An Open-Label, Multicenter, Single-Dose Pharmacokinetic Study of a Novel Amphetamine Extended-Release Orally Disintegrating Tablet in Preschool-Aged Children.

Objective: In the U.S. ∼33% of children with attention-deficit/hyperactivity disorder (ADHD) are diagnosed during their preschool years (<6 years of age). The majority of these children are treated with a psychopharmacological treatment, despite limited data on pharmacokinetics (PKs), efficacy, or safety of these medications in this population. A phase 4, single-dose open-label study was conducted to assess the PK profile of amphetamine extended-release orally disintegrating tablets (AMP XR-ODT) under fasted conditions in preschool-aged children with ADHD. Methods: Preschool-aged children (aged 4 to <6 years) with a confirmed ADHD diagnosis were enrolled and administered AMP XR-ODT 3.1 mg under fasted conditions. Plasma samples were analyzed for d- and l-amphetamine (AMP) via liquid chromatography-tandem mass spectrometry. Area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-inf), area under the concentration-time curve from time 0 to the last measurable plasma concentration (AUC0-T), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), terminal half-life (t1/2), apparent volume of distribution (Vz/F), and apparent clearance (CL/F) for d- and l-AMP and safety were assessed. Results: The PK and safety analyses included 15 preschool-aged children (4 years old, n = 6; 5 years old, n = 9); 14 completed the study. Quantifiable plasma concentrations for d- and l-AMP were observed 1.5 hours postdose and throughout the 24-hour sampling period. For d- and l-AMP, mean AUC0-inf was 315.2 and 104.4 h·ng/mL, AUC0-T was 296.0 and 96.8 h·ng/mL, t1/2 was 8.0 and 9.2 hours, Cmax was 23.0 and 7.0 ng/mL, Tmax was 3.9 and 4.0 hours, CL/F was 6996.3 and 6837.1 mL/h, and Vz/F was 75,874.5 and 84,140.0 mL, respectively. Adverse events included tachycardia (n = 2), neutropenia (n = 1), increased alanine aminotransferase (n = 1), and aspartate aminotransferase (n = 1). Conclusions: AMP XR-ODT 3.1 mg was well tolerated in preschool-aged children, with detectable plasma AMP concentrations over 24 hours, and a PK profile consistent with once-daily dosing.

Discovery of new C3aR ligands. Part 2: amino-piperidine derivatives.

The synthesis and structure-activity relationships against the C3a receptor of a series of substituted aminopiperidine derivatives are reported. DMPK properties and functional activities of selected compounds are described. The compounds obtained are the first non-arginine ligands of C3aR.

Simple rapid method for quantification of antiretrovirals by liquid chromatography-tandem mass-spectrometry.

OBJECTIVES: The aim of the current study was to develop a simple, fast and universal method for quantification of any combination of all currently marketed anti-HIV drugs in human plasma, using a LC-tandem mass spectrometer (API-2000, SCIEX, Toronto, Canada). METHODS: 80 microL plasma were spiked with internal standard (cimetidine), and protein precipitated with 200 microL acetonitrile. The sample was centrifuged and 30 microL aliquot was injected onto the HPLC column, where it underwent an online extraction with ammonium acetate. After that the automatic switching valve was activated, changing the mobile phase to methanol and thereby eluting the analytes into the tandem mass spectrometer. Stavudine, AZT and efavirenz were analyzed in the negative MS/MS mode, while all other drugs were analyzed in the positive mode. The high selectivity of a tandem mass analyzer allows determination of any combination of the drugs within a 4.5 min run. RESULTS: Between-day precision was below 10% for all analytes at the concentrations tested. Accuracy ranged between 95% and 105% (n = 20). The method was linear over the measuring ranges of all analytes. Within-run precision gave a CV < 7% for all analytes. Good correlation with other analytical methods was observed. CONCLUSIONS: The simplicity, universality and high throughput of the method make it suitable for application in a clinical laboratory. The method has been implemented in our laboratory for routine use.