Extemporaneous preparation strategy for early phase clinical studies.

Extemporaneous preparations (EPs) of investigational drugs, which are compounded at the clinical study site by a pharmacist, are being increasingly used in early phase clinical studies to accelerate the development of new medicines. The successful application of EP strategies in clinical studies requires 'fit-for-purpose' formulation design and preparation processes, as well as administration procedures that are safe, flexible, cost-effective, and simple to adapt by a compounding pharmacist at the clinical site. DNS-7801 is a weakly basic investigational compound that exhibits a higher aqueous solubility at lower pH with its solubility dropping off precipitously with increase in pH. This phenomenon is known to result in potential risk of variable and decreased exposure in vivo. Combination of citrate buffer at pH 3.0 and hydroxypropylbetadex enabled formulation of DNS-7801 solutions that were stable as formulated and up on manipulation for oral administration. The solutions were compatible with apple juice, used to mask (blind) the potential taste differences between the placebo and DNS-7801 solutions when dosing study subjects. The oral administration of the solutions resulted in dose proportional Cmax, AUC0-24, and AUC0-∞ of DNS-7801 in non-elderly and elderly subjects. A key advantage of the use of an EP approach with DNS-7801 was the flexibility in dose selection that this approach offered because DNS-7801 concentration in the preparation and/or volume could be readily adjusted based on real-time cohort data.

Paroxetine treatment in children and adolescents with obsessive-compulsive disorder: a randomized, multicenter, double-blind, placebo-controlled trial.

OBJECTIVE: To assess the efficacy and safety of paroxetine for the treatment of pediatric obsessive-compulsive disorder. METHOD: Children (7-11 years of age) and adolescents (12-17 years of age) meeting DSM-IV criteria for obsessive-compulsive disorder were randomized to paroxetine (10-50 mg/day) or placebo for 10 weeks. The primary efficacy measure was change from baseline in the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) total score at week 10 last observation carried forward end point. Safety was assessed primarily through adverse event monitoring. RESULTS: A total of 207 patients were randomized to treatment. Of these, 203 were included in the intention-to-treat population. Adjusted mean changes from baseline at week 10 observation carried forward end point in CY-BOCS total score for patients receiving paroxetine and placebo were -8.78 (SE=0.82) and -5.34 points (SE=0.77), respectively. The adjusted mean difference, -3.45 in favor of paroxetine, was statistically significant (95% confidence interval=-5.60 to -1.29, p=.002). Adverse events were generally mild to moderate in intensity. A total of 10.2% (10/98) of patients in the paroxetine group and 2.9% (3 of 105) in the placebo group discontinued treatment because of adverse events. CONCLUSIONS: Paroxetine is an effective and generally well-tolerated treatment for obsessive-compulsive disorder in children and adolescents.