Non-Compartmental Pharmacokinetics and Safety of Single-Dose Eldecalcitol (ED-71) in Healthy Chinese Adult Males.

BACKGROUND AND OBJECTIVES: Eldecalcitol (ED-71) is a novel active vitamin D3 derivative, used for the treatment of osteoporosis. This is the first clinical study to investigate the pharmacokinetics and safety of eldecalcitol in Chinese subjects. METHODS: This was an open, single-center, randomized, two-dose level, two-period crossover phase I study in 24 healthy Chinese adult males. Eligible subjects received a single oral dose of eldecalcitol capsule 0.5 or 0.75 µg at period 1 or period 2, monitored over a 144-h observation period for pharmacokinetics and a 14-day observation period for safety. The wash-out time was 14 days. The data observed in this study were compared with historical data in Japanese subjects to evaluate the inter-ethnic differences in pharmacokinetics. RESULTS: After single doses of 0.5 and 0.75 µg eldecalcitol, the maximum serum concentration (Cmax) of eldecalcitol was reached within 3.0-4.0 h (Cmax was 0.0638 ± 0.0076 ng/ml in the 0.5-µg group and 0.0944 ± 0.0126 ng/ml in the 0.75-µg group, area under the concentration-time curve from 0 to 24 h (AUC(0-24h)) was 1.02 ± 0.15 ng·h/mL in the 0.5-µg group and 1.57 ± 0.26 ng·h/mL in the 0.75-µg group). The pharmacokinetic parameters was similar between the Chinese and Japanese subjects; both Cmax and partial AUCs could be considered to be dose-proportional over the tested dose range of 0.5-0.75 µg in Chinese subjects, which was in line with previously published results on eldecalcitol linear pharmacokinetics (range 0.1-1.0 µg) in Japanese subjects. Alanine aminotransferase increase was the most common adverse event (AE). No drug-related serious AEs were reported. All of the drug-related AEs of eldecalcitol were mild in severity. CONCLUSION: Pharmacokinetic exposure (Cmax and partial AUCs) was dose-proportional over the tested dose range of 0.5-0.75 µg in healthy Chinese adult males. The pharmacokinetic character of eldecalcitol in Chinese subjects was similar to historical data from Japanese subjects. Eldecalcitol was well tolerated at doses ranging from 0.5 to 0.75 µg, with no new safety signals identified. CLINICAL TRIAL REGISTRATION: This study was registered at the China Food and Drug Administration (Registration number: 2014L02212 and 2014L02213), and also registered at http://www.chinadrugtrials.org.cn (No. CTR20160430).

LC-MS/MS determination of alectinib and its major human metabolite M4 in human urine: prevention of nonspecific binding.

AIM: Alectinib (Alecensa®) is an anaplastic lymphoma kinase inhibitor for the treatment of anaplastic lymphoma kinase positive non-small-cell lung cancer, and M4 is its major pharmacologically active metabolite. To characterize the pharmacokinetics and excretion of alectinib and M4 in human urine, a bioanalytical method was required. RESULTS: An LC-MS/MS method using supported liquid extraction was developed for the determination of alectinib and M4 in human urine over the concentration range 0.5-500 ng/ml. Accuracy ranged from 92.0 to 112.2% and precision (CV) was below 9.6%. CONCLUSION: The method was successfully employed to determine alectinib and M4 concentrations in urine samples from a clinical mass balance study. Addition of the surfactant Tween-20 to urine prevented nonspecific binding of the analytes.

Bioanalysis of alectinib and metabolite M4 in human plasma, cross-validation and impact on PK assessment.

BACKGROUND: Alectinib is a novel anaplastic lymphoma kinase (ALK) inhibitor for treatment of patients with ALK-positive non-small-cell lung cancer who have progressed on or are intolerant to crizotinib. To support clinical development, concentrations of alectinib and metabolite M4 were determined in plasma from patients and healthy subjects. METHODS: LC-MS/MS methods were developed and validated in two different laboratories: Chugai used separate assays for alectinib and M4 in a pivotal Phase I/II study while Roche established a simultaneous assay for both analytes for another pivotal study and all other studies. CONCLUSION: Cross-validation assessment revealed a bias between the two bioanalytical laboratories, which was confirmed with the clinical PK data between both pivotal studies using the different bioanalytical methods.