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PurposeTo demonstrate the pharmacokinetic/pharmacodynamic (PK/PD) equivalence of a biosimilar enoxaparin to the reference drug, and to assess its safety and tolerability in healthy volunteers.Patients and methodsA randomized, double-blind, crossover, 2-sequence, single-dose study was conducted in healthy volunteers of both sexes. Participants were sequentially and randomly administered single subcutaneous injections of enoxaparin 100 mg manufactured by Rovi (test; Madrid, Spain) and Clexane® (enoxaparin 100 mg manufactured by Sanofi, reference) separated by a 1-week washout period. The primary PK/PD variables were maximum activity (Amax) and area under the effect curve from time 0 to the last measured activity (T) (AUEC0–T) and AUEC from time 0 to infinity (AUEC0–inf) of anti-FXa activity, and Amax and AUEC0–T of anti-FIIa activity. Secondary variables were Amax and AUEC0–T, AUEC0–inf of tissue factor pathway inhibitor, and the ratio of AUEC0–T anti-FXa to anti-FIIa activity. Biosimilarity would be shown when the 95% CI of the ratio of geometric least squares means (95% CI RGLSMs) of primary PK/PD parameters fell within the standard range of bioequivalence, ie, 80%–125%.ResultsThe study sample consisted of 46 volunteers (33 males) aged 18–44 years and with body mass index ranging from 19.0 to 31.1 kg/m2. Three subjects did not complete the study. The curves of anti-FXa, anti-FIIa and tissue factor pathway inhibitor activities corresponding to administration of the test and reference products were comparable. The 95% CI RGLSMs of Amax, AUEC0–T and AUEC0–inf for anti-FXa activity were 94.6%–105.9%, 99.8%–108.0% and 100.0%–108.6% respectively; Amax and AUEC0–T for anti-FIIa activity were 94.7%–112.6% and 90.9%–117.9% respectively. In addition, the 95% CI RGLSMs of all secondary variables fell within the range 80%–125%. The incidence and types of adverse events after administration of the test and reference drugs were similar.ConclusionThe results conclusively showed that the enoxaparin manufactured by Rovi is equivalent to the reference enoxaparin in all primary and secondary PK/PD parameters, as required by the European Medicines Agency to grant marketing authorization to a biosimilar low molecular-weight heparin.

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The aim of this study was to characterize the pharmacokinetics and to evaluate the safety of risperidone ISM in patients with schizophrenia or schizoaffective disorder after a single gluteal intramuscular injection at three different dose strengths (50, 75, and 100 mg). A total of 36 patients were randomized and blood samples were collected to measure the plasma concentrations. The pharmacokinetic of the active moiety was biphasic for all three dose groups, and the mean plasma concentration was 21.45, 24.60, and 29.68 ng/ml in the 50, 75, and 100 mg group, respectively, 24 h after dose administration; 22.81, 24.57, and 31.41 ng/ml in the 50, 75, and 100 mg group, respectively, 48 h after dose administration, and 12.26, 17.31, and 20.01 ng/ml in the 50, 75, and 100 mg group, respectively, 30 days after dose administration. Overall, 34 patients experienced at least one treatment-emergent adverse event (TEAE). Two patients experienced a serious TEAE and no deaths occurred. There were no extrapyramidal symptoms-related serious TEAEs and no significant changes in any Columbia Suicide Severity Rating Scale parameter were observed during the study. Risperidone ISM provided a sustained release of risperidone that achieved therapeutic plasma levels within the first day. Risperidone ISM was safe, well tolerated, and should be suitable for a 4-weekly administration without oral supplementation.

Introduction: This open-label, one-sequence study evaluated the steady-state comparative bioavailability of risperidone in situ microimplants (ISM ® ) and oral risperidone in patients stabilized on oral risperidone treatment. Methods: Repeat oral administration of once daily 4 mg risperidone for 7 days was followed by 4 monthly (once every four weeks) intramuscular (IM) doses of risperidone ISM 100 mg. Mean steady-state concentration versus time profiles for risperidone, 9-OH risperidone, and risperidone active moiety was characterized. Results: A total of 104 subjects were enrolled, 81 were included in the safety population and 58 completed the study. Intersubject variability for the steady-state concentrations versus time profiles for risperidone active moiety presented a greater variability range for oral risperidone versus risperidone ISM (% coefficient of variation [CV] range: 40-65% and 38-52%, respectively). Minimum plasma concentration at steady-state (C min, ss) and fluctuation in plasma concentrations (Fluc) of risperidone active moiety after risperidone ISM administration met bioequivalence criteria compared to the reference oral risperidone (geometric mean ratio [GMR] = 1.09 and 0.96, respectively; both 90% CIs were within 0.80-1.25). Area under the curve during the dosing interval (AUC tau) , maximum plasma concentration at steady-state (C max, ss) and average plasma concentration (C ave) were only slightly higher (GMR [90%

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In this study, poly (D,L-lactide-co-glycolide) (PLGA) microspheres encapsulating Olea europaea pollen extracts were prepared by using the double emulsion (w/o/w) based on a solvent evaporation/extraction method. The resulting microspheres were 1.93 microns in size. The total allergen loading and surface-associated allergen were 8 and 0.64%, respectively. The release of the allergen from the microspheres showed a biphasic profile with an initial burst release followed by a sustained release phase. Finally, the polyacrylamide gel electrophoresis (SDS-PAGE) results showed that the encapsulation process does not affect the stability of the protein. We describe here some preliminary observations concerning the use of these microspheres as parenteral antigen delivery systems for immunization with O. europaea pollen extracts, in a small animal model, the mouse.

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