Objective— ACT017 is a novel, first in class, therapeutic antibody to platelet GPVI (glycoprotein VI) with potent and selective antiplatelet effects. This first-in-human, randomized, placebo-controlled phase 1 study was conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ACT017 in healthy subjects. Approach and Results— Six cohorts of 8 healthy male and female subjects each received ascending single doses of ACT017 (n=6) or placebo (n=2) as a 6-hour intravenous infusion, with ¼ of the total dose administered within 15 minutes and the rest of the dose (¾ of the total dose) administered within 5 hours and 45 minutes. The 6 investigated doses ranged from 62.5 to 2000 mg. All doses of ACT017 were well tolerated, and no serious adverse events occurred during the study. None of the subjects reported an infusion site reaction. Template bleeding time was not affected in a clinically significant manner by any of the ACT017 doses. Plasma concentrations, determined by liquid chromatography-tandem mass spectrometry, increased linearly with the dose received as were the established pharmacokinetics values. There was no change in the platelet count, platelet GPVI expression assessed by flow cytometry, or plasma levels of soluble GPVI assessed by ELISA. In contrast, administration of ACT017 inhibited collagen-induced platelet aggregation measured by light transmission aggregometry on platelet-rich plasma, and the extent and duration of the effect were dose-dependent. Conclusions— The novel antiplatelet agent ACT017 has consistent pharmacokinetic/pharmacodynamic properties and favorable safety and tolerability profiles warranting further clinical development.

Abstract. As part of the overall product development and manufacturing strategy, pharmaceutical companies routinely change formulation and manufacturing site. Depending on the type and level of change and the BCS class of the molecule, dissolution data and/or bioequivalence (BE) may be needed to support the change for immediate release dosage forms. In this report, we demonstrate that for certain weakly basic low-solubility molecules which rapidly dissolve in the stomach, absorption modeling could be used to justify a BE study waiver even when there is failure to show dissolution similarity under some conditions. The development of an absorption model for etoricoxib is described here, which was then used to a priori predict the BE outcome of tablet batches manufactured at two sites. Dissolution studies in 0.01 N HCl media (pH 2.0) had demonstrated similarity of etoricoxib tablets manufactured at two different sites. However, dissolution testing at pH 4.5 and pH 6.8 media failed to show comparability of the tablets manufactured at the two sites. Single simulations and virtual trials conducted using the 0.01 N HCl dissolution showed similarity in AUC and C max for all tablet strengths for batches manufactured at the two manufacturing sites. These predicted results were verified in a definitive bioequivalence study, which showed that both tablet batches were bioequivalent. Since the development of traditional in vitro-in vivo correlations (IVIVC) for immediate release (IR) products is challenging, in cases such as etoricoxib, absorption modeling could be used as an alternative to support waiver of a BE study.

Org 26576 acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. The aim of this Phase 1b study (N=54) was to explore safety, tolerability, pharmacokinetics, and pharmacodynamics of Org 26576 in depressed patients. Part I (N=24) evaluated the maximum tolerated dose (MTD) and optimal titration schedule in a multiple rising dose paradigm (range 100 mg BID to 600 mg BID); Part II (N=30) utilized a parallel groups design (100 mg BID, 400 mg BID, placebo) to examine all endpoints over a 28-day dosing period. Based on the number of moderate intensity adverse events reported at the 600 mg BID dose level, the MTD established in Part I was 450 mg BID. Symptomatic improvement as measured by the Montgomery-Asberg Depression Rating Scale was numerically greater in the Org 26576 groups than in the placebo group in both study parts. In Part II, the 400 mg BID dose was associated with improvements in executive functioning and speed of processing cognitive tests. Org 26576 was also associated with growth hormone increases and cortisol decreases at the end of treatment but did not influence prolactin or brain-derived neurotrophic factor. The quantitative electroencephalogram index Antidepressant Treatment Response at Week 1 was able to significantly predict symptomatic response at endpoint in the active treatment group, as was early improvement in social acuity. Overall, Org 26576 demonstrated good tolerability and pharmacokinetic properties in depressed patients, and pharmacodynamic endpoints suggested that it may show promise in future well-controlled, adequately powered proof of concept trials.

The development and validation of methods for determining concentrations of the antipsychotic drug asenapine (ASE) and three of its metabolites [N-desmethylasenapine (DMA), asenapine-N(+) -glucuronide (ASG) and 11-O-sulfate-asenapine (OSA)] in human plasma using LC-MS/MS with automated solid-phase extraction is described. The three assessment methods in human plasma were found to be acceptable for quantification in the ranges 0.0250-20.0 ng/mL (ASE), 0.0500-20.0 ng/mL (DMA and OSA) and 0.250-50.0 ng/mL (ASG).

