Modulating protein ubiquitination via proteasome inhibition represents a promising target for cancer therapy, because of the higher sensitivity of cancer cells to the cytotoxic effects of proteasome inhibition. Here we show that CEP-18770 is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome that down-modulates the nuclear factor-kappaB (NF-kappaB) activity and the expression of several NF-kappaB downstream effectors. CEP-18770 induces apoptotic cell death in multiple myeloma (MM) cell lines and in primary purified CD138-positive explant cultures from untreated and bortezomib-treated MM patients. In vitro, CEP-18770 has a strong antiangiogenic activity and potently represses RANKL-induced osteoclastogenesis. Importantly, CEP-18770 exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells. Intravenous and oral administration of CEP-18770 resulted in a more sustained pharmacodynamic inhibition of proteasome activity in tumors relative to normal tissues, complete tumor regression of MM xenografts and improved overall median survival in a systemic model of human MM. Collectively, these findings provide evidence for the utility of CEP-18770 as a novel orally active proteasome inhibitor with a favorable tumor selectivity profile for the treatment of MM and other malignancies responsive to proteasome inhibition.

The ubiquitin-proteasome pathway plays a central role in regulation of the production and destruction of cellular proteins. These pathways mediate proliferation and cell survival, particularly in malignant cells. The successful development of the 20S human proteasome inhibitor bortezomib for the treatment of relapsed and refractory multiple myeloma has established this targeted intervention as an effective therapeutic strategy. Herein, the potent, selective, and orally bioavailable threonine-derived 20S human proteasome inhibitor that has been advanced to preclinical development, [(1R)-1-[[(2 S,3 R)-3-hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]-1-oxobutyl]amino]-3-methylbutyl]boronic acid 20 (CEP-18770), is disclosed.

A physiologic pharmacokinetic model of cyclosporin has been developed in the rat aimed at predicting the time course of drug concentrations in blood, organs, and tissues. The model assumes that tissue distribution is perfusion-rate limited and that each tissue acts as a well-stirred compartment. The unbound equilibrium distribution ratios as well as the values of the fraction unbound and the distribution isotherm of cyclosporin between erythrocytes and plasma are included in the rate equations describing the time course of the drug concentration in each tissue. Parameter values for the rat were obtained experimentally from a continuous infusion study, in which 2.7 and 13.9 mg/kg per day doses of cyclosporin were administered subcutaneously to each of two groups of rats by osmotic pumps for 6 days. Steady-state cyclosporin concentrations in blood, CSF, and 18 different organs and tissues, were determined by a monoclonal antibody RIA. Differences in values of the unbound equilibrium distribution ratios in some tissues and unbound clearance indicated that both the processes of distribution and elimination may have elements of nonlinearity over the range of dosing rates tested. The model was evaluated in the rat with a kinetic experiment in which a 6-mg/kg dose of cyclosporin was infused intravenously over 15 min, with measurements of blood concentrations until 56 hr. Good agreement was obtained for the volume of distribution at steady state (blood), Vss, between the perfusion model and that calculated from the kinetic experiment. Also, the model prediction of the blood concentration temporal profile agreed closely with that observed except in the early moments, when distribution out of blood occurred considerably slower than predicted. On scaling the model up to humans, good agreement was found between the predicted plasma concentration-time profile and Vss and experimental data from the literature. Both rat and human data suggest that partition into adipose tissue plays an important role in the pharmacokinetics of cyclosporin.

Nimesulide is a selective COX-2 inhibitor used in a variety of inflammatory, pain and fever states. After healthy volunteers received oral nimesulide 100 mg in tablet, granule or suspension form the drug was rapidly and extensively absorbed. Mean peak concentrations (Cmax) of 2.86 to 6.50 mg/L were achieved within 1.22 to 2.75 hours of administration. The presence of food did not reduce either the rate or extent of nimesulide absorption. When nimesulide was administered in the suppository form, the Cmax was lower and occurred later than after oral administration; the bioavailability of nimesulide via suppository ranged from 54 to 64%, relative to that of orally administered formulations. Nimesulide is rapidly distributed and has an apparent volume of distribution ranging between 0.18 and 0.39 L/kg. It is extensively bound to albumin; the unbound fraction in plasma was 1%. The unbound fraction increased to 2 and 4% in patients with renal or hepatic insufficiency. With oral administration, the concentrations of nimesulide declined monoexponentially following Cmax. The estimated mean terminal elimination half-life varied from 1.80 to 4.73 hours. Excretion of the unchanged drug in urine and faeces is negligible. Nimesulide is largely eliminated via metabolic transformation and the principal metabolite is the 4'-hydroxy derivative (M1). Minor metabolites have been detected in urine and faeces, mainly in a conjugated form. Pharmacological tests in vivo have shown that the metabolites are endowed with anti-inflammatory and analgesic properties, although their activity is lower than that of nimesulide. Excretion in the urine and faeces accounted for 50.5 to 62.5% and 17.9 to 36.2% of an orally administered dose, respectively. The total plasma clearance of nimesulide, was 31.02 to 106.16 ml/h/kg, reflecting almost exclusive metabolic clearance. The drug has a low extraction ratio, close to 0.1. With twice daily oral or rectal administration of nimesulide, steady-state was achieved within 24 to 48 hours (2 to 4 administrations); only modest accumulation of nimesulide and M1 occurred. Gender has only a limited influence on the pharmacokinetic profiles of nimesulide and M1. The pharmacokinetic profiles of nimesulide and M1 in children and the elderly did not differ from that of healthy young individuals. Hepatic insufficiency affected the pharmacokinetics of nimesulide and M1 to a significant extent: the rate of elimination of nimesulide and M1 was remarkably reduced in comparison to the rate of elimination in healthy individuals. Therefore, a dose reduction (4 to 5 times) is required in patients with hepatic impairment. The pharmacokinetic profile of nimesulide and M1 was not altered in patients with moderate renal failure and no dose adjustment in patients with creatinine clearances higher than 1.8 L/h is envisaged. Pharmacokinetic interactions between nimesulide and other drugs given in combination [i.e. glibenclamide, cimetidine, antacids, furosemide (frusemide), theophylline, warfarin and digoxin] were absent, or of no ...

Paclitaxel poliglumex (CT-2103; XYOTAX) is an innovative macromolecular taxane designed to increase the therapeutic index of paclitaxel. This large macromolecule conjugate of paclitaxel and poly-L-glutamic acid accumulates in tumor tissues by taking advantage of the enhanced permeability of tumor vasculature and lack of lymphatic drainage. Paclitaxel poliglumex prolongs exposure to active drug and minimizes systemic exposure. Preclinical studies in animal tumor models demonstrate enhanced safety and efficacy relative to paclitaxel when administered as a single agent or in conjunction with radiation. Clinical pilot studies with paclitaxel poliglumex showed improved outcomes compared to standard taxanes and allowed a more convenient administration schedule. Human pharmacokinetic data are consistent with prolonged tumor exposure to active drug and a limited systemic exposure. Based on these results, three ongoing randomized phase III trials were initiated to test the efficacy of paclitaxel poliglumex in patients with advanced non-small cell lung carcinoma.