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A highly sensitive liquid chromatographic method with online solid-phase extraction (SPE) and tandem mass spectrometric detection was developed for the quantification of the synthetic peptide drug taspoglutide in human and animal plasma. Sample preparation consisted of simple protein precipitation or automated off-line SPE using mixed mode cation exchange material, optionally preceded by cleavage of potential antidrug antibody complexes. Excellent selectivity was obtained by a novel orthogonal column switching approach, employing hydrophilic interaction liquid chromatography (HILIC) for online SPE followed by chromatographic separation on a 300 [Angstrom] pore size C18 column. The use of a stable isotope labeled drug (C-terminal arginine containing six [sup.13]C and four [sup.15]N atoms) as internal standard improved the quality and ruggedness of the method. The lower limits of quantitation (LLOQ) in human and animal plasma were 10.0 and 50.0 pg/mL, respectively, extracting only 250 or 100 [micro]L sample aliquots. Precisions and accuracies were below 15% CV and between 89% and 114%, respectively. The method was successfully employed to analyze samples from pharmacokinetic studies.

The analytical capabilities of liquid chromatography tandem mass spectrometry for sensitive and highly selective determination of target compounds in complex biological samples makes it well suited for high-throughput analysis. We report the fast separation of six benzodiazepines isolated from human urine via selected reaction monitoring liquid chromatography/mass spectrometry using short dwell times to accommodate fast-eluting chromatographic peaks. The analytes were extracted from human urine samples along with their deuterium-labeled internal standards by a simple liquid-liquid extraction in 96-well plates. Using four autosamplers coupled to one chromatographic column and one tandem mass spectrometer operated in the turbo ion spray mode with positive ion detection, 1152 samples (12 96-well plates) were analyzed in less than 12 h. Through an electronic switching box designed and constructed in-house, the autosamplers were synchronized with the mass spectrometer so that injections were made as soon as the mass spectrometer was ready to collect data. Each run required 30 s to complete with another 7-8 s for the data system to load the next data file to be collected. Chromatographic integrity and ion current response remained relatively constant for the duration of the analyses. The results show acceptable precision and accuracy and demonstrate the feasibility of using fast separations with tandem mass spectrometry for high-throughput analysis of biological samples containing multiple analytes.

Fatty alcohol ethoxylates (FAEs) are applied in commercial formulations (laundry detergents) as complex mixtures of alkyl and ethoxylate homologues. Therefore, efficient analytical methods are required for product control. Capillary electrophoresis, a modern analytical separation technique, was used to separate FAEs in technical products and household formulations after derivatization with phthalic anhydride. The well-established high-performance liquid chromatography was used as reference and supplementary method. UV detection after derivatization with phenyl isocyanate or light scattering detection has been carried out. Sample components have been identified by standard addition or by comparison to known products. The peak pattern can be considered as a 'fingerprint' of the product and is characteristic for a defined composition.

Aims: Risdiplam (RG7916, RO7034067) is an orally administered, centrally and peripherally distributed, survival of motor neuron 2 (SMN2) mRNA splicing modifier for the treatment of spinal muscular atrophy (SMA). The objectives of this entry‐into‐human study were to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of risdiplam, and the effect of the strong CYP3A inhibitor itraconazole on the PK of risdiplam in healthy male volunteers. Methods: Part 1 had a randomized, double‐blind, adaptive design with 25 subjects receiving single ascending oral doses of risdiplam (ranging from 0.6–18.0 mg, n = 18) or placebo (n = 7). A Bayesian framework was applied to estimate risdiplam's effect on SMN2 mRNA. The effect of multiple doses of itraconazole on the PK of risdiplam was also assessed using a two‐period cross‐over design (n = 8). Results: Risdiplam in the fasted or fed state was well tolerated. Risdiplam exhibited linear PK over the dose range with a multi‐phasic decline with a mean terminal half‐life of 40–69 h. Food had no relevant effect, and itraconazole had only a minor effect on plasma PK indicating a low fraction of risdiplam metabolized by CYP3A. The highest tested dose of 18.0 mg risdiplam led to approximately 41% (95% confidence interval 27–55%) of the estimated maximum increase in SMN2 mRNA. Conclusions: Risdiplam was well tolerated and proof of mechanism was demonstrated by the intended shift in SMN2 splicing towards full‐length SMN2 mRNA. Based on these data, Phase 2/3 studies of risdiplam in patients with SMA are now ongoing. [ABSTRACT FROM AUTHOR]

1. Alectinib is a highly selective, central nervous system-active small molecule anaplastic lymphoma kinase inhibitor. 2. The absolute bioavailability, metabolism, excretion and pharmacokinetics of alectinib were studied in a two-period single-sequence crossover study. A 50 μg radiolabelled intravenous microdose of alectinib was co-administered with a single 600 mg oral dose of alectinib in the first period, and a single 600 mg/67 μCi oral dose of radiolabelled alectinib was administered in the second period to six healthy male subjects. 3. The absolute bioavailability of alectinib was moderate at 36.9%. Geometric mean clearance was 34.5 L/h, volume of distribution was 475 L and the hepatic extraction ratio was low (0.14). 4. Near-complete recovery of administered radioactivity was achieved within 168 h post-dose (98.2%) with excretion predominantly in faeces (97.8%) and negligible excretion in urine (0.456%). Alectinib and its major active metabolite, M4, were the main components in plasma, accounting for 76% of total plasma radioactivity. In faeces, 84% of dose was excreted as unchanged alectinib with metabolites M4, M1a/b and M6 contributing to 5.8%, 7.2% and 0.2% of dose, respectively. 5. This novel study design characterised the full absorption, distribution, metabolism and excretion properties in each subject, providing insight into alectinib absorption and disposition in humans. [ABSTRACT FROM PUBLISHER]