FXa) inhibitor.

Abstract: Objective:To investigate plasma and skin suction-blister-fluid pharmacokinetics of oral mizolastine in order to determine whether the drug concentration in the fluid of suction-induced skin blisters could better predict the antihistamine activity than the plasma concentration. Setting:Department of Internal Medicine, Université Paris 6.Subjects:Ten healthy male volunteers.Methods:The volunteers (mean age 26.8 years, mean weight 75.8 kg) received a single 10-mg oral dose of mizolastine at 1000 hours. The pharmacokinetic study included 11 plasma and 9 blister fluid samples and blister epidermal-roof specimens. Mizolastine was assayed by high-performance liquid chromatography (HPLC). Each volunteer also received nine intradermal injections of 5 μg histamine. Antihistamine activity was assessed as the post-treatment percentages of changes in the histamine-induced relative wheal and flare areas versus baseline. Results:Mizolastine mean Cmax (SD) and median tmax were, respectively, 380 ng ⋅ ml−1and 0.8 h in plasma, and 21.8 ng ⋅ ml−1 and 10 h in blister fluid. Mizolastine could not be quantified in the epidermis. The maximal histamine-induced relative flare inhibition was 72.5% and was attained at the median time of 3 h post-dosing and therefore was delayed by 2.2 h with respect to the plasma tmax. Mean relative wheal inhibition, although lower, showed the same time profile. A direct relationship could not be found between drug concentrations in blister fluid and antihistamine activity. Simulated concentrations in the peripheral compartment better explain the maximum inhibition effect on flare, observed 3 h post-dosing, with a flatter hysteresis loop obtained when plotting relative flare inhibition versus plasma or blister-fluid drug concentrations. Conclusion:The mizolastine concentrations in the skin suction-blister fluid were not predictive of the antihistamine activity.

RTV, a potent CYP3A4 inhibitor, is used at low doses to enhance plasma concentrations of other protease inhibitors being primarily metabolised by CYP3A4. NFV, as part of an antiretroviral combination regimen, is approved for the treatment of HIV-1 infected adults and children.NFV was given alone or in combination with RTV to HIV-1 infected patients. Patients received 1250 mg of NFV with or without 200 mg of RTV bid for 48 weeks.In total, 83 patients with sparse PK samples contributed to 611 concentrations each of NFV and its major metabolite M8 having in vitro antiviral activity comparable to NFV. The analysis method was based on non-linear mixed effect modelling. Individual estimates for AUCt, C12h & Cmax were assessed for NFV and M8.The model that fitted NFV and M8 data was a one-compartment model with first order elimination and absorption with lag time for NFV and M8. Oral clearance and distribution volume for NFV were 31.5 L/h and 345 L, and were not influenced by RTV. At week 48, NFV AUCt, C12h & Cmax were 42 h.mg/L, 2.3 & 4.6 mg/L with NFV, and 39 h.mg/L, 2.2 & 4.1 mg/L with NFV & RTV. The clearance of M8 was decreased by 42% when NFV was given with RTV. At week 48, M8 AUCt, C12h & Cmax were 13 h.mg/L, 0.7 & 1.4 mg/L with NFV, and 24 h.mg/L, 1.5 & 2.6 mg/L with NFV & RTV.Clinical Pharmacology & Therapeutics (2004) 75, P84–P84; doi: 10.1016/j.clpt.2003.11.322

Overnight blood sampling, regarded as the most physiological assessment of GH status, may cause some disturbances In patients' sleep. It Is thus of interest to determine whether the nocturnal GH profile (GH peak, GH sum of peaks, time to first and max. GH peak, AUG, mean integrated concentration) relate with the clinically-recorded characteristics of sleep (sleep onset, sleep duration, number of awakenings), during overnight blood sampling.We studied the influence of an hypnotic drug (Zolpidem 10 mg) on nocturnal GH profile (blood sampling every 20 minutes from 8 P.M. to 6 A.M.) in a group of 12 young adult volunteers (27.9+/-4.3 years) and in a group of 12 children (10.8+/-2.8 years) with short stature and normal GH pharmacological tests. The adult volunteers were studied over 2 nights at 7 day interval in a double blind cross-over versus placebo design. The children were studied over one night in a double blind versus placebo parallel group design.Mean GH profiles showed no difference between Zolpidem and control in adults as well as in children. Furthermore, GH profile did not relate with sleep duration and number of awakenings in both populations.Although, in these experimental conditions, sleep onset latency was significantly reduced with Zolpidem in the adult population (1.0+/-0.2 hour; p=0.004), the mean time to first GH peak remained unchanged.We therefore conclude that sleep disturbances, induced by overnight blood sampling for physiological evaluation of GH status, do not alter the profile of GH nocturnal secretion which seems to be specific to each patient.