Use of solubilizers in preclinical formulations: Effect of Cremophor EL on the pharmacokinetic properties on early discovery compounds.

The aim of the present study was to determine whether Cremophor EL is a suitable surfactant that can be routinely applied to pharmacokinetic (PK) studies in early drug discovery without influencing the intrinsic PK characteristics of the new chemical entities (NCEs). Cremophor EL, a polyoxyl 35 castor oil, has been used as a solubilization aid for water-insoluble compounds in pre-clinical drug discovery. The effect of Cremophor EL on the PK properties of NCEs was examined in seven structurally diverse discovery compounds after intravenous administration. Significant effects of Cremophor EL on plasma volume of distribution (Vss) and plasma clearance (CL) were observed in compounds with moderate to high Vss or CL. The plasma Vss decreased more than 2-fold and the Vss binning category decreased by one unit (e.g. from moderate to low Vss) in 6 of 7 test compounds. Two to five-fold reduction of CL was observed with these 6 compounds. Effect on the terminal half-life (T1/2) was minimal. Using one of these 7 NCEs, concentration dependent effect of Cremophor EL in the vehicle was also determined. Higher percentage of Cremophor EL in vehicle resulted in progressively increased alterations on the plasma CL and Vss. Taken together, these findings indicated that Cremophor EL altered the intrinsic PK properties of these discovery compounds in a concentration dependent manner.

Aggressive approach to salvage non-maturing arteriovenous fistulae: a retrospective study with follow-up.

PURPOSE: To establish a standardized approach for the maturation of non-maturing arteriovenous fistulae. METHODS: Consecutive patients (n=122) with non-maturing fistulae presented to our outpatient vascular access center for percutaneous interventions to assist in maturation. The techniques used included flow rerouting, competing branch vein elimination, staged balloon angioplasty, and limited controlled extravasation. RESULTS: Successful fistula maturations were achieved in 118/122 patients. Fistulae were divided into two classes according to initial vessel size: class 1 (6.0-8.0 mm diameter, >6 mm deep) and class 2 (2.0-5.0 mm diameter) fistulae were evaluated for differences in technical procedures and clinically successful fistula maturation. Class 1 and class 2 fistulae were evaluated for mean number of procedures to maturation (1.6 and 2.6, respectively), and time to maturation (5 and 7 weeks, respectively). Follow-up for 109 of the initial 118 patients was achieved (mean=24 months, range=0.25-60 months). Class 1 and class 2 fistulae had primary patencies of 17 and 39% at 6 months; and secondary patencies of 72 and 77% at 12 months, 53 and 61% at 24 months, and 42 and 32% at 36 months, respectively. Primary and secondary patencies (Mann-Whitney test, p=0.44 and p=0.38, respectively) of class 1 and class 2 fistulae did not differ significantly, and secondary patencies were comparable to other fistula salvage studies. CONCLUSION: Fistula salvage attempts should not be limited by factors such as a diffusely small diameter or an inaccessibly deep position.