Posaconazole in oral suspension must be taken multiple times a day with food (preferably a high-fat meal) to ensure adequate exposure among patients. We evaluated the effect of food on the bioavailability of a new delayed-release tablet formulation of posaconazole at the proposed clinical dose of 300 mg once daily in a randomized, open-label, single-dose, two-period crossover study with 18 healthy volunteers. When a single 300-mg dose of posaconazole in tablet form (3 tablets ؋ 100 mg) was administered with a high-fat meal, the posaconazole area under the concentration-time curve from 0 to 72 h (AUC 0 -72 ) and maximum concentration in plasma (C max ) increased 51% and 16%, respectively, compared to those after administration in the fasted state. The median time to C max (T max ) shifted from 5 h in the fasted state to 6 h under fed conditions. No serious adverse events were reported, and no subject discontinued the study due to an adverse event. Six of the 18 subjects reported at least one clinical adverse event; all of these events were mild and short lasting. The results of this study demonstrate that a high-fat meal only modestly increases the mean posaconazole exposure (AUC), ϳ1.5-fold, after administration of posaconazole tablets, in contrast to the 4-fold increase in AUC observed previously for a posaconazole oral suspension given with a high-fat meal. P osaconazole (MK-5592) is a registered extended-spectrum triazole with demonstrated efficacy as antifungal prophylaxis for invasive fungal infections (IFIs) in high-risk patients (1, 2) and as treatment for refractory IFIs (3, 4). Posaconazole was initially developed and marketed as an oral suspension; the suspension must be administered multiple times a day and taken with food (preferably a high-fat meal) (5, 6) or a nutritional supplement or acidic beverage (6-8) to ensure adequate exposure. Reliable and adequate levels of posaconazole exposure are important to ensure continued antifungal prophylaxis. In fact, a clear exposure-efficacy relationship for posaconazole has been identified based on the results of prior pivotal studies conducted with the oral suspension (4, 9).Antifungal prophylaxis recipients routinely include the following two key populations: (i) patients with acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), or other acute hematological malignancies, who may develop neutropenia and chemotherapy-induced side effects, namely, severe nausea or vomiting; and (ii) allogeneic hematopoietic stem cell transplant (HSCT) recipients, who routinely develop graft-versus-host disease (GVHD) and its associated complications, including severe mucositis or diarrhea. Adequate food intake to obtain optimal posaconazole exposure may be difficult for these patients (10, 11). In order to overcome the burden of taking multiple doses per day together with food intake for the target population, a new solid oral tablet formulation of posaconazole has been developed that can be taken once daily and without the need for food intake to support adequate...

Standard toxicological studies in dogs using high doses of vasodilators and positive inotropic/vasodilating agents give rise to a species-specific cardiotoxicity. The reason may be the extreme sensitivity of the dog to the pharmacological effects of these drugs; exaggerated pharmacodynamic effects and prolonged disturbance of homeostasis mechanisms often are responsible for the observed organ lesions. An assessment of the toxicological relevance and the risk for patients taking the drugs at therapeutic doses cannot be made without taking into account their pathomechanisms and the pathophysiological basis of the exceptional reaction patterns occurring in dogs. A large series of vasodilating and positive inotropic agents are presented, their pharmacological properties are described, and toxicological effects in dogs are compared. In view of the poor correlation between the distinct cardiac lesions induced in dogs and a lack of comparable toxicity in humans, it appears desirable to reassess the adequacy of the standard toxicological approaches for these substances.

These data suggest that dilutional effects related to a modest increase in plasma volume may explain the haematological changes seen in other clinical trials with high doses of troglitazone, although this study has shown that the changes in plasma volume are not statistically significant.

Isolated rat hepatocytes were incubated with ATP to induce high intracellular free Ca2+ concentrations as determined with the Quin-2 method. Immediately after addition of ATP, the intracellular concentration of Ca2+ rose from 200 nM to more than 2.5 microM. It stayed at this value during the first 1/2 h; the rise was absolutely dependent on extracellular Ca2+. After the first 1/2 h the Ca2+ concentration decreased to 1-2 microM (5-10 times the control value). These high intracellular free Ca2+ concentrations did not lead to an immediate loss of cell viability. Only after 2 h of incubation a substantial number of cells lost viability. This was preceded by a decrease in cellular NADH (greater than 40%) and accompanied by a sharp increase in the intracellular Ca2+ concentration. Under these conditions the NADPH concentration was not affected. Cellular GSH was decreased to 30% of the initial value, but no lipid peroxidation or protein-thiol depletion was observed. Intracellular ATP, ADP and AMP were increased in the presence of extracellular ATP. Ca2+-dependent proteases seemed not to be involved in cell death. These observations are consistent with a collapse of mitochondrial functions as a final trigger of cell death.