Interest in antimyocardial ischemic activity of a graminan-type fructan with a weight average molecular weight of 4.8 kDa extracted from Radix Ophiopogonis (ROP) has necessitated the study of its pharmacokinetics and tissue distribution. For that, a simple HPGPC-FD method was developed for the sensitive and specific determination of FITC-ROP (fluorescein-isothiocyanate-labeled ROP) in plasma and rat tissues (heart, liver, spleen, lung, kidney, brain and stomach). The analyte was separated on a Shodex Sugar KS-802 high-performance gel column with 0.1 M phosphate buffer (pH 7.0) as mobile phase at a flow rate of 0.5 mL/min, and fluorescence detection at lambda(ex) 495 nm and lambda(em) 515 nm. The calibration curve for FITC-ROP was linear over the range 0.25-20.0 or 50.0 microg/mL in all studied biosamples with correlation coefficients > 0.995. The inter-day and intra-day precisions of analysis were not more than 10%, and assay accuracy ranged from 93 to 105% for plasma and from 89 to 108% for tissue homogenates. This method has been confirmed here to be suitable for the study of pharmacokinetics and tissue distribution of ROP and the achieved results are highly instructive for the further pharmaceutical development of ROP, suggesting the promising application of the method to the increasingly important carbohydrate-based drugs.

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Background Dalpiciclib (SHR6390) is a novel inhibitor of cyclin-dependent kinase 4/6 which demonstrated promising anti-tumor potency in preclinical models. This first-in-human study was conducted to evaluate the tolerability, pharmacokinetics, safety, and preliminary antitumor activity of dalpiciclib in patients with advanced breast cancer (ABC). Methods In this open-label, phase 1 study, Chinese patients who had failed standard therapy were enrolled to receive oral dalpiciclib in 3 + 3 dose-escalation pattern at doses of 25–175 mg. Eligible patients were given a single-dose of dalpiciclib in week 1, followed by once daily continuous doses for 3 weeks, and 1 week off in 28-day cycles. Based on the tolerability, pharmacokinetics, and activity data revealed from the dose-escalation phase, three dose cohorts were selected to expand to 8–10 patients. The primary endpoints were maximum tolerated dose (MTD) and pharmacokinetics. Results Between Apr 15, 2016 and Dec 21, 2018, 40 patients were enrolled; all were diagnosed of hormone receptor-positive and HER2-negative ABC. Dalpiciclib 100 mg, 125 mg, and 150 mg cohorts were expanded to 10 patients. No dose-limiting toxicity was observed and the MTD was not reached. Adverse events (AEs) of grade 3 or 4 were observed in 22 (55.0%) of 40 patients, being neutropenia (52.5%), leukopenia (35.0%), thrombocytopenia (5.0%), and hypertension (2.5%). No serious AEs were reported. At the doses of 50–175 mg, steady state areas under the concentration-time curve and peak concentration increased almost proportionally with dose. The disease control rate (DCR) was 62.5% (25/40, 95% CI: 45.8–77.3). Two patients (5%; 125 mg and 150 mg cohorts) achieved partial response, with responses lasting 169 and 356+ days, respectively. Among the three expansion cohorts, the 150 mg cohort had the numerically highest DCR of 80.0% (95% CI: 44.4–97.5) and longest median progression-free survival of 8.4 months (95% CI: 2.1–not reached). Conclusions Dalpiciclib showed acceptable safety profile and dose-dependent plasma exposure in Chinese patients with ABC. The recommended phase 2 dose was 150 mg. Preliminary evidence of clinical activity was observed, which warrants further validation. Trial registration ClinicalTrials.gov identifier: NCT02684266. Registered Feb 17, 2016.

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