Clinical Pharmacokinetics of a Lipid-Based Formulation of Risperidone, VAL401: Analysis of a Single Dose in an Open-Label Trial of Late-Stage Cancer Patients.

BACKGROUND AND OBJECTIVES: A clinical trial was conducted to measure and analyse the pharmacokinetic parameters of a lipid formulation of risperidone, VAL401. The VAL401 formulation is designed to repurpose risperidone from an antipsychotic to an adenocarcinoma treatment, with the lipid formulation altering the cellular uptake of risperidone, thus enabling anticancer biology to be exhibited in preclinical testing. METHODS: This first human trial of VAL401 measured the concentrations of risperidone and its primary metabolite, 9-hydroxyrisperidone, in the blood of patients after treatment with a single 2-mg dose of VAL401. RESULTS: The trial provided information on differences in the pharmacokinetic profile of risperidone in VAL401 that may be caused by the formulation and/or the nature of the cancer patient population. VAL401 provided the following key pharmacokinetic parameters for the risperidone plasma concentration after a single 2-mg dose of VAL401, with results normalised to a dosage of 1 mg for comparison with literature values: Tmax, 2 h; Cmax, 8 ng/ml; half-life, 3.5 h; area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), 58.2 ng h2/mL. CONCLUSIONS: Further comparisons of the pharmacokinetic parameters of risperidone and 9-hydroxyrisperidone in plasma of patients administered VAL401 and the corresponding parameters obtained from published data for conventionally formulated risperidone provide evidence for altered biological processing of VAL401 as compared to risperidone. The absolute values obtained provide support for future studies of VAL401 as a cancer treatment, as the Cmax demonstrates sufficient exposure to reach the concentrations seen during preclinical anticancer testing, yet the overall exposure to the active moiety supports the use of the safety and tolerability data from conventional risperidone during future clinical trials.

Pimping up Drugs Recovered, Superannuated and Under Exploited Drugs - An Introduction to the Basics of Drug Reprofiling.

Drug development has moved along way forward from the days of with doctors peddling cauldrons of herbs and spices, however, the process can still miss opportunities for full exploitation of a drug's potential. Drug reprofiling provides a chance for an established or a forgotten drug to move into a new area of therapy, whether related to the known effects or in a completely new area. In an era of environmental awareness and spiraling costs for traditional drug development, a strategy to squeeze every benefit out of drugs with known safety, tolerability and pharmacological parameters must be a strategically sound desire. We explore examples of success in reprofiling, draw comparisons between techniques, and finally provide two examples from the Valirx plc development pipeline currently undergoing the process.

Prospective, randomized, controlled trial of parathyroidectomy versus observation in patients with "asymptomatic" primary hyperparathyroidism.

BACKGROUND: Disruptions in cognitive function have been described in the constellation of symptoms associated with "asymptomatic" primary hyperparathyroidism (PHPT). The aim of this study was to determine the impact of parathyroidectomy (PTX) on brain function and sleep in "asymptomatic" PHPT patients. METHODS: We conducted a prospective, randomized trial comparing immediate PTX with observation in patients with asymptomatic PHPT. We performed functional magnetic resonance imaging (fMRI) of the brain, sleep assessment, and validated neuropsychological battery at baseline, 6 weeks, and 6 months. Wilcoxon rank-sum and Pearson and Spearman correlations were used. RESULTS: A total of 18 patients were randomized. Subjective sleepiness correlated with worse performance on executive function tests during fMRI at 6 weeks (Pearson, -0.473; P = .047) and 6 months (Pearson, -0.673; P = .002). Total sleep time correlated with PTH levels at both 6 weeks (Pearson, 0.518; P = .048) and 6 months (Pearson, 0.567; P = .018). At 6 weeks, hypersomnolence as measured subjectively was decreased in the PTX group, but increased in those observed (-2.56 vs 2.22; P = .03) CONCLUSION: This prospective, randomized trial for asymptomatic PHPT patients demonstrated an association of sleep with brain function. Sleep seemed to be an indicator of brain activation in the anterior cingulate gyrus and precentral cortex. Subjective sleepiness was associated with executive function. The results of this pilot study suggest that decreased serum PTH levels correlate with improved sleep and that PTX decreases sleepiness in patients with asymptomatic PHPT